Revista Medicina y Salud Publica (MSP)

CONTENIDO 04

AVANCES EN LA INMUNOLOGÍA 71

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SUPLEMENTO ESPECIAL

DEFICIENCIAS DE INMUNOLOGÍA PUEDEN REFLEJARSE EN CONDICIONES AUTOINMUNE

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19 AUTOINMUNIDAD Y TIROIDES

REVISIÓN ACTUALIZADA EN EL MANEJO DE HIPERLIPIDEMIA DEL PACIENTE DIABÈTICO

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ENFERMEDAD INFLAMATORIA INTESTINAL EN NIÑOS Y ADOLESCENTES

40 VASCULITIS ASOCIADAS A ANTICUERPOS ANTI-CITOPLASMA DE NEUTRÓFILOS

CIRUGÍA METABÓLICA COMO ALTERNATIVA PARA LA DIABETES DEL TIPO 2

PUNTO DE VISTA DEL PACIENTE…

CAUSAS SEUNDARIAS DE LA DIABETES

97 58 DIABETES EN PUERTO RICO: DATOS SOBRE LA PREVALENCIA, INCIDENCIA Y MORTALIDAD

PALLETS COMO REMPLAZO HORMONAL

EDITOR FUNDADOR Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR Alberto Santiago Cornier, MD, PhD EDITORA INVITADA Elivette Zambrana-Flores, MD, FACR PRINCIPAL OFICIAL EJECUTIVA Ileana Santiago Álvarez, MBA VICEPRESIDENTA EDITORIAL MUNDO Y FUNDADORA Laila Paloma Lorraine CONTABILIDAD Julio Soto ADMINISTRACIÓN Marta Ivelisse Vélez Ramos, MBA PERIODISTAS Mayra Acevedo, Jean Vélez, César Fuquen, Laura Mojica, PROGRAMADORES WEB Diego Esteban Gutiérrez, Frank Arley Carvajal Rincón ARTISTAS GRÁFICOS Pablo Bermúdez Robayo, Andrés Pinzón Segura, Lorena Castillo FOTOS : Revista Medicina y Salud Pública CORRECCIÓN DE ESTILO Rosmery Cernadas 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

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COMITÉ EDITORIAL CIENTÍFICO COMITÉ EDITORIAL 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).

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Medicina y Salud Pública es una publicación de la REVISTA PUERTORRIQUEÑA DE MEDICINA Y SALUD PÚBLICA. Medicina y Salud Pública tiene como política corregir y aclarar cualquier información incorrecta que pueda ser publicada en su revista. Medicina y Salud Pública no asume responsabilidad alguna por los anuncios, artículos y otros servicios anunciados en nuestra publicación.

Revista Puertorriqueña de Medicina y Salud Pública

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CARTA DEL EDITOR

TRECE AÑOS HACIENDO HISTORIA: Son trece años de investigación científica de relevancia académica e investigativa los que respaldan a la Revista Medicina y Salud Pública. Más de una década de divulgación, sin precedentes, de la labor científica de investigadores, doctores y todo el personal sanitario en Puerto Rico nos identifica.

Difundimos nuevo conocimiento científico de alta calidad mediante la trasmisión de artículos originales, actualizados y con temáticas novedosas. De esta manera, convergemos casos clínicos, artículos de revisión y más, siempre desde un modelo único que ofrece MSP. Nuestra labor durante estos años ha permitido informar sobre salud pública a toda la comunidad puertorriqueña. A pasos agigantados hemos evolucionado desde todas las aristas posibles, siempre de la mano de los más recientes avances tecnológicos; por ello, nuestra revista cuenta con una sólida combinación de las artes: redacción y contenido, desarrollo audiovisual y diseño gráfico.

La evolución se ha visualizado en gran medida, sin dejar de lado los principios y virtudes que nos rigen y que forman parte de cada una de nuestras prestigiosas publicaciones en el ámbito de la salud pública.

Son trece años de labor invaluable, donde hemos dado vida a miles de publicaciones y hemos logrado dirigir amplios conocimientos a la sociedad, incluidos pacientes y profesionales de la salud pública.

Nuestro trabajo nunca ha contemplado fronteras: la salud pública, en todo el sentido de la palabra, es nuestra principal premisa.

Con el fin de contribuir al desarrollo y la innovación, procuramos mantener amplio el concepto de salud pública al abarcar temas relacionados con la contaminación lumínica, el ambiente, el cambio climático y las enfermedades en general. Nuestra satisfacción es conocer que nuestro producto es líder y que, con nuestra contribución desde este medio, aportamos nuestro grano de arena a la salud pública y a la sociedad boricua. La Revista Medicina y Salud Pública y todos los que contribuimos con su avance y desarrollo poseemos un alto sentido de responsabilidad en la búsqueda constante de la excelencia científica e investigativa que demanda la comunidad de Puerto Rico.

ALBERTO SANTIAGO CORNIER, MD PHD Jefe División de Genética del San Jorge Children´s Hospital Director Centro Investigaciones Clínicas del San Jorge Children´s Hospital Catedrático Asociado de la Universidad Central del Caribe, Departamento de Pediatría Catedrático Asociado de la Ponce Health Sciences University, Departamento de Salud Pública Práctica Privada Torre Médica Hospital San Jorge y SER de Puerto Rico

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Revista Puertorriqueña de Medicina y Salud Pública

EDITORIAL

DE LA AUTOINMUNIDAD A LAS ENFERMEDADES AUTOINMUNES Con gran placer ponemos en sus manos una nueva edición de MSP; esta vez dedicada a la autoinmunidad. Teniendo en cuenta que se trata del sistema de respuestas inmunológicas del organismo contra sus propias células y tejidos sanos, esta edición reúne la investigación de varios subespecialistas pediátricos y de adultos expertos en diferentes condiciones de este tipo. Comenzamos con la realización de un recorrido con los más recientes avances y actualizaciones del sistema inmunológico que incluye, además, los nuevos conocimientos adquiridos por especialistas de las ciencias. Por otro lado, se analizan las principales deficiencias en el sistema inmunológico y su enlace con las condiciones autoinmunes.

Se discuten varias condiciones autoinmunes prominentes que afectan a nuestros pacientes adultos y pediátricos, entre las que resaltan las vasculitis, las enfermedades inflamatorias gastrointestinales y los problemas de la glándula tiroides. Finalizamos nuestra edición con una historia de vida: la experiencia de una de nuestras pacientes y psicóloga, que comparte su perspectiva y nos ofrece múltiples recomendaciones.

Esta edición se ha preparado con mucho esmero para que nuestros colegas tengan una información de referencia actualizada y práctica. Les agradecemos infinitamente a todos los autores por su compromiso con la salud y por hacer posible esta edición una vez más.

Elivette Zambrana, MD, FACR Board Certified en Reumatología Pediátrica y Pediatría Hospital HIMA San Pablo Caguas Hospital HIMA San Pablo Bayamón

Revista Puertorriqueña de Medicina y Salud Pública

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MSP ARTÍCULO / ORIGINAL Por: Cristina Ramos Romey, MD Alergista e Inmunóloga

AVANCES EN LA INMUNOLOGÍA

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RESUMEN

ABSTRACT

Los avances científicos han logrado cambios significativos en la vida de los pacientes con enfermedades reumáticas.

La identificación de nuevos mecanismos inmunológicos son importantes para el desarrollo de nuevas terapias más específicas y con mejor perfil de seguridad.

Scientific advances have made significant changes in the lives of patients with rheumatic diseases. Identification of new immunological mechanisms are important for the development of new and specific therapies with a better safety profile.

Revista Puertorriqueña de Medicina y Salud Pública

LOS AVANCES CIENTÍFICOS HAN LOGRADO CAMBIOS SIGNIFICATIVOS EN LA VIDA DE LOS PACIENTES

PALABRAS CLAVES Autoinmunidad, microbioma, sistema inmunológico, inferferón, espondilitis anquilosante, lupus sistémica eritematosa, artritis reumática.

KEYWORDS Autoimmunity, microbioma, immune system, interferon, ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis.

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MSP ARTÍCULO / ORIGINAL

EL SISTEMA INMUNOLÓGICO TIENE UNA ALTA COMPLEJIDAD Y REDUNDANCIA, POR EL CUAL, EL DESARROLLO DE TERAPIAS EFECTIVAS ES UN RETO

Introducción Durante la última década, hemos podido presenciar un aumento en el conocimiento del sistema inmunológico y su rol en las enfermedades autoinmunes. Estos avances científicos han permitido el desarrollo de terapias novedosas y altamente específicas en cuanto a los mecanismos inmunológicos responsables de producir enfermedades autoinmunes.

Los reumatólogos han podido observar los avances relacionados con el

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Revista Puertorriqueña de Medicina y Salud Pública

Microbioma intestinal, ilustración en 3D que muestra la anatomía del sistema digestivo humano y las bacterias entéricas Ecsherichia coli, E. coli, íleon, otras partes del intestino.

Flora intestinal normal - Ilustración

desarrollo de medicamentos biológicos, los cuales trabajan de manera específica en los mecanismos de inflamación.

Estas terapias han impactado la calidad de vida de múltiples pacientes de forma positiva y han permitido que, pacientes -que quizás hoy estarían discapacitados- puedan participar en actividades diarias.

Sin embargo, muchos de los mecanismos inmunológicos que producen las enfermedades autoinmunes aún no han sido dilucidados. Por ende, continúan los

estudios para escalecer el mecanismo de la enfermedad y, de esta manera, lograr el desarrollo de terapias aún más específicas, debido a que el desarrollo de medicamentos con alta especificidad a nivel molecular podría ser altamente efectivo y ofrecería un mejor perfil de seguridad.

El microbioma Un área de gran interés y actividad investigativa es el microbioma. La importancia de este ha sido descrita en varias condiciones como la atopia, alergias a alimentos, enfermedad intestinal inflamatoria, entre otras. La interacción entre las células del epitelio intestinal, el microbioma y el sistema inmunológico es importante, no solo para la homeostasis del sistema digestivo, sino también para el sistema inmunológico.

La permeabilidad intestinal aumentada puede resultar en daño a la inmunidad de la mucosa intestinal en la entrada de microbiota del intestino al torrente sanguíneo y de citoquinas proinflamatorias.

Estudios en el rol de este sistema se han publicado también para la espondilitis anquilosante. Además, investigaciones en pacientes y familiares han demostrado que estos tienen una mayor permeabilidad del intestino. Por otro lado, data preliminar demuestra que, pacientes con espondilitis anquilosante, tienen defectos en la barrera intestinal.

Una mejor comprensión de los mecanismos de Il-23y IL-17 puede ayudar a un mejor control de la enfermedad. Estudios adicionales son requeridos para poder describir el rol de la inflamación en el intestino y explicar en qué lugar y en qué momento citoquinas como IL-17, IL22 y IL-2 afectan la patogénesis de la condición.

Pobre respuesta a medicamentos Otra área de suma impor tancia es la variabilidad de los pacientes al responder a los medicamentos. Se ha demostrado que el desarrollo de anticuerpos dirigidos a los medicamentos tiene una correlación negativa con la actividad de la condición. Estudios recientes han demostrado que, pacientes con ar tritis reumatoide con pobre respuesta a medicamentos anti-TNF, tienen niveles más altos de anticuerpos dirigidos al medicamento. Ello resalta la importancia de utilizar y desarrollar pruebas que puedan detectar estos anticuerpos para poder prevenir o predecir fallo terapéutico.

El sistema inmunológico tiene una alta complejidad y redundancia, por lo cual, el desarrollo de terapias efectivas es un reto. Múltiples estudios han demostrado que las citoquinas de la familia interferón, en especial la interferón alfa, son de gran importancia en la patogénesis del lupus sistémico eritematoso (LES). Basado en estos estudios, se desarrolló un anticuerpo monoclonal (anifrolumab) que se adhiere al receptor tipo 1 de interferón y que tiene el efecto de bloquear la actividad de todos los interferones tipo 1; esto incluye alpha, beta y omega; lo que disminuye, en teoría, la cascada de inflamación pues, en estudios clínicos fase 3, este medicamento no mostró una diferencia significativa contra el placebo en la disminución de los síntomas del LES. Sin embargo, los estudios continúan con el objetivo de demostrar su efectividad -a largo plazo- en el LSE y en la nefritis lúpica. Resultados de estudios como este, demuestran la complejidad de las condiciones autoinmunes y la dificultad de desarrollar medicamentos efectivos en una población heterogénea.

Nuevos mecanismos La proteínafosfatasa 2A (PP2A) es la una fosfatasa de serina/treonina que se ha encontrado en aumento en pacientes con LSE. La PP2A contribuye a una disminución de IL-2, hipometilación de genes, aumento de Il-7, entre otros. Estudios en modelos murinos con sobreexpresión e PPAc en células T periféricas resultaron desarrollar granulocitosis, glomerulonefritis y aumento en la producción de Ll-17. Modelos murinos con deficiencia de PP2Ac solo en células T reguladoras, desarrollaron autoinmunidad severa e inflamación sistémica. El desarrollo de terapias dirigidas a PP2A a subtipos de células T puede ser una nueva alternativa de terapias para LSE y otras enfermedades autoinmunes.

Para la artritis reumática ya se utilizan -como tratamiento- pequeñas moléculas que interfieren con el señalamiento de procesos intracelulares.

Estas moléculas usualmente afectan a todas las células, pero no de manera específica. Estas terapias pueden tener efectos adversos que -quizás- se podrían evitar con una inhibición de estos mecanismos de manera más específica. Sehnert et al desarrollaron unas proteínas “sneaky lingand fusion

proteins” que tienen la capacidad de modular el señalamiento intracelular específico a un tipo de célula y aumentar el riego contra el beneficio de los medicamentos.

Recientemente, investigadores dividieron a pacientes de SLE por los fenotipos de células B y encontraron que aquellos con células T foliculares (Tfh) de memoria tienen una enfermedad más refractaria a tratamiento. Los investigadores postulan que las terapias dirigidas a estas células Tfh de memoria pueden ser de beneficio para estos subgrupos de pacientes de LSE. Conclusiones Aún quedan muchas preguntas que atender, como las diferencias marcadas en el sexo, el rol de los factores ambientales, la integridad intestinal y el papel de la respuesta del sistema innato en la patogénesis de las enfermedades autoinmunes. El esclarecimiento de estos procesos en las enfermedades autoinmunes tiene un potencial para adelantar el cuidado médico de estos pacientes.

REFERENCIAS Farhad B, et al. The role of gut microbiota and IL-23/IL-17 pathway in ankylosing spondylitis immunopathogenesis: New insights and updates. Immunology Letters 2018; 196: 52-62.

Arends S, et al. The formation of autoantibodies and antibodies to TNF-α blocking agents in relation to clinical response in patients with ankylosing spondylitis. Clin Exp Rheumatol 2010; 28: 661-8.

Sharabi A,Kasper IR, Tsokos GC. The serine/threonine protein phosphatase 2A controls autoimmunity. 2018 Jan; 186:38-42 Sehnert B, et al.The sneaking ligand approach for cell type-specific modulation of intracellular signalling pathways.Clin Immunol2018 Jan;186:14-20.

Tanaka y. et ai. B cell phenotypes, signaling and their roles in secretion of antibodies in systemic lupus erythematosus.Clin Immunol 2018 Jan;186:21-25.

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

EMBRACE THE OPPORTUNITY TO GIVE

COMPLETELY CLEAR SKIN TO YOUR PATIENTS WITH MODERATE TO SEVERE PLAQUE PSORIASIS

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients.

WARNINGS AND PRECAUTIONS Infections Taltz may increase the risk of infection. In clinical trials of patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%). A similar increase in risk of infection was seen in placebo-controlled trials of patients with psoriatic arthritis. Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.

Pre-Treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Closely monitor patients receiving Taltz for signs and symptoms of active TB during and after treatment.

Hypersensitivity Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz. If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.

Inflammatory Bowel Disease During Taltz treatment, monitor patients for onset or exacerbations of inflammatory bowel disease. Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group (Crohn’s disease 0.1%, ulcerative colitis 0.2%) than in the placebo group (0%) during clinical trials in patients with plaque psoriasis.

Immunizations Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz.

ADVERSE REACTIONS

Most common adverse reactions (≥1%) associated with Taltz treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. Overall, the safety profile observed in patients with psoriatic arthritis was consistent with the safety profile in patients with plaque psoriasis, with the exception of influenza and conjunctivitis.

Please see Brief Summary of Prescribing Information on the following pages. Please see Instructions for Use included with the device.

IX HCP ISI 01DEC2017

CONSIDER TALTZ FOR MODERATE TO SEVERE PLAQUE PSORIASIS AND FOR PSORIATIC ARTHRITIS In patients with moderate to severe plaque psoriasis, Taltz can provide a chance of completely clear skin1

In biologic-naive patients with psoriatic arthritis, Taltz can provide significant joint symptom improvement1

UNCOVER-2: PASI RESPONSES AT WEEK 12, NRI

SPIRIT-P1 (BIOLOGIC-NAIVE): ACR RESPONSES AT WEEK 24, NRI

90% PASI 75 40% PASI 100 vs 2%

vs 1%

Taltz 80 mg every 2 weeks (n=351)

71% PASI 90 83% sPGA 0,1 vs 1%

vs 2%

Placebo (n=168)

ADDITIONAL WEEK 12 RESULTS FROM UNCOVER-1 AND -3 TRIALS In UNCOVER-1 (Taltz n=433; placebo n=431) and UNCOVER-3 (Taltz n=385; placebo n=193), Taltz patients achieved similar results: 89% and 87% of Taltz patients achieved PASI 75 vs 4% and 7% for placebo. Additionally, 71% and 68% of Taltz patients achieved PASI 90 vs 1% and 3% for placebo, and 35% and 38% achieved PASI 100 vs 0% and 0% for placebo. Also, 82% and 81% of Taltz patients achieved sPGA 0,1 vs 3% and 7% for placebo.

PASI=Psoriasis Area Severity Index; sPGA=static Physician's Global Assessment.

58 % ACR20 40% ACR50 23% ACR70 vs 15%

vs 30%

vs 6%

Taltz 80 mg every 4 weeks (n=107)

Placebo (n=106)

ADDITIONAL WEEK 24 RESULTS FROM SPIRIT-P2 TRIAL In SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=122; placebo n=118), 53% of patients receiving Taltz achieved ACR20 at week 24 vs 20% for placebo. Additionally, 35% and 22% of patients receiving Taltz achieved ACR50 and ACR70, respectively, at week 24 vs 5% and 0% for placebo.

Nonresponder imputation (NRI) of intent-to-treat population through week 24.

Inadequate responders (<20% improvement in tender and in swollen joint counts) at week 16 were analyzed as nonresponders after week 16 until the primary endpoint.

Primary endpoint=ACR20 response at week 24.

ACR20/50/70=American College of Rheumatology 20%/50%/70% response rate.

UNCOVER-1, -2, -3 TRIAL DESIGN

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

SPIRIT-P1 AND -P2 TRIAL DESIGN

SPIRIT-P1 (N=417) and SPIRIT-P2 (N=363) were phase 3, randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of Taltz compared with placebo in patients with active psoriatic arthritis. Patients in SPIRIT-P1 were biologic-naive. Patients in SPIRIT-P2 were tumor necrosis factor inhibitor (TNFi)-experienced, having had an inadequate response and/or intolerance to 1 or 2 prior TNFis. In both trials, the primary efficacy endpoint was the proportion of patients achieving ACR20 response at week 24. All patients were ≥18 years of age and had ≥3 swollen and ≥3 tender joints. Patients were randomized to placebo or Taltz 80 mg every 2 or 4 weeks following a 160 mg starting dose. In SPIRIT-P1, an active reference arm of adalimumab 40 mg every 2 weeks was included.

Patients in all study arms were allowed to continue taking stable background medications during the trial. Inadequate responders (as defined by blinded criteria of <20% improvement in tender and in swollen joint counts) at week 16 received rescue therapy and were analyzed as nonresponders after week 16 until the primary endpoint. After receiving rescue therapy, inadequate responders in the placebo and adalimumab arms were re-randomized to Taltz 80 mg every 2 or 4 weeks. NRI methods were used for categorical efficacy analyses during the double-blind treatment period.1-3

Learn more about The Taltz Clear Access Program at taltzsavings.com References: 1. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018. 2. Mease PJ, van der Heijde D, Ritchlin CT, et al; on behalf of SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)controlled period of the phase 3 trial SPIRIT-P1. Ann Rheum Dis. 2017;76(suppl):1-30. 3. Nash P, Kirkham B, Okada M, et al; on behalf of SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389:2317-2327.

Taltz® is a registered trademark of Eli Lilly and Company.

PP-IX-US-2314 10/2018 ©LILLY USA, LLC, 2018. ALL RIGHTS RESERVED.

Taltz® (ixekizumab) injection Brief Summary: Consult the package insert for complete prescribing information.

INDICATIONS AND USAGE Plaque Psoriasis—Taltz is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Psoriatic Arthritis— Taltz is indicated for the treatment of adult patients with active psoriatic arthritis.

CONTRAINDICATIONS Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients (Warnings and Precautions).

WARNINGS AND PRECAUTIONS Infections—Taltz may increase the risk of infection. In clinical trials in patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%).

Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in the Taltz group than in the placebo group. A similar increase in risk of infection was seen in placebo-controlled trials in patients with psoriatic arthritis (Adverse Reactions). Instruct patients treated with Taltz to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy, monitor the patient closely and discontinue Taltz until the infection resolves.

Pre-treatment Evaluation for Tuberculosis—Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Consider anti-TB therapy prior to initiating Taltz in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving Taltz should be monitored closely for signs and symptoms of active TB during and after treatment.

Hypersensitivity—Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz (Adverse Reactions). If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.

Inflammatory Bowel Disease— During Taltz treatment, monitor for onset or exacerbation of inflammatory bowel disease. Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group (Crohn’s disease 0.1%, ulcerative colitis 0.2%) than in the placebo group (0%) during the 12-week, placebo-controlled period in clinical trials in patients with plaque psoriasis.

Immunizations—Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz. No data are available on the response to live vaccines.

ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: • Infections (Warnings and Precautions) • Hypersensitivity Reactions (Contraindications and Warnings and Precautions) • Inflammatory Bowel Disease (Warnings and Precautions) Clinical Trials Experience—Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Plaque Psoriasis Weeks 0 to 12 : Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of Taltz compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received Taltz (160 mg at Week 0, 80 mg every 2 weeks [Q2W] for 12 weeks) subcutaneously. In two of the trials, the safety of Taltz (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept.

In the 12-week, placebo-controlled period, adverse events occurred in 58% of the Taltz Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subject-year of follow-up). Serious adverse events occurred in 2% of the Taltz group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up).

Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Taltz group than the placebo group during the 12-week placebo-controlled period of the pooled clinical trials.

Table 1: Adverse Reactions Occurring in ≥1% of the Taltz Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Clinical Trials through Week 12 Adverse Reactions Injection site reactions Upper respiratory tract infectionsa Nausea Tinea infections a b

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

Etanerceptb (N=287) (n%) 32 (11)

Placebo (N=791) (n%) 26 (3)

163 (14)

23 (8)

101 (13)

23 (2) 17 (2)

1 (<1) 0

5 (1) 1 (<1)

Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection.

U.S. approved etanercept.

Taltz® (ixekizumab) injection

IX HCP BS 01DEC2017

Taltz, IX HCP BS 01DEC2017 - 7.125 x 9.875

Adverse reactions that occurred at rates less than 1% in the Taltz group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, inflammatory bowel disease, and angioedema.

Weeks 13 to 60 : A total of 332 subjects received the recommended maintenance regimen of Taltz 80 mg dosed every 4 weeks.

During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with Taltz (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with Taltz (0.05 per subject-year of follow-up) and none in the subjects treated with placebo.

Weeks 0 to 60 : Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with Taltz (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with Taltz (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up).

Specific Adverse Drug Reactions: Injection Site Reactions : The most frequent injection site reactions were erythema and pain.

Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of Taltz.

Infections : In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with Taltz (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with Taltz (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up) (Warnings and Precautions).

During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with Taltz (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with Taltz (0.01 per subject-year of follow-up) and none in the subjects treated with placebo.

Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with Taltz (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with Taltz (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up).

Laboratory Assessment of Cytopenia: Neutropenia—Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with Taltz (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with Taltz, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12.

In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm3) occurred in 0.2% of the Taltz group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subject-year of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for Taltz 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm3) or Grade 1 (7% for Taltz 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm3 to <2,000 cells/mm3).

Neutropenia in the Taltz group was not associated with an increased rate of infection compared to the placebo group.

Thrombocytopenia—Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for Taltz 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm3 to <150,000 cells/mm3).

Thrombocytopenia in subjects treated with Taltz was not associated with an increased rate of bleeding compared to subjects treated with placebo.

Active Comparator Trials : In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S.-approved etanercept and 2% for Taltz 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for Taltz 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for Taltz 80 mg Q2W. The rate of serious infections was 0.3% for both Taltz 80 mg Q2W and U.S. approved etanercept.

Psoriatic Arthritis Taltz was studied in two placebo-controlled trials in patients with psoriatic arthritis. A total of 678 patients were studied (454 patients on Taltz and 224 on placebo). A total of 229 patients in these trials received TALTZ 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with psoriatic arthritis treated with Taltz Q4W is consistent with the safety profile in patients with plaque psoriasis with the exception of the frequencies of influenza (1.3%) and conjunctivitis (1.3%).

Immunogenicity—As with all therapeutic proteins there is the potential for immunogenicity with Taltz. The assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated.

Plaque Psoriasis Population

By Week 12, approximately 9% of subjects treated with Taltz every 2 weeks developed antibodies to ixekizumab. Approximately 22% of subjects treated with Taltz at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical Taltz® (ixekizumab) injection

IX HCP BS 01DEC2017

PRINTER VERSION 1 OF 2

effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response.

Of the subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with Taltz at the recommended dosing regimen, had antibodies that were classified as neutralizing. Neutralizing antibodies were associated with reduced drug concentrations and loss of efficacy.

Psoriatic Arthritis Population For subjects treated with Taltz 80 mg every 4 weeks for up to 52 weeks (PsA1), 11% developed antidrug antibodies, the majority of which were low titer, and 8% had confirmed neutralizing antibodies.

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 Taltz across indications or with the incidences of antibodies to other products may be misleading.

Postmarketing Experience—The following adverse reactions have been identified during postapproval use of Taltz. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Taltz exposure.

OVERDOSAGE—In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.

PATIENT COUNSELING INFORMATION—Advise the patient and/or caregiver to read the FDAapproved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Taltz and each time the prescription is renewed, as there may be new information they need to know.

Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or prefilled syringe correctly (Instructions for Use).

Infection: Inform patients that Taltz may lower the ability of their immune system to fight infections.

Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection (Warnings and Precautions).

Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions (Warnings and Precautions).

Additional information can be found at www.Taltz.com.

Immune system disorders: anaphylaxis (Contraindications and Warnings and Precautions) DRUG INTERACTIONS Live Vaccinations—Avoid use of live vaccines in patients treated with Taltz (Warnings and Precautions).

Cytochrome P450 Substrates—The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, Taltz, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes.

Therefore, upon initiation or discontinuation of Taltz in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary—There are no available data on Taltz use in pregnant women to inform any drug associated risks. Human IgG is known to cross the placental barrier; therefore, Taltz may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD [see Data]. The clinical significance of these nonclinical findings is unknown.

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

Data Animal Data—An embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). Ixekizumab crossed the placenta in monkeys.

In a pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical significance of these findings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age.

Lactation Risk Summary—There are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Taltz and any potential adverse effects on the breastfed infant from Taltz or from the underlying maternal condition.

Pediatric Use—The safety and effectiveness of Taltz in pediatric patients (<18 years of age) have not been evaluated.

Geriatric Use—Of the 4204 psoriasis subjects exposed to Taltz, a total of 301 were 65 years or older, and 36 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects. ®

Taltz (ixekizumab) injection

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Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2016, 2017, Eli Lilly and Company. All rights reserved.

IX HCP BS 01DEC2017 Taltz® (ixekizumab) injection

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MSP ARTÍCULO / ORIGINAL

Por: Anardi Agosto, MD Alergista e Inmunólogo/Médico Internista y Pediatra Profesor Asociado en Recinto de Ciencias Médicas Expresidente de la Sociedad Puertorriqueña de Alergistas

DEFICIENCIAS DE INMUNOLOGÍA PUEDEN REFLEJARSE EN CONDICIONES AUTOINMUNES

12

PALABRAS CLAVES

KEYWORDS

Autoinmune, inmunodeficiencia primaria, homeostasis.

Autoimmune, primary immunodeficiency, homeostasis.

Revista Puertorriqueña de Medicina y Salud Pública

EL SISTEMA INMUNE APRENDE A TOLERARSE A SÍ MISMO MEDIANTE LA ELIMINACIÓN DE LINFOCITOS AUTOREACTIVOS DE ALTA AFINIDAD EN EL TIMO

RESUMEN El sistema inmune permite a nuestro cuerpo mantener la homeostasis. Cuando tenemos problemas en alguna parte del mismo, ya sea una inmunodeficiencia primaria o una enfermedad autoinmune, debemos tratarlo como un todo y estar seguros que estudiamos cada uno de sus componentes. Entre los defectos específicos que causan inmunodeficiencias primarias, existen asociaciones importantes con la autoinmunidad, lo que nos confirma la importancia de una evaluación completa del sistema inmune, para así entender estas desregulaciones inmunológicas.

ABSTRACT Immune system is design to help our body maintain homeostasis.

When there is a problem in any part of the immune system, a primary immunodeficiency or an autoimmune disease, we have to make sure we treat that system as one and study each component.

Specific defects causing immunodeficiencies show significant association with autoimmunity, showing the importance of a complete immune system evaluation to understand the immunologic dysregulation.

INTRODUCCIÓN El sistema inmune trabaja para mantener la homeostasis en nuestro cuerpo, nos protege de infecciones, elimina las células deficientes e -incluso- las cancerosas. Los problemas en cualquier parte de nuestro sistema provocan enfermedades; ya sea inmunodeficiencias, problemas autoinmunes o malignidades.

Las inmunodeficiencias primarias consisten en defectos genéticos que afectan diferentes áreas del sistema inmune; lo que provoca que el paciente sea más susceptible a las infecciones. Como el sistema inmune es solo uno, los problemas en una determinada área predisponen a otros problemas, como las enfermedades autoinmunes y malignidades. Es por esto que se habla de desregulación del sistema inmune.

El sistema inmune aprende a tolerarse a sí mismo mediante la eliminación de linfocitos autoreactivos de alta afinidad en el timo, la médula ósea o en la periferia, mediante mecanismos como la anergia o la apoptosis, ignorando antígenos, usando receptores inhibidos y mediante la inhibición de células T autoreactivas.

Revista Puertorriqueña de Medicina y Salud Pública

13

MSP ARTÍCULO / ORIGINAL

DEFICIENCIAS INMUNOLÓGICAS CAUSAN AUTOINMUNIDAD Problemas en estas áreas del sistema inmune causan autoinmunidad. Sin embargo, no son la única razón para ella. Las enfermedades autoinmunes son condiciones complejas con muchos mecanismos propuestos; por ejemplo, susceptibilidad genética (HLA-27, que causa espondilitis anquilosante después de infecciones con E. Coli), estímulos ambientales o por una regulación defectiva del sistema inmune por mutaciones (FOXP3, CD25, CTLA-4).

No obstante, en pacientes con inmunodeficiencias primarias, una inflamación crónica con una presentación persistente de antígenos al sistema inmune -debido a infecciones recurrentes- son factores esenciales para el desarrollo de autoinmunidad. Esta estimulación crónica, causada por antígenos microbiales, puede fomentar respuestas inflamatorias crónicas y exageradas por otras células del sistema inmune que, tratando de “ayudar” a las que no funcionan bien, terminan afectando sus propias células.

Aunque, en primera instancia, no parece tener sentido, ya ha sido demostrada la asociación de condiciones autoinmunes en pacientes con inmunodeficiencias primarias. Por ejemplo, las enfermedades autoinmunes son más comunes en pacientes con inmunodeficiencia común variable (CVID), el síndrome de Wiskott-Aldrich, entre otros.

Las inmunodeficiencias primarias monogénicas nos ayudan a entender la asociación entre autoinmunidad e inmunodeficiencias; por ejemplo, el síndrome IPEX (Immunodyregulation, polyendocrinopathy, enteropathy X linked syndrome). Esta inmunodeficiencia primaria es causada por mutaciones en el gen que codifica FOXP3.

Además de infecciones recurrentes, se observa que la pérdida de función en FOXP3 causa una enteropatía autoinmune severa, 14

endocrinopatías como la diabetes mellitus tipo 1, la tiroiditis y la dermatitis. Este gen es fundamental para el desarrollo de linfocitos T reguladores (Treg) y, si su funcionamiento no es adecuado, además de haber más susceptibilidad a infecciones, hay respuestas exageradas a estas, lo que causa este fenotipo autoinflamatorio.

Por otro lado, podemos observar asociaciones en otras inmunodeficiencias; la IgA es la inmunoglobulina más abundante en el cuerpo. Se encuentra en tejidos y secreciones, especialmente del tracto gastrointestinal y respiratorio. Su función incluye la defensa de patógenos y el desarrollo de tolerancia.

Revista Puertorriqueña de Medicina y Salud Pública

La deficiencia de IgA es la inmunodeficiencia primaria más común y, aunque la mayoría de las personas afectadas son asintomáticas, algunos pueden presentar infecciones respiratorias recurrentes, enfermedades alérgicas y autoinmunidad. Se ha observado que, comparado con la población general, la deficiencia de IgA es más alta en pacientes con enfermedad celíaca, tiroiditis autoinmune, artritis reumatoide (idiopática) juvenil (JRA, JIA), lupus (SLE); además, ha sido reportada su relación con citopenias autoimmunes, miastenia gravis e -incluso- malignidades.

Otra inmunodeficiencia habitual es la inmunodeficiencia

25% común variable (CVID). Debemos aclarar que no se trata de una sola enfermedad, sino un grupo de síndromes que presentan hipogammaglobulinemia como resultado de diferentes defectos genéticos.

Más del 25% de los pacientes con CVID tienen complicaciones autoinmunes que resultan difíciles de comprender y manejar. Resulta realmente increíble que una condición como la CVID, donde las inmunoglobulinas son bajas y con pobre respuesta a antígenos, produzca autoanticuerpos y células B autoreactivas y se ataque a sí mismo.

Además de autoinmunidad e inmunodeficiencia, la CVID se asocia con una desregulación del sistema inmune que también puede causar linfoproliferación e inflamación.

La manifestación autoinmune más común en la CVID son las citopenias, trombocitopenia autoinmune (ITP) y la anemia inmunohemolítica (AIHA, por sus siglas en inglés). Es impor tante saber que, hasta en un 60% de los pacientes diagnosticados con

MÁS DEL 25% DE LOS PACIENTES CON CVID TIENEN COMPLICACIONES AUTOINMUNES QUE RESULTAN DIFÍCILES DE COMPRENDER Y MANEJAR

CVID, una citopenia precedió a la hipogammaglobulinemia. Es por esto que, se recomienda obtener niveles de inmunoglobulinas en estos pacientes. Aunque, también es obligatorio realizar un seguimiento para condiciones autoinmunes e inflamatorias crónicas en pacientes con CVID.

REFERENCIAS

CONCLUSIONES Teniendo en cuenta que el sistema inmune es solo uno, y que la desregulación del sistema inmune se manifiesta en cualquiera de sus componentes -ya sea aumentando la susceptibilidad a infecciones, causando inflamación por reacciones exageradas o atacándose a sí mismo- es importante reconocer cuándo sospechar de las mismas. Como regla general, cuando se desarrollan desórdenes autoinmunes a temprana edad o cuando se afectan múltiples órganos y no se puede explicar con una sola condición reumatológica, se debe considerar una inmunodeficiencia. Finalmente, en pacientes con inmunodeficiencias primarias es imperativo evaluar constantemente la autoinmunidad.

Blood, Markus G. Seidel. (2014) Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment. 2014; 124:2337-2344.

No obstante, en pacientes con inmunodeficiencias primarias, una inflamación crónica con una presentación persistente de antígenos al sistema inmune -debido a infecciones recurrentesson factores esenciales para el desarrollo de autoinmunidad

Baldovino, Simone; Montin, Davide; Martino, Silvana; Sciascia, Savino; Menegatti, Elisa; Dario Roccatello.

(2013) Common variable immunodeficiency: Crossroads between infections, inflammation and autoimmunity. Autoimmunity Reviews. 2013; 12:796–801.

Gholamreza, Azizi; Reza, Yazdani; Rae, William; Abolhassani, Hassani; Rojas, Manuel, Aghamohammadi, Asghar, Anaya, Juan Manuel. (2018) Monogenic polyautoimmunity in primary immunodeficiency diseases. Autoimmunity Reviews. 2018; 17(10):1028-1039.

Goyal, Ramona; Bulua, Ariel C.; Nikolov, Nikolay P.; Schwartzberg, Pamela L.; Siegel, Richard M. (2009) Rheumatologic and autoimmune manifestations of primary immunodeficiency disorders. Current Opinion in Rheumatology 2009; 21:78-84.

Karmtej, Singh; Chang, Christopher; Gershwin, M. Eric. (2014) IgA deficiency and autoimmunity. Autoimmunity Reviews; 2014; 13:163–177.

Katz-Agranov, Nurit, Khattri, Saakshi, Zandman-Goddard, Gisele. (2015) The role of intravenous immunoglobulins in the treatment of rheumatoid arthritis. Autoimmunity Reviews; 2015; 14:651-658.

Romani, Luignina. (2008) Parasites and autoimmunity: The case of fungi.

Autoimmunity Reviews 8:129-133

Revista Puertorriqueña de Medicina y Salud Pública

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For your patients with episodic migraine (4-14 migraine headache days [MHDs] per month),

ONE OF THESE IS POSSIBLE WITH EMGALITY®

THE WALRUS THAT

WENT TO THE MOON

THE WOMAN WHO EXPERIENCED

A MONTH OF TOTAL MIGRAINE HEADACHE FREEDOM

Emgality can give some patients the chance to be totally migraine-free for a month1 Emgality demonstrated ≥50%, ≥75%, and 100% reductions in the number of monthly MHDs from baseline for a significantly greater mean percentage of patients vs placebo1 Mean Percentage of Patients Meeting Defined

Mean Percentage of Patients Meeting Defined Levels Levels of Reduction in Monthly MHDs1 of Reduction in Monthly MHDs EVOLVE-1 (over Months 1 to 6)

60

40

80

62%a

Mean Percentage of Patients

Mean Percentage of Patients

80

39% 39%a 19%

20

EVOLVE-2 (over Months 1 to 6)

16%a

60

40

59%a

36% 34%a 18%

20

6% 0

≥50%

100%

≥75%

0

Level of Reduction Emgality 120 mg (N=210)

≥50%

12%a

6%

100%

≥75%

Level of Reduction

Placebo (N=425)

Emgality 120 mg (N=226)

Placebo (N=450)

p<0.001 vs placebo.

a

In REGAIN, in patients with ≥15 headache days per month, Emgality 120 mg was not significantly better than placebo for the mean percentage of patients with ≥75% or 100% reduction from baseline in the number of monthly MHDs over the 3-month treatment period.1

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

SELECT IMPORTANT SAFETY INFORMATION

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

For your patients with ≥15 headache days per month (REGAIN),

28% of patients taking Emgality (N=273) achieved a ≥50% reduction in monthly MHDs from baseline vs 15% with placebo (N=538) over Months 1 to 3 (p<0.001)1 In REGAIN, Emgality 120 mg was not significantly better than placebo for the mean percentage of patients with ≥75% or 100% reduction from baseline in the number of monthly MHDs over the 3-month treatment period.1 For your patients with 4-14 MHDs per month (EVOLVE-1/EVOLVE-2) or ≥15 headache days per month (REGAIN),

Emgality prevented significantly more mean MHDs per month vs placebo (p<0.001)1 EVOLVE-1: 4.7 vs 2.8 (baseline mean: 9.2 vs 9.1)

EVOLVE-2: 4.3 vs 2.3 (baseline mean: 9.1 vs 9.2)

REGAIN: 4.8 vs 2.7 (baseline mean: 19.4 vs 19.6)

Help eligible patients save at EmgalitySavings.com Governmental beneficiaries excluded. Subject to Terms and Conditions.

Study designs1 EVOLVE-1 and EVOLVE-2 were 6-month, double-blind, placebo-controlled studies that enrolled adult patients with episodic migraine (defined as 4-14 MHDs per month) (N=1773). REGAIN was a 3-month, double-blind, placebo-controlled study that enrolled adult patients with chronic migraine (defined as ≥15 headache days per month with ≥8 migraine days per month) (N=1113).

In all 3 studies, patients were randomized to receive once-monthly placebo, Emgality 120 mg after an initial loading dose of 240 mg, or Emgality 240 mg. 240 mg is an unapproved dose.

In EVOLVE-1 and EVOLVE-2, treatments for prevention were not allowed. In REGAIN, a subset of patients (15%) continued 1 concomitant migraine preventive medication. EVOLVE-1 and EVOLVE-2 excluded patients with medication overuse headache. In all 3 studies, patients were allowed to use acute headache treatments including migraine-specific medications (ie, triptans, ergotamine derivatives), nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen during the study. All 3 studies excluded patients with electrocardiogram (ECG) abnormalities compatible with an acute cardiovascular event and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening. For each study, the primary endpoint was the mean change from baseline in the number of monthly MHDs over the double-blind treatment period in the intent-to-treat population.

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

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

Please see Brief Summary of Prescribing Information on following page. See Instructions for Use included with the device.

GZ HCP SISI 27SEP2018 Reference: 1. Emgality [Prescribing Information].

Indianapolis, IN: Lilly USA, LLC. Emgality® is a registered trademark owned or licensed

by Eli Lilly and Company, its subsidiaries, or affiliates.

PP-GZ-US-0219 02/2019 ©Lilly USA, LLC 2019.

All rights reserved.

MORE IS POSSIBLE

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Administration of galcanezumab-gnlm (0, 30, or 100 mg/kg) by subcutaneous injection to pregnant rabbits throughout the period of organogenesis produced no adverse effects on embryofetal development. The higher dose tested was associated with a plasma Cave, ss 64 times that in humans at the RHD. Administration of galcanezumab-gnlm (0, 30, or 250 mg/kg) by subcutaneous injection to rats throughout pregnancy and lactation produced no adverse effects on pre- and postnatal development. The higher dose tested was associated with a plasma Cave, ss 34 times that in humans at the RHD. Lactation Risk Summary There are no data on the presence of galcanezumab-gnlm in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Emgality and any potential adverse effects on the breastfed infant from Emgality or from the underlying maternal condition.

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

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

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

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

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

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

See Instructions for Use accompanying the device.

GZ HCP BS 28SEP2018

Eli Lilly and Company, Indianapolis, IN 46285, USA ©Lilly USA, LLC 2019.

All rights reserved.

PP-GZ-US-0219 Emgality® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

MSP ARTÍCULO / ORIGINAL

Por: Mónica A. Vega Vázquez, MD Diplomate of the American Board of Endocrinology Endocrinología, Diabetes y Metabolismo

AUTOINMUNIDAD Y TIROIDES

PALABRAS CLAVES

KEY WORDS

Autoinmune, enfermedad de Graves, hipertiroidismo, hipotiroidismo, tiroiditis de Hashimoto.

Autoimmune, graves disease, hyperthyroidism, hypothyroidism, Hashimoto’s Thyroiditis.

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ABSTRACT

La enfermedad autoinmune de la glándula tiroidea comúnmente comprende dos entidades principales: la tiroiditis de Hashimoto y la enfermedad de Graves. Frecuentemente, se caracterizan por el hipotiroidismo y el hipertiroidismo. Si se reconocen los factores de riesgo y los signos y síntomas de estas condiciones se puede ofrecer tratamiento temprano en el transcurso de la enfermedad y así minimizar sus síntomas mediante el reemplazo o la restauración de su función tiroidea.

Autoimmune thyroid disease commonly comprises two major entities, Hashimoto's Thyroiditis and Graves ' Disease. These are often characterized by hypothyroidism and hyperthyroidism. If you recognize the risk factors and the signs and symptoms of these conditions, the patient may be offered early treatment in the course of the disease and thus minimize the symptoms by replacing or restoring the thyroid function.

Introducción La enfermedad autoinmune de la glándula tiroidea comúnmente comprende dos entidades principales, la tiroiditis de Hashimoto y la enfermedad de Graves; las cuales exponen a los pacientes a una amplia gama de signos y manifestaciones clínicas que, frecuentemente, se caracterizan principalmente por el hipotiroidismo y el hipertiroidismo, respectivamente.

Sus patogénesis son muy complejas, y son influenciadas por un sinnúmero de factores de riesgo: ambientales, endógenos y genéticos.

Tiroiditis de Hashimoto La tiroiditis de Hashimoto fue descrita inicialmente en el 1912 y es la causa más común de hipotiroidismo en regiones yodo-suficientes del mundo. Se caracteriza por el fallo progresivo de la función tiroidea debido a la destrucción autoinmune y apoptosis de las células en la glándula del tiroides. Específicamente, esta tiroiditis se distingue por una destrucción de las células foliculares, mediada por la infiltración linfocítica difusa, en la cual predominan las células B y células T. Esta infiltración puede resultar en dos formas extremas del trastorno, y causa el característico bocio o agrandamiento de la glándula de tiroides y la tiroiditis atrófica autoinmune.

El hallazgo serológico más común presentado en todos estos pacientes es la presencia de anticuerpos contra la peroxidasa de tiroides (TPO, por sus siglas en inglés) y anticuerpos contra las tiroglobulinas (Tg). La tiroglobulina es sintetizada por las células foliculares del tiroides, son secretadas en el lumen del folículo y luego son cortadas por peptidasas, lo que produce tiroxina (T4) y triiodotironina (T3). Por su parte, el TPO es una enzima clave en la hormonogénesis; juntas desempeñan un papel fundamental para la producción de hormonas de tiroides.

Como muchos otros desórdenes autoinmunes, esta tiroiditis de Hashimoto es comúnmente vista en mujeres. Aunque la incidencia específica en nuestra población puertorriqueña se desconoce, se estima que, en Estados Unidos, su incidencia sea de 3.5 por cada mil mujeres anualmente y 0.8 por cada 1000 hombres por año. Mientras algunos de estos pacientes pueden estar asintomáticos y bioquímicamente eutiroideos, con su función de la glándula preservada, el curso usual comprende la pérdida gradual de su función resultando en un hipotiroidismo franco. Este hipotiroidismo es caracterizado por un aumento en los niveles de la hormona estimulante de

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Glándula tiroides bajo un microscopio.

Tiroiditis autoinmune, enfermedad de Hashimoto. Ilustración 3D que muestra anticuerpos atacando la glándula tiroides.

tiroides (TSH, por sus siglas en inglés) y una disminución en los niveles de hormona de tiroxina (T4). Sus manifestaciones clínicas son variables, dependiendo de la edad de inicio, su duración y la severidad de la deficiencia de hormona tiroidea.

Signos y Síntomas Entre los signos y síntomas más comunes se encuentran los siguientes:

Tratamiento Generalmente, el tratamiento consiste en el reemplazo de la hormona tiroidea mediante la levotiroxina sintética; y su meta se enfoca en restablecer o normalizar los niveles de TSH en un rango aproximado de 0.4 a 4 mU/L, mejorar los signos o síntomas clínicos presentados por el paciente y disminuir el tamaño del bocio en los pacientes que así lo presenten. Aunque existen preparados desecados de tiroides de animales en el mercado, su uso no se recomienda para la mayoría de los pacientes, ya que la proporción de T3 a T4 no es fisiológica.

Por otro lado, el suplemento con selenio ha sido estudiado por sus efectos en la función inmune y, aunque ha demostrado una reducción en los niveles de anticuerpos contra la peroxidasa de tiroides (TPO) y ha demostrado que puede mejorar la estructura de la glándula en estudios de imagen por ultrasonografía, el suplemento con selenio no ha demostrado una mejoría en la restauración per se de la función de la glándula tiroidea.

Enfermedad de Graves La enfermedad de Graves, también conocida como bocio tóxico difuso, es la causa más común de hipertiroidismo. Sin embargo, se presenta generalmente como un síndrome que también incluye el bocio o agrandamiento en la glándula del tiroides, enfermedad ocular u orbitopatía, y ocasionalmente dermopatía o mixedema localizado pretibial.

El autoantígeno principal en este desorden es el receptor de la hormona estimulante de tiroides (TSHR, por sus siglas en inglés), el cual regula el crecimiento de la glándula, así como la producción y secreción de su hormona. En la gran mayoría de estos pacientes podemos ver una glándula difusamente agrandada que se caracteriza histológicamente por una hiperplasia folicular con infiltración linfocítica multifocal con

presencia intratiroidal de linfocitos T y abundantes células B. Estos linfocitos de los tejidos tiroideos de pacientes con Graves son los responsables de secretar también autoanticuerpos contra tiroglobulinas (anti-Tg) y contra la peroxidasa de tiroides (anti-TPO); pero -sobre todo- contra los receptores de tirotropina (TRab, por sus siglas en inglés) que activan su receptor.

Es importante destacar que estos anticuerpos, entiéndase los TRab, son específicos para la enfermedad de Graves y promueven el consumo de yodo por los tejidos tiroideos en ausencia de la hormona estimulante de tiroides o TSH. Similar a la tiroiditis de Hashimoto, la enfermedad de Graves es más común en mujeres, con una incidencia más marcada entre los 30 a 50 años de edad. Estudios científicos han demostrado que existe una predisposición genética para su desarrollo. Sin embargo, el consumo de yodo o medicamentos con alto contenido de este, como la amiodarona y el medio de contraste que se usa para estudios de tomografía computarizada, también han sido estudiados como agentes precipitantes para el desarrollo de la enfermedad de Graves en pacientes susceptibles.

Signos y Síntomas El diagnóstico de esta enfermedad generalmente envuelve anormalidades bioquímicas en las pruebas de función tiroidea que se caracteriza por niveles bajos de hormona estimulante de tiroides (TSH) con niveles altos de tiroxina libre (T4); y se confirma el diagnóstico con la presencia de los anticuerpos previamente mencionados. Su presentación clínica generalmente se determina por la severidad de la tirotoxicosis, su duración y la edad del paciente. Entre los signos y síntomas más comunes reportados por los pacientes con hipertiroidismo, se encuentran los siguientes:

Sumado a los síntomas asociados al exceso de hormona de tiroides, los pacientes de la enfermedad de Graves también pueden presentar síntomas oculares como la oftalmopatía de Graves. Esta orbitopatía se caracteriza por el engrosamiento de los músculos extraoculares y retroculares, mediado por un aumento en el tejido conectivo secundario al depósito y proliferación de fibroblastos, inflamación y acumulación de glicosaminoglicanos liberados por estos fibroblastos. Al igual que ocurre en el tiroides, el antígeno principal de esta orbitopatía es el TSHR; el cual también está presente en los adipocitos y en los fibroblastos. Estos cambios ocasionan un desplazamiento anterior del ojo (también conocido como proptosis o exoftalmia), causando disfunción en el movimiento ocular, visión doble, dolor, compresión del nervio y hasta pérdida de visión.

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MSP ARTÍCULO / ORIGINAL

Ilustración 3d glándula tiroides

Los pacientes con enfermedad de Graves, también pueden presentar menos comúnmente mixedema pretibial o también conocida como dermopatía tiroidea. Esta patología también resulta de la acumulación de glicosaminoglicanos generados por los fibroblastos, bajo la estimulación local de citoquinas en respuesta a los anticuerpos contra los receptores de TSH. Estas lesiones suelen ser bilaterales, asimétricas y son caracterizadas por descamación, induración e hiperpigmentación de la piel sobre el área pretibial.

Aunque, es importante recordar que también puede aparecer en otras áreas del cuerpo como los pies, codos, rodillas y/o cuello.

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Tratamiento El tratamiento para el hipertiroidismo asociado a la enfermedad de Graves se enfoca en mejorar los síntomas asociados a la activación adrenérgica, para el cual generalmente usamos bloqueadores beta y, en disminuir la producción de hormonas generadas por la glándula tiroidea. Las alternativas de tratamiento para disminuir la síntesis de hormonas tiroideas incluyen las drogas antitiroideas, el yodo-radioactivo o la cirugía de tiroides y -aunque todas han resultado ser efectivas- sus efectos adversos pueden ser significativos. Las tionamidas,

Los pacientes con enfermedad de Graves, también pueden presentar menos comúnmente mixedema pretibial o también conocida como dermopatía tiroidea

Entre los efectos más serios reportados con la terapia de tionamidas se encuentra la agranulocitosis y la disfunción hepática

el tratamiento con la cápsula de yodo radioactivo se considera como definitivo en la mayoría de los pacientes, ya que el mismo se incorpora rápidamente en los tejidos de la glándula y causa destrucción en las células y tejidos tiroideos, lo que resulta, en muchas ocasiones, en hipotiroidismo. Por otro lado, los pacientes que presentan síntomas de bocio obstructivo, orbitopatía severa o activa, o que poseen alguna otra contraindicación a los otros tratamientos para el hipertiroidismo, suelen ser referidos a tiroidectomía como terapia definitiva a su enfermedad.

Conclusiones Como podemos ver, las enfermedades autoinmunes de la glándula tiroidea son complejas y pueden resultar en afecciones clínicas que definitivamente afectan la calidad de vida de los pacientes que la presentan. Sin embargo, si se reconocen los factores de riesgo y los signos y síntomas de estas condiciones, se puede ofrecer tratamiento temprano en el curso de la enfermedad y así minimizar sus síntomas mediante el reemplazo o la restauración de su función tiroidea.

REFERENCIAS Hollowell JG, Staehling NW, Flander WD et al.

Serum TSH, T(4) and Thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87:489 McLeod, D.S.A. and Cooper, D.S. The incidence and prevalence of thyroid autoimmunity. Endocrine (2012) 42: 252-265.

específicamente el metimazol y el propiltiouracilo, son fármacos con un efecto inhibidor en la función de la enzima TPO: reducen la oxidación y la organificación de yodo, las cuales son pasos claves en la formación de hormonas tiroideas. Sin embargo, estos medicamentos pueden ser una alternativa para pacientes con síntomas leves o moderados, aunque cabe reconocer que solo un 20 a un 30% de los pacientes alcanzan una remisión permanente con este tratamiento. Entre los efectos más serios reportados con la terapia de tionamidas se encuentra la agranulocitosis y la disfunción hepática. Por su parte,

Artalenta L. Diagnosis and management of Graves disease: a global overview. Nat Rev Endocrinol. 2013 Dec;9(12):724-34.

Y.H. Dong, D.G. Fu. Autoimmune thyroid disease: mechanism, genetics and current knowledge. Eur Rev Med Pharmacol Sci. 2014;18(23):3611-8.

Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other Causes of Thyrotoxicosis.

Thyroid 2016: 26: 134

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NUESTRA MISIÃ&#x201C;N

ES SERVIRLES

MSP ARTÍCULO / DE REVISIÓN

Por: Wihelma Echevarría Cortés, MD Gastroenteróloga Pediátrica HIMA San Pablo Caguas y Bayamón

ENFERMEDAD INFLAMATORIA INTESTINAL EN NIÑOS Y ADOLESCENTES

PALABRAS CLAVES

KEY WORDS

Autoinmunidad, enfermedad inflamatoria intestinal, colitis ulcerosa, enfermedad de Crohn.

Autoimmunity, inflammatory bowel disease, ulcerative colitis, Crohn’s disease.

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MSP ARTÍCULO / DE REVISIÓN

La enfermedad inflamatoria intestinal (EII) consiste en una inflamación intestinal crónica causada por la interacción de la genética, los factores ambientales y la microbiota.

En aproximadamente el 25% de los pacientes, la EII se diagnostica antes de los 20 años de edad.

RESUMEN La enfermedad inflamatoria intestinal (EII) es un término que utilizamos para agrupar las enfermedades conocidas como colitis ulcerosa y enfermedad de Crohn. La EII es un trastorno inflamatorio del tracto gastrointestinal; muchas veces es diagnosticado en la adolescencia y la adultez joven. Todos, o al menos la mayoría de pediatras y otros médicos pediátricos se encontrarán con niños con EII en su práctica general. La EII es causada por una respuesta inmune intestinal desregulada en personas genéticamente predispuestas. Aunque los niños -generalmente- presentan síntomas de pérdida de peso, dolor abdominal y diarrea sanguinolenta, muchos presentan un crecimiento deficiente, anemia u otras manifestaciones extraintestinales. Una vez que se diagnostica la EII, los objetivos de la terapia consisten en eliminar los síntomas, normalizar la calidad de vida, restablecer el crecimiento y prevenir las complicaciones, minimizando los efectos adversos de los medicamentos. Consideraciones únicas al tratar a niños y adolescentes con EII incluyen la atención a los efectos de la enfermedad en el crecimiento y desarrollo, y el funcionamiento psicosocial. El propósito de esta revisión es proporcionar una visión contemporánea de las características epidemiológicas, la patogénesis, el diagnóstico y el manejo de la EII en niños y adolescentes.

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Los objetivos del tratamiento con EII son: eliminar los síntomas, restablecer el crecimiento normal y prevenir complicaciones quirúrgicas.

La presentación de EII en pacientes pediátricos es variable, y los médicos de atención primaria deben estar familiarizados con las presentaciones atípicas, como un crecimiento deficiente inexplicable o anemia.

ABSTRACT Inflammatory Bowel Disease (IBD) is a term used to group Ulcerative Colitis and Crohn Disease. IBD is a chronic inflammatory disorder of the gastrointestinal tract, many times diagnosed in adolescence and young adulthood. All if not all pediatricians and other pediatric clinicians will encounter children with IBD in their general practice. IBD is caused by a dysregulated mucosal immune response to the intestinal microflora in genetically predisposed hosts. Although children usually present with symptoms of weight loss, abdominal pain, and bloody diarrhea, many present with poor growth, anemia, or other extraintestinal manifestations. Once IBD is diagnosed, the goals of therapy consist of eliminating symptoms, normalizing quality of life, restoring growth, and preventing complications while minimizing the adverse effects of medications. Unique considerations when treating children and adolescents with IBD include attention to the effects of the disease on growth and development, and psychosocial functioning. The purpose of this review is to provide a contemporary overview of the epidemiologic features, pathogenesis, diagnosis, and management of IBD in children and adolescents.

INTRODUCCIÓN La enfermedad inflamatoria intestinal.(EII) es una condición intestinal crónica y de origen autoinmune. La EII se clasifica como enfermedad de Crohn o colitis ulcerosa. En los pasados años hemos visto un aumento dramático en la incidencia y prevalencia de esta condición en la población pediátrica.

Recientemente, la EII se ha convertido en una de las enfermedades crónicas más significativas en niños y adolescentes.

Aunque algunos pacientes con EII presentan pérdida aguda de peso, otros muestran un patrón más insidioso de deceleración en las curvas de peso y crecimiento

ENFERMEDAD DE CROHN VERSUS COLITIS ULCEROSA En pediatría, es más común la enfermedad de Crohn que la colitis ulcerosa; aunque ambas condiciones presentan un aumento en cuanto a incidencia recientemente.

Aunque muy parecidas, estas condiciones tienen diferencias significativas, siendo la más obvia la localización y profundidad del proceso inflamatorio. La enfermedad de Crohn puede afectar cualquier área del tracto gastrointestinal, desde la EPIDEMIOLOGÍA boca hasta el ano; mientras que la colitis • 1 a 1.5 millones de personas en Estados ulcerosa solo afecta el intestino grueso.

Unidos padecen EII El envolvimiento perianal que se puede • El 25% de los casos se diagnostican ver en la enfermedad de Crohn (20% en edad pediátrica de los casos) no se observa en la colitis • De 7 a 10 niños ulcerosa. Esta última por cada 100.000 afecta la mucosa o desarrollan EII capa superficial del anualmente en los colon; mientras que, la Los niños y Estados Unidos enfermedad de Crohn • El 4% de la enpuede incluir todas las adolescentes con EII fermedad Crohn capas del intestino delexhiben una tasa más ocurre en niños gado y el colon. Cuando alta de desórdenes menores de 5 años sucede este fenómeno de depresión y en los pacientes con ansiedad; aun ETIOLOGÍA Crohn, se considera MULTIFACTORIAL que la enfermedad es comparados con niños La causa exacta de penetrante y puede que sufren de otras la EII no se conoce, resultar en fístulas condiciones crónicas pero se sabe que y estrecheces. Las es multifactorial. fístulas son tractos del Primero, tiene que intestino que pueden existir una predisllevar al desarrollo de posición genética (se ha vinculado a abscesos intraabdominales o perianales, NOD2/CARD15). Pensamos que, en o pueden crear una conexión entre el aquellas personas con la predisposiintestino y otros órganos como la piel, ción genética, una infección intestinal la vejiga, etc. La estrechez es un tipo de o cambios en la microflora del pacienobstrucción parcial o completa, debido te, afectan el sistema inmunológico y a que tejido sano ha sido sustituido por desencadenan una reacción inflamatejido de cicatriz. Aunque estas complitoria, la cual -por alguna razón- el orcaciones pueden responder a tratamienganismo del paciente no puede apagar to médico y es usual que el paciente que por completo. La sobreproducción de las desarrolle requiera cirugía. citoquinas proinflamatorias o la pobre Distinguir entre Crohn y colitis ulceproducción de citoquinas reguladoras o rosa puede ser difícil, especialmente si antiinflamatorias podrían estar relala inflamación es solamente colónica. El cionadas con esta respuesta anormal diagnóstico de Crohn es definitivo si se del sistema inmunológico. Factores observa claramente inflamación en el inambientales como fumar, el estrés testino delgado, la colitis es discontinua, emocional o físico, la contaminación, hay enfermedad perianal o si hay granuentre otros; y el uso de cier tos medicalomas en las biopsias. Los pacientes de mentos, por ejemplo, los antiinflamaCrohn pueden desarrollar estrechez, abstorios no esteroidales (NSAIDS) podrían cesos abdominales, y fístulas perianales ser eventos que inicien esta cascada mientras que los de UC principalmente inmunológica. presentan diarreas con sangre.

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SIGNOS Y SÍNTOMAS Los signos y síntomas más comunes de la EII son diarrea, sangrado rectal, dolor abdominal, falla en crecimiento, pérdida de peso, cansancio generalizado, fiebres nocturnas, enfermedad perianal, úlceras orales, artralgia y anemia. Frecuentemente, el paciente presenta los síntomas por un tiempo prolongado antes de ser diagnosticado.

LABORATORIOS Sangre: CBC, CRP, ESR, CMP, Hierro, PANCA, CANCA Heces fecales: Calprotectina, sangre oculta, cultivo, Clostridium difficile (estas dos últimas para descartar una infección por Yersinia o Cdiff, las cuales emulan la condición).

Radiologías CT o MRI abdominopélvicos, enterografía de CT o MRI

DIAGNÓSTICO Se estima que todo pediatra y médico de atención primaria atenderá -en algún momento- al menos a un paciente con EII. El diagnóstico de EII conlleva un alto índice de sospecha. Un buen historial médico, evaluación de las curvas de crecimiento, historial familiar y examen físico son primordiales para lograr un diagnóstico certero.

ESTUDIOS INVASIVOS Endoscopía y colonoscopía con biopsias (necesarias para el diagnóstico) Endoscopía de vídeo cápsula

CURVA DE CRECIMIENTO Aunque algunos pacientes con EII presentan pérdida aguda de peso, otros muestran un patrón más insidioso de deceleración en las curvas de peso y crecimiento. Por otro lado, no debe descartarse la posibilidad de EII en pacientes con sobrepeso u obesidad (25% de los casos).

EXAMEN FÍSICO El examen abdominal puede revelar dolor, molestia a la palpación o presencia de masas. El área perianal debe ser evaluada para descartar la presencia de colgajos (“anal tags”), fisuras o fístulas. Otros hallazgos físicos pueden incluir aftas orales, lesiones en la piel, hinchazón en las articulaciones o palillos de tambor (“clubbing”) en las uñas.

PRUEBAS DIAGNÓSTICAS Entre las pruebas que ayudan a determinar la condición se encuentran (no todas son necesarias):

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TRATAMIENTO Las metas de tratamiento en la EII han cambiado dramáticamente en los últimos años. Cuando las opciones de terapia eran escasas, la meta primaria era reducir los síntomas.

Ahora, con el advenimiento de la terapia biológica, tenemos la oportunidad de alterar la historia natural de la condición. Por lo tanto, nuestra meta de tratamiento es alcanzar la remisión de la enfermedad. La meta inmediata del tratamiento es mejorar los síntomas lo antes posible. A largo plazo, queremos sanar la mucosa gastrointestinal, mejorar la calidad de vida, restituir la razón de crecimiento, eliminar complicaciones y disminuir hospitalizaciones y cirugías. Para los síntomas más leves se utilizan antibióticos, nutrición enteral y aminosalicilatos (acción tópica antiinflamatoria en la mucosa intestinal).

Los corticoesteroides se utilizan en enfermedad moderada a severa. Los inmunosupresores (metotrexato, 6-mercaptopurina, imuran) y las terapias biológicas-bloqueadores del factor de necrosis tumoral (adalimumab, infliximab) se administran en casos más severos y/o donde hay una dependencia de los esteroides. Actualmente, hay una tendencia a ser más agresivos con el tratamiento y, en ciertos casos, a comenzar

LA CIRUGÍA Y PERÍODOS PROLONGADOS DE NPO SE RESERVAN PARA CASOS EXTREMOS, DONDE LA TERAPIA MÉDICA NO HA FUNCIONADO

las terapias biológicas e inmunosupresores más temprano en el curso de la enfermedad para así tratar de lograr le meta principal: la sanación de la mucosa intestinal.

La cirugía y períodos prolongados de NPO se reservan para casos extremos, donde la terapia médica no ha funcionado.

FACTORES PSICOSOCIALES Los niños y adolescentes con EII exhiben una tasa más alta de desórdenes de depresión y ansiedad; aun comparados con niños que sufren de otras condiciones crónicas. La psicoterapia, el yoga y -a veces- la psicofarmacoterapia, son herramientas altamente efectivas. Los médicos que atienden a estos pacientes deben observar cuidadosamente los signos y síntomas de depresión y ansiedad, y referirlos para evaluación y tratamiento, de ser necesario. Los síntomas de dolor abdominal, cansancio y diarreas afectan la calidad de vida y el funcionamiento social de los pacientes con EII. Estos pacientes cualifican para Acomodo Razonable en la escuela, universidad y empleos.

EL FUTURO DE LA EII Existen medicamentos biológicos que suspenden la cascada de inflamación a nivel de interleuquinas e integrinas; estos son efectivos en casos de EII que no respondan a los bloqueadores del factor de necrosis tumoral. Actualmente, estos medicamentos no tienen indicación en pacientes menores de 18 años, pero se perfilan como una alternativa factible para la población pediátrica en el futuro. Se están estudiando también alternativas para modificar permanentemente la microbiota en estos pacientes con la meta de alcanzar remisión más sostenida y efectiva. El objetivo es lograr que los pacientes con EII disfruten de una calidad de vida saludable y que no perciban la EII como un obstáculo en su vida.

CONCLUSIONES La EII es una condición agresiva y potencialmente incapacitante, pero, con un tratamiento temprano y adecuado, los menores pueden llevar una vida normal y productiva. Los niños y adolescentes podrían tener problemas físicos, emocionales, sociales y familiares, por lo cual es sumamente importante la detección temprana y el tratamiento precoz de la condición. Es imperativo que los médicos tengamos un amplio conocimiento de estas condiciones y un alto índice de sospecha.

REFERENCIAS: Baldassano RN, Piccoli DA. Inflammatory bowel disease in pediatric and adolescent patients. Gastroenterol Clin North Am. 1999;28(2):445–458. [PubMed] Knights D, Lassen KG, Xavier RJ. Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut. 2013;62(10):1505–1510. [PMC free article] [PubMed] Hyams J, Crandall W, Kugathasan S, et al. REACH Study Group Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132(3):863–873. [PubMed] Colombel J-F, Sandborn WJ, Reinisch W, et al. SONIC Study Group Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383–1395. [PubMed] Mackner LM, Greenley RN, Szigethy E, Herzer M, Deer K, Hommel KA. Psychosocial issues in pediatric inflammatory bowel disease: report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J.

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HUMIRA® (adalimumab) WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Discontinue HUMIRA if a patient develops a serious infection or sepsis.

Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before HUMIRA use and during therapy. Initiate treatment for latent TB prior to HUMIRA use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with HUMIRA prior to initiating therapy in patients with chronic or recurrent infection.

Monitor patients closely for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy [see Warnings and Precautions and Adverse Reactions].

MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including HUMIRA [see Warnings and Precautions].

Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis.

It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants [see Warnings and Precautions].

INDICATIONS AND USAGE Rheumatoid Arthritis HUMIRA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

Juvenile Idiopathic Arthritis HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. HUMIRA can be used alone or in combination with methotrexate.

Psoriatic Arthritis HUMIRA is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HUMIRA can be used alone or in combination with non-biologic DMARDs. Ankylosing Spondylitis HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

Adult Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Pediatric Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.

Ulcerative Colitis HUMIRA is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to TNF blockers.

Plaque Psoriasis HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warning and Warnings and Precautions].

Hidradenitis Suppurativa HUMIRA is indicated for the treatment of moderate to severe hidradenitis suppurativa.

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION Uveitis HUMIRA is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Serious Infections Patients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death [see Boxed Warning]. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers.

Patients have frequently presented with disseminated rather than localized disease.

The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions].

Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection.

Tuberculosis Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating HUMIRA and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating HUMIRA, assess if treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin skin test result, even for patients previously vaccinated with Bacille CalmetteGuerin (BCG).

Consider anti-tuberculosis therapy prior to initiation of HUMIRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection.

Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with HUMIRA. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during HUMIRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with HUMIRA. Discontinue HUMIRA if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with HUMIRA, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.

Invasive Fungal Infections If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections.

Malignancies Consider the risks and benefits of TNF-blocker treatment including HUMIRA prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.

Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including HUMIRA, more cases of malignancies have been observed among TNFblocker-treated adult patients compared to control-treated adult patients.

During the controlled portions of 39 global HUMIRA clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS) and uveitis (UV), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years among 7973 HUMIRA-treated patients versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated patients (median duration of treatment of 4 months for HUMIRA-treated patients and 4 months for control-treated patients). In 52 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the most frequently observed malignancies,

other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in HUMIRA-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).

In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.

Non-Melanoma Skin Cancer During the controlled portions of 39 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among HUMIRA-treated patients and 0.2 (0.10, 0.59) per 100 patient-years among control-treated patients. Examine all patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of NMSC prior to and during treatment with HUMIRA. Lymphoma and Leukemia In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated patients compared to control-treated patients. In the controlled portions of 39 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, 2 lymphomas occurred among 7973 HUMIRA-treated patients versus 1 among 4848 control-treated patients. In 52 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV with a median duration of approximately 0.7 years, including 24,605 patients and over 40,215 patient-years of HUMIRA, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). Rates of lymphoma in clinical trials of HUMIRA cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population.

Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications.

Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which HUMIRA is a member [see Boxed Warning]. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA [see Boxed Warning]. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and HUMIRA should be carefully considered.

Hypersensitivity Reactions Anaphylaxis and angioneurotic edema have been reported following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of HUMIRA and institute appropriate therapy. In clinical trials of HUMIRA in adults, allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed.

Hepatitis B Virus Reactivation Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus.

In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. For patients who are carriers of HBV and require treatment with TNF blockers, closely monitor such patients for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop HUMIRA and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of HUMIRA therapy in this situation and monitor patients closely.

Neurologic Reactions Use of TNF blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of HUMIRA should be considered if any of these disorders

develop. There is a known association between intermediate uveitis and central demyelinating disorders.

Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Consider discontinuation of HUMIRA therapy in patients with confirmed significant hematologic abnormalities.

Use with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNFblocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions].

Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. HUMIRA has not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully.

Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, discontinue treatment [see Adverse Reactions].

Immunizations In a placebo-controlled clinical trial of patients with RA, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with HUMIRA. Similar proportions of patients developed protective levels of anti-influenza antibodies between HUMIRA and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving HUMIRA. The clinical significance of this is unknown. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines.

No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA. It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines.

The safety of administering live or live-attenuated vaccines in infants exposed to HUMIRA in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants [see Use in Specific Populations].

Use with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended [see Drug Interactions].

ADVERSE REACTIONS The most serious adverse reactions described elsewhere in the labeling include the following: • Serious Infections [see Warnings and Precautions] • Malignancies [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.

The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

Infections In the controlled portions of the 39 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient-years in 7973 HUMIRA-treated patients versus a rate of 2.9 per 100 patient-years in 4848 control-treated patients.

Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions].

Tuberculosis and Opportunistic Infections In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV that included 24,605 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of 10,113 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.05 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions].

Autoantibodies In the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA

titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.

The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown.

Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In a controlled Phase 3 trial of HUMIRA in patients with polyarticular JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% of HUMIRA-treated patients and 1.5% of control-treated patients (ALT more common than AST); liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment. No ALT elevations ≥ 3 x ULN occurred in the open-label study of HUMIRA in patients with polyarticular JIA who were 2 to <4 years.

In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in adult patients with CD with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In the Phase 3 trial of HUMIRA in pediatric patients with Crohn’s disease which evaluated efficacy and safety of two body weight based maintenance dose regimens following body weight based induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these patients discontinued due to abnormalities in ALT tests. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of HUMIRA-treated patients and 1.0% of controltreated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients.

In controlled trials of HUMIRA (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in subjects with HS with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of HUMIRA-treated subjects and 0.6% of control-treated subjects. In controlled trials of HUMIRA (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in HUMIRA-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of HUMIRA-treated patients and 2.4% of control-treated patients.

Immunogenicity Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult RA patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate (MTX) had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed.

With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibodypositive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown.

In patients with polyarticular JIA who were 4 to 17 years of age, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant MTX, the incidence was 6% compared to 26% with HUMIRA monotherapy. In patients with polyarticular JIA who were 2 to <4 years of age or 4 years of age and older weighing <15 kg, adalimumab antibodies were identified in 7% (1 of 15) of HUMIRA-treated patients, and the one patient was receiving concomitant MTX. In patients with AS, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with RA. In patients with PsA, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with RA; however, in patients receiving concomitant MTX the rate was 7% compared to 1% in RA. In adult patients with CD, the rate of antibody development was 3%.

In pediatric patients with Crohn’s disease, the rate of antibody development in patients receiving HUMIRA was 3%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 32% of total patients studied), the immunogenicity rate was 10%.

In patients with moderately to severely active UC, the rate of antibody development in patients receiving HUMIRA was 5%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 25% of total patients studied), the immunogenicity rate was 20.7%.

In patients with Ps, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In Ps patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.

In subjects with moderate to severe HS, the rate of anti-adalimumab antibody development in subjects treated with HUMIRA was 6.5%.

However, because of the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among subjects who stopped HUMIRA treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to < 2 mcg/mL (approximately 22% of total subjects studied), the immunogenicity rate was 28%.

In patients with non-infectious uveitis, anti-adalimumab antibodies were identified in 4.8% (12/249) of patients treated with adalimumab.

However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 23% of total patients studied), the immunogenicity rate was 21.1%. Using an assay which could measure an anti-adalimumab antibody titer in all patients, titers were measured in 39.8% (99/249) of non-infectious uveitis patients treated with adalimumab.

No correlation of antibody development to safety or efficacy outcomes was observed.

The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab or titers, and are highly dependent on the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading.

Other Adverse Reactions Rheumatoid Arthritis Clinical Studies The data described below reflect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration.

The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week.

Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.

Table 1. Adverse Reactions Reported by ≥5% of Patients Treated with HUMIRA During Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) HUMIRA 40 mg subcutaneous Every Other Week

Placebo

(N=705)

(N=690)

Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection

17%

13%

Sinusitis

11%

9%

Flu syndrome

7%

6%

Nausea

9%

8%

Abdominal pain

7%

4%

Gastrointestinal

Laboratory Tests* Laboratory test abnormal

8%

7%

Hypercholesterolemia

6%

4%

Hyperlipidemia

7%

5%

Hematuria

5%

4%

Alkaline phosphatase increased

5%

3%

Headache

12%

8%

Rash

12%

6%

Accidental injury

10%

8%

Injection site reaction **

8%

1%

Back pain

6%

4%

Other

Urinary tract infection

8%

5%

Hypertension

5%

3%

* Laboratory test abnormalities were reported as adverse reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the HUMIRA-treated patients in the polyarticular juvenile idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important findings and differences from adults are discussed in the following paragraphs.

In Study JIA-I, HUMIRA was studied in 171 patients who were 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis.

Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.

In Study JIA-I, 45% of patients experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment.

The types of infections reported in HUMIRA-treated patients were generally similar to those commonly seen in polyarticular JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this patient population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in patients receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment.

In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity reactions were seen in approximately 6% of patients and included primarily localized allergic hypersensitivity reactions and allergic rash.

In Study JIA-I, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.

Approximately 15% of patients treated with HUMIRA developed mildto-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients.

Most patients were able to continue HUMIRA without interruption.

In Study JIA-II, HUMIRA was studied in 32 patients who were 2 to <4 years of age or 4 years of age and older weighing <15 kg with polyarticular JIA. The safety profile for this patient population was similar to the safety profile seen in patients 4 to 17 years of age with polyarticular JIA. In Study JIA-II, 78% of patients experienced an infection while receiving HUMIRA. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity. Serious infections were observed in 9% of patients receiving HUMIRA in the study and included dental caries, rotavirus gastroenteritis, and varicella.

In Study JIA-II, non-serious allergic reactions were observed in 6% of patients and included intermittent urticaria and rash, which were all mild in severity.

Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with RA, HUMIRA Studies RA-I through IV. Adult Crohn’s Disease Clinical Studies HUMIRA has been studied in 1478 adult patients with Crohn’s disease (CD) in four placebo-controlled and two open-label extension studies. The safety profile for adult patients with CD treated with HUMIRA was similar to the safety profile seen in patients with RA. Pediatric Crohn’s Disease Clinical Studies HUMIRA has been studied in 192 pediatric patients with Crohn’s disease in one double-blind study (Study PCD-I) and one open-label extension study.

The safety profile for pediatric patients with Crohn’s disease treated with HUMIRA was similar to the safety profile seen in adult patients with Crohn’s disease.

During the 4 week open label induction phase of Study PCD-I, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (6% and 5%, respectively).

A total of 67% of children experienced an infection while receiving HUMIRA in Study PCD-I. These included upper respiratory tract infection and nasopharyngitis.

A total of 5% of children experienced a serious infection while receiving HUMIRA in Study PCD-I. These included viral infection, device related sepsis (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis.

In Study PCD-I, allergic reactions were observed in 5% of children which were all non-serious and were primarily localized reactions.

Ulcerative Colitis Clinical Studies HUMIRA has been studied in 1010 patients with ulcerative colitis (UC) in two placebo-controlled studies and one open-label extension study. The safety profile for patients with UC treated with HUMIRA was similar to the safety profile seen in patients with RA. Plaque Psoriasis Clinical Studies HUMIRA has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies. The safety profile for subjects with Ps treated with HUMIRA was similar to the safety profile seen in subjects with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps subjects, HUMIRA-treated subjects had a higher incidence of arthralgia when compared to controls (3% vs. 1%).

Hidradenitis Suppurativa Clinical Studies HUMIRA has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebo-controlled studies and one open-label extension study.

The safety profile for subjects with HS treated with HUMIRA weekly was consistent with the known safety profile of HUMIRA. Flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from HUMIRA treatment following the primary efficacy timepoint in two studies.

Uveitis Clinical Studies HUMIRA has been studied in 464 patients with uveitis (UV) in placebocontrolled and open-label extension studies. The safety profile for patients with UV treated with HUMIRA was similar to the safety profile seen in patients with RA. Postmarketing Experience The following adverse reactions have been identified during post-approval use of HUMIRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMIRA exposure.

Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis General disorders and administration site conditions: Pyrexia Hepato-biliary disorders: Liver failure, hepatitis Immune system disorders: Sarcoidosis Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin) Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia Vascular disorders: Systemic vasculitis, deep vein thrombosis DRUG INTERACTIONS Methotrexate HUMIRA has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX.

Biological Products In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of HUMIRA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of HUMIRA with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.

Live Vaccines Avoid the use of live vaccines with HUMIRA [see Warnings and Precautions].

Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for a molecule that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of HUMIRA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Limited clinical data are available from the Humira Pregnancy Registry.

Excluding lost-to-follow-up, data from the registry reports a rate of 5.6% for major birth defects with first trimester use of adalimumab in pregnant women with rheumatoid arthritis (RA), and a rate of 7.8% and 5.5% for major birth defects in the disease-matched and non-diseased comparison groups [see Data]. Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant. In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate [see Data].

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

Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester [see Data]. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to HUMIRA in utero [see Use in Specific Populations].

Data Human Data In a prospective cohort pregnancy exposure registry conducted in the U.S. and Canada between 2004 and 2013, 74 women with RA treated with adalimumab at least during the first trimester, 80 women with RA not treated with adalimumab and 218 women without RA (non-diseased) were enrolled. Excluding lost-to-follow-up, the rate of major defects in the adalimumab-exposed pregnancies (N=72), disease-matched (N=77), and non-diseased comparison groups (N=201) was 5.6%, 7.8% and 5.5%, respectively. However, this study cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. Data from the Crohn’s disease portion of the study is in the follow-up phase and the analysis is ongoing.

In an independent clinical study conducted in ten pregnant women with inflammatory bowel disease treated with HUMIRA, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth. The last dose of HUMIRA was given between 1 and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 μg/mL in cord blood, 4.28-17.7 μg/mL in infant serum, and 0-16.1 μg/mL in maternal serum. In all but one case, the cord blood level of adalimumab was higher than the maternal serum level, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum levels at each of the following: 6 weeks (1.94 μg/mL), 7 weeks (1.31 μg/mL), 8 weeks (0.93 μg/mL), and 11 weeks (0.53 μg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth.

Lactation Risk Summary Limited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0.1% to 1% of the maternal serum level. There are no reports of adverse effects of adalimumab on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HUMIRA and any potential adverse effects on the breastfed child from HUMIRA or from the underlying maternal condition.

Pediatric Use Safety and efficacy of HUMIRA in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohn’s disease have not been established. Due to its inhibition of TNFα, HUMIRA administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to HUMIRA in utero suggest adalimumab crosses the placenta [see Use in Specific Populations]. The clinical significance of elevated adalimumab levels in infants is unknown. The safety of administering live or liveattenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.

Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA [see Boxed Warning and Warnings and Precautions].

Juvenile Idiopathic Arthritis In Study JIA-I, HUMIRA was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age. In Study JIA-II, the safety profile for patients 2 to <4 years of age was similar to the safety profile for patients 4 to 17 years of age with polyarticular JIA [see Adverse Reactions].

HUMIRA has not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg.

The safety of HUMIRA in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions [see Adverse Reactions].

Pediatric Crohn’s Disease The safety and effectiveness of HUMIRA for reducing signs and symptoms and inducing and maintaining clinical remission have been established in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate. Use of HUMIRA in this age group is supported by evidence from adequate and well-controlled studies of HUMIRA in adults with additional data from a randomized, double-blind, 52week clinical study of two dose levels of HUMIRA in 192 pediatric patients (6 to 17 years of age) with moderately to severely active Crohn’s disease. The safety and effectiveness of HUMIRA has not been established in pediatric patients with Crohn’s disease less than 6 years of age.

Geriatric Use A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received HUMIRA in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among HUMIRA treated patients over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population, use caution when treating the elderly.

OVERDOSAGE Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies of HUMIRA have not been conducted to evaluate the carcinogenic potential or its effect on fertility.

PATIENT COUNSELING INFORMATION Patient Counseling Provide the HUMIRA “Medication Guide” to patients or their caregivers, and provide them an opportunity to read it and ask questions prior to initiation of therapy and prior to each time the prescription is renewed. If patients develop signs and symptoms of infection, instruct them to seek medical evaluation immediately.

Advise patients of the potential benefits and risks of HUMIRA. • Infections Inform patients that HUMIRA may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections.

• Malignancies Counsel patients about the risk of malignancies while receiving HUMIRA. • Allergic Reactions Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the gray needle cap of the 27 gauge HUMIRA pen and prefilled syringe contains natural rubber latex.

• Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.

AbbVie Inc. North Chicago, IL 60064, U.S.A. US License Number 1889 Ref: 03-B467-R44/20015346 Revised: 04/2017 64C-1915014 MASTER

64E-1932644

MSP ARTÍCULO / DE REVISIÓN

Por: Elivette Zambrana-Flores, MD, FACR Reumatóloga Pediátrica Directora de la División Pediátrica de la Fundación Puertorriqueña de Enfermedades Reumáticas Board Certified en Reumatología Pediátrica y Pediatría Centro de Subespecialistas Pediátricos HIMA Caguas y Bayamón

VASCULITIS ASOCIADAS A ANTICUERPOS ANTI-CITOPLASMA DE NEUTRÓFILOS

40

PALABRAS CLAVES

KEY WORDS

Anticuerpos ANCA, autoinmunidad, granulomatosis con poliangiiis, poliangeitis microscópica, vasculitis de Wegener’s, vasculitis Churg-Strauss.

ANCA antibodies, autoimmunity, granulomatosis with polyangiitis, microscopic polyangiitis, Wegener’s vasculitis, ChurgStrauss vasculitis.

Revista Puertorriqueña de Medicina y Salud Pública

LAS VASCULITIS SE CARACTERIZAN POR LA INFLAMACIÓN DE LOS VASOS SANGUÍNEOS Y OBTIENEN SU CALIFICACIÓN EN DEPENDENCIA DE SU HISTOLOGÍA Y PREDILECCIÓN DE CALIBRE

RESUMEN Las vasculitis se caracterizan por la inflamación de los vasos sanguíneos. Existe un grupo de vasculitis asociadas a la presencia de anticuerpos que tienen como blanco el citoplasma de los neutrófilos, comúnmente conocido como ANCA (Anti-neutrophil cytoplasmic antibodies) por sus siglas en inglés. Un diagnóstico temprano es imprescindible para ayudar a mejorar el desenlace de estas vasculitis.

ABSTRACT Vasculitis is characterized by inflammation of the blood vessels. There is a group of vasculitis associated with the presence of antibodies that target the cytoplasm of neutrophils commonly known as ANCA (Anti-neutrophil cytoplasmic antibodies). An early diagnosis is essential to help improve the outcome of these vasculitis.

INTRODUCCIÓN Las vasculitis se caracterizan por la inflamación de los vasos sanguíneos.

Dependiendo de su histología y predilección de calibre obtienen su clasificación. Al igual que en adultos, los niños padecen de vasculitis. Debido a la rareza de estas condiciones en niños, mucha de la literatura médica de vasculitis juvenil es adaptada de la literatura de los pacientes adultos.

Hay un grupo de vasculitis asociadas a la presencia de anticuerpos que tienen como blanco el citoplasma de los neutrófilos comúnmente conocido como ANCA (Anti-neutrophil cytoplasmic antibodies) por sus siglas en inglés. Estos ANCA están dirigidos a enzimas contenidas en los gránulos de células polimorfonucleares. Estos se detectan por microscopía de inmunofluorescencia en varios patrones. Los más comunes son el patrón citoplásmico (cANCA) y el periferal (pANCA). El blanco de cANCA es la proteinasa-3 (PR-3) y el de pANCA es la mieloperoxidasa (MPO). Cuando hablamos de las vasculitis asociadas a ANCA, nos referimos a la granulomatosis con poliangeítis (granulomatosis with polyangiitis-GPA), antes conocida como granulomatosis de Wegener, poliangeítis microscópica (microscopic polyangiitis- MPA) y al síndrome de Churg-Strauss (Churg-Strauss Syndrome-CCS). Estas vasculitis tienen predilección por los vasos de calibre pequeño y mediano. Su afección es multisistémica y potencialmente conlleva una morbilidad/mortalidad alta.

Revista Puertorriqueña de Medicina y Salud Pública

41

MSP ARTÍCULO / DE REVISIÓN

LA POLIANGEITIS MICROSCÓPICA (MPA) ES UNA VASCULITIS NO GRANULOMATOSA, NECROTIZANTE, PAUCI-INMUNE QUE AFECTA PRIMORDIALMENTE LOS VASOS DE CALIBRE PEQUEÑO

Patrón citoplásmico (cANCA) y el periferal (pANCA). El blanco de cANCA es la proteinasa-3 (PR-3) y el de pANCA es la mieloperoxidasa (MPO).

Signos y síntomas La granulomatosis con poliangeitis (GPA) afecta primordialmente el tracto respiratorio alto y bajo, y los riñones. La edad promedio para el diagnóstico en los niños es de 14 años. Los niños diagnosticados con GPA, presentan síntomas constitucionales como fiebre, malestar general y pérdida de peso en el 90% de los casos. Un 80% presenta manifestaciones pulmonares como hemorragia, nódulos infiltrados, pleuresía y fallo respiratorio. El 80% tiene envolvimiento del tracto respiratorio alto y se manifiesta como úlceras nasales y orales, perforación del septo nasal -característica nariz de silla de caballo-, epistaxis, sinusitis, mastoiditis, pérdida de audición y estenosis subglótica. El 75% de los pacientes tiene envolvimiento renal. Es muy raro en niños no tener envolvimiento renal en algún momento. El 90% tiene un ANCA positivo de los cuales del 80 al

42

Revista Puertorriqueña de Medicina y Salud Pública

90% son c-ANCA con especificidad PR-3.

A diferencia de los adultos, en niños, es más común ver un envolvimiento multisistémico, envolvimiento renal y estenosis subglótica.

Su criterio de diagnóstico está enlistado en la Tabla 1.

La poliangeitis microscópica (MPA) es una vasculitis no granulomatosa, necrotizante, pauci-inmune que afecta primordialmente los vasos de calibre pequeño.

Se caracteriza por capilaritis y glomerulonefritis necrotizante. Casi todos los niños presentan síntomas constitucionales.

Una tercera parte presenta fallo renal y cerca de un 100% tiene enfermedad renal, que se manifiesta como hipertensión, hematuria o proteinuria. El envolvimiento pulmonar fluctúa entre 17-62% de los niños afectados. Rara vez se presenta sin envolvimiento renal. Insultos isquémicos del cerebro y lesiones necrotizantes en la piel se observan en un 30% de los pacientes. La MPA está asociada a pANCA con especificidad MPO. No hay criterios

de diagnóstico establecidos. Su diagnóstico es clínico con exclusión de otras etiologías.

El síndrome de Churg-Strauss (CSS) es una vasculitis granulomatosa con predilección de los vasos de calibre pequeño y mediano que afecta mayormente a niños con asma severa y alergias. No existe un criterio pediátrico para esta vasculitis, por lo que se utiliza el criterio de adultos del American College of Rheumatology (ACR). El CSS comienza gradualmente a través de los años. Las características más comunes en niños al ser diagnosticados son asma (91%), infiltrados pulmonares (85%), sinusitis (77%), envolvimiento de piel (66%), enfermedad cardíaca (55%), síntomas gastrointestinales (40%), neuropatía periferal (39%) y enfermedad renal (16%). La enfermedad renal es leve y rara vez progresa. El 25% de los niños tienen un ANCA positivo.

Tratamiento El régimen de tratamiento a seguir en las vasculitis asociadas a ANCA dependerá del tipo de vasculitis y del sistema afectado. Las estrategias de tratamiento han sido adaptadas de la literatura de la población adulta y de pocos casos pediátricos.

La terapia de inducción -por lo general- incluye corticoesteroides y ciclofosfamida oral o intravenosa. Sin embargo, este régimen se considera subóptimo por las toxicidades realacionadas como lo son: cistitis hemorrágica, infección seria, infertilidad y malignidad. Por esta razón, los estudios más recientes han examinado el rol de los medicamentos biológicos y plasmaféresis. Se puede utilizar una combinación de metotrexato y corticoesteroides para inducir remisión en casos leves. Para terapia de mantenimiento, típicamente, se utiliza mofetil micofeno-

Tabla 1.

El diagnóstico requiere 3 de los siguientes 6 criterios:

Tabla 2.

El diagnóstico requiere 4 de los siguientes 7 criterios:

1. Evidencia histopatológica de inflamación granulomatosa

1. Historial de asma

2. Envolvimiento del tracto respiratorio alto 3. Envolvimiento laríngeo-traqueo-bronquial

2. Historial de alergias (estacional, comida, contacto) 3. Eosinofilia periferal mayor de 10%

4. Envolvimiento pulmonar (radiografía o CT scan) 5. Presencia de ANCA

4. Mono o polineuropatia periferal 5. Infiltrados pulmonares migratorios

6. Envolvimiento renal (proteinuria, hematuria, cilindros urinarios de glóbulos rojos, glomerulonefritis pauci-innmune necrotizante)

6. Dolor u opacificación radiográfica de los senos paranasales 7. Biopsia demostrando eosinofilia extravascular

EULAR/PReS classification criteria for childhood-onset Granulomatosis with polyangiitis (GPA)

lato o azatioprina por un tiempo entre 18 a 24 meses. Para casos refractarios se pueden considerar otras opciones como lo son: infliximab (5 mg/kg dos veces al mes), rituximab (375 mg/m2/semana por 4 semanas) e inmunoglobulinas intravenosas (2g/kg/mes).

Conclusiones Diagnosticar una vasculitis en pediatría puede ser un gran reto, especialmente cuando los síntomas de inicio son poco específicos. Es importante mantener un alto índice de sospecha en aquellos niños con síntomas constitucionales y con factores de inflamación aguda elevados, aunque estos últimos pudiesen estar normales en etapas tempranas. Un diagnóstico temprano requiere un alto nivel

CR classification criteria for adult-onset Churg-Strauss syndrome (CSS)

de sospecha clínica. Este es imprescindible para ayudar a mejorar el desenlace de estas vasculitis.

REFERENCIAS: ANCA associated vasculitis Foundation. What is ANCA Associated Vasculitis (AAV). Recuperado de https://www. vasculitisfoundation.org/mcm_faq/ in-anca-associated-vasculitis-including-granulomatosis-with-polyangiitis-wegeners-gpa-and-microscopic-polyangiitis-mpa-do-increases-in-the-anca-tests-predict-disease-relapse/.

Lazarus B, John GT, O’Callaghan C & Ranganathan D. (2016) Recent advances in anti-neutrophil cytoplasmic antibody-associated

vasculitis. Indian Journal of Nephrology.

2016; 26(2):86–96. Recuperado de http:// www.ncbi.nlm.nih.gov/pmc/articles/ PMC4795442/.

Millet A, Pederzoli-Ribeil M, Guillevin L, Witko-Sarsat V & Mouthon L. (2013) Antineutrophil Cytoplasmic Antibody-Associated Vasculitides. Is It Time to Split up the Group? Ann Rheum Dis. 2013; 72(8):12731279. Recuperado de http://www.medscape.com/viewarticle/809119.

Santana ANC, Viktoria W, Radu HAS & Carmen BSV. (2011) Treatment of antineutrophil cytoplasmic antibody-associated vasculitis: update. J. bras. pneumol. December, 2011; 37(6):809816.Recuperado de http://www.scielo. br/scielo.php?script=sci_arttext&pid=S1806-37132011000600016&lng=en.

El régimen de tratamiento a seguir en las vasculitis asociadas a ANCA dependerá del tipo de vasculitis y del sistema afectado

Revista Puertorriqueña de Medicina y Salud Pública

43

DISCOVER DISCOVER OLUMIANT OLUMIANT INDICATION INDICATION Olumiant Olumiant is a is Janus a Janus kinase kinase (JAK) (JAK) inhibitor inhibitor indicated indicated forfor thethe treatment treatment ofof adult adult patients patientswith withmoderately moderatelyto toseverely severelyactive active rheumatoid rheumatoid arthritis arthritis (RA)(RA) whowho have have hadhad an an inadequate inadequate response response toto one one oror more more tumor tumornecrosis necrosisfactor factor(TNF) (TNF)antagonist antagonisttherapies. therapies.

Limitation Limitation of Use: of Use: UseUse of Olumiant of Olumiant in combination in combination with with other other JAK JAK inhibitors, inhibitors, biologic biologicdisease-modifying disease-modifyingantirheumatic antirheumaticdrugs drugs (DMARDs), (DMARDs), or with or with potent potent immunosuppressants, immunosuppressants, such such asas azathioprine azathioprine and and cyclosporine, cyclosporine,isisnot notrecommended. recommended.

IMPORTANT IMPORTANT SAFETY SAFETY INFORMATION INFORMATION FOR FOR OLUMIANT OLUMIANT (baricitinib) (baricitinib) tablets tablets WARNING: WARNING: SERIOUS SERIOUS INFECTIONS, INFECTIONS, MALIGNANCY, MALIGNANCY, AND AND THROMBOSIS THROMBOSIS SERIOUS SERIOUS INFECTIONS: INFECTIONS: Patients Patients treated treated with with Olumiant Olumiant areare at at risk risk forfor developing developingserious seriousinfections infectionsthat thatmay maylead leadto to hospitalization hospitalization or death. or death.

Most Most patients patients who who developed developed these these infections infections were were taking takingconcomitant concomitantimmunosuppressants immunosuppressants suchsuch as methotrexate as methotrexate or corticosteroids. or corticosteroids.

If aIfserious a serious infection infection develops, develops, interrupt interruptOlumiant Olumiantuntil untilthe theinfection infectionisis controlled. controlled.

Reported Reported infections infections include: include: • Active • Active tuberculosis tuberculosis (TB), (TB), which which may may present present with with pulmonary pulmonary oror extrapulmonary extrapulmonary disease. disease.Test Testpatients patientsfor forlatent latentTB TBbefore before initiating initiating Olumiant Olumiant andand during during therapy. therapy.

Treatment Treatment forfor latent latent infection infection should should bebe considered consideredprior priortotoOlumiant Olumiantuse. use.

• Invasive • Invasive fungal fungal infections, infections, including including candidiasis candidiasis and and pneumocystosis. pneumocystosis.

Patients Patientswith withinvasive invasivefungal fungalinfections infectionsmay may present present withwith disseminated, disseminated, rather rather than than localized, localized, disease. disease.

• Bacterial, • Bacterial, viral, viral, andand other other infections infections duedue to opportunistic to opportunistic pathogens. pathogens.

Carefully Carefully consider consider thethe risks risks andand benefits benefits of Olumiant of Olumiant prior prior to to initiating initiating therapy therapy inin patients patientswith withchronic chronicororrecurrent recurrentinfection. infection.

Closely Closely monitor monitor patients patients for for thethe development development of of signs signs and and symptoms symptoms ofof infection infectionduring duringand andafter aftertreatment treatmentwith with Olumiant Olumiant including including thethe possible possible development development of of TBTB in patients in patients who who tested tested negative negativefor forlatent latentTB TBinfection infectionprior priorto to initiating initiating therapy. therapy.

MALIGNANCIES: MALIGNANCIES: Lymphoma Lymphoma andand other other malignancies malignancies have have been been observed observed inin patients patientstreated treatedwith withOlumiant.

Olumiant.

THROMBOSIS: THROMBOSIS: Thrombosis, Thrombosis, including including deep deep venous venous thrombosis thrombosis (DVT) (DVT) and and pulmonary pulmonaryembolism embolism(PE), (PE),has hasbeen beenobserved observed at anatincreased an increased incidence incidence in patients in patients treated treated with with Olumiant Olumiant compared compared toto placebo. placebo.InInaddition, addition,there therewere werecases casesof of arterial arterial thrombosis. thrombosis.

Many Many of these of these adverse adverse events events were were serious serious and and some some resulted resultedinindeath. death.Patients Patientswith withsymptoms symptomsof of thrombosis thrombosis should should be promptly be promptly evaluated. evaluated.

Please Please seesee the the following following pages pages forfor additional additional Important Important Safety Safety Information Informationand andBrief BriefSummary SummaryofofPrescribing Prescribing Information, Information, including including Boxed Boxed Warning Warning about about Serious Serious Infections, Infections, Malignancies, Malignancies,and andThrombosis.

Thrombosis.

Visit olumiant.com/hcp Visit olumiant.com/hcptotolearn learnififOlumiant Olumiant is is appropriate appropriatefor foryour yourpatients patients

1-3 1-3 Olumiant ofof RARA in in TNFi-IR patients Olumiantreduced reducedsigns signsand andsymptoms symptoms TNFi-IR patients

Patients demonstrated higher ACR response rates vs placebo + cDMARDs Patientsreceiving receivingOlumiant Olumiant+ +cDMARDs cDMARDs demonstrated higher ACR response rates vs placebo + cDMARDs at atweeks weeks12 12and and24 24 ACR Response Rates ACR Response Rates

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PERCENTAGE PERCENTAGE OF OF PATIENTS PATIENTS (NRI) (NRI)

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Placebo + cDMARD Olumiant 2 mg + cDMARD cDMARD Olumiant 2 mg + cDMARD PatientsPlacebo who+were were rescued discontinued treatments were considered non-responders in the analysis.

Patients who rescued oror discontinued treatments were considered non-responders in the analysis. n=176 n=176

n=174 n=174

StudyIV IV(BEACON) (BEACON)was wasa a24-week, 24-week, randomized, double-blind trial in 527 patients with moderately to severely active Study randomized, double-blind trial in 527 patients with moderately to severely active RA RA whohad hadan aninadequate inadequateresponse response intolerance least 1 TNF inhibitor.

Patients received Olumiant 2 (n=174) mg (n=174) who oror intolerance toto atat least 1 TNF inhibitor.

Patients received Olumiant 2 mg or or baricitinib44mg mg(n=177) (n=177)once-daily once-daily placebo (n=176), added background cDMARD treatment. primary endpoint baricitinib oror placebo (n=176), added to to background cDMARD treatment.

TheThe primary endpoint wasthe theproportion proportionofofpatients patientsachieving achieving ACR20 response week was ACR20 response at at week 12.12.

Baricitinib44mg mgisisnot notanan approved dose.

Baricitinib approved dose.

††

TNFi-IR=tumornecrosis necrosis factor-inadequate response; cDMARDs=conventional disease-modifying antirheumatic drugs; NRI=non-responder imputation; TNFi-IR=tumor factor-inadequate response; cDMARDs=conventional disease-modifying antirheumatic drugs; NRI=non-responder imputation; ACR20/50/70=American College Rheumatology 20%/50%/70% improvement criteria.

ACR20/50/70=American College ofof Rheumatology 20%/50%/70% improvement criteria.

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TheThe support representative keep checking representative willwill keep checking in with your patients’ insurance in with your patients’ insurance provider to determine if coverage provider to determine if coverage ‡§ ‡§ changed. hashas changed.

This Thisoffer offerisisinvalid invalidfor for patients patients whose whose prescription prescription claims claims areare eligible eligible to be to reimbursed, be reimbursed, in whole in whole or inor part, in part, by any by governmental any governmental program. program.

EligibilityCriteria: Criteria:ByByusing using the Olumiant Savings Card (“Card”), attest meet eligibility criteria andcomply will comply the Terms Eligibility the Olumiant Savings Card (“Card”), youyou attest thatthat youyou meet the the eligibility criteria and will with with the Terms and and Conditionsdescribed describedbelow: below: Conditions §§ Terms Termsand andConditions: Conditions:Offer Offer good good until until 12/31/2020.

12/31/2020. $5$5 monthly monthly offer offer subject subject to wholesale to wholesale acquisition acquisition costcost plusplus usualusual and customary and customary pharmacy pharmacy charges charges and andaaseparate separatemaximum maximum annual annual cap cap ofof $12,000. $12,000. $25 $25 monthly monthly offer offer subject subject to monthly to monthly andand annual annual cap cap of wholesale of wholesale acquisition acquisition cost cost plus usual plus usual and and customary customarypharmacy pharmacycharges. charges.

This This offer offer is is invalid invalid forfor patients patients without without commercial commercial insurance insurance coverage coverage or those or those whose whose prescription prescription claims claims are eligible are eligible to tobe bereimbursed, reimbursed,ininwhole whole oror inin part, part, byby Medicare Medicare Part Part D, D, Medicaid, Medicaid, TRICARE TRICARE or any or any other other state state or federal or federal program. program.

OfferOffer void void where where prohibited prohibited by by law lawand andsubject subjecttotochange change oror discontinue discontinue without without notice. notice.

Card Card activation activation is required. is required.

Subject Subject to additional to additional terms terms and conditions, and conditions, whichwhich can be can found be found at at olumiant.com. olumiant.com. ‡‡

INFORMATION FOR OLUMIANT OLUMIANT tablets tablets (cont’d) (cont’d) IMPORTANT IMPORTANT SAFETY SAFETY INFORMATION INFORMATION FOR FOR OLUMIANT OLUMIANT tablets tablets (cont’d) (cont’d) WARNINGS WARNINGS AND AND PRECAUTIONS PRECAUTIONS SERIOUS SERIOUS INFECTIONS: INFECTIONS: TheThe most most common common serious serious infections infections reported reported withwith Olumiant Olumiant included included pneumonia, pneumonia, herpes herpes zoster, zoster, andand urinary urinary tract tract infection. infection.

Among Among opportunistic opportunistic infections, infections, tuberculosis, tuberculosis, multidermatomal multidermatomal herpes herpes zoster, zoster, esophageal esophageal candidiasis, pneumocystosis, acute histoplasmosis, candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cryptococcosis, cytomegalovirus, cytomegalovirus, andand BKBK virus virus were were reported reported withwith Olumiant.

Olumiant.

Some Some patients patients have have presented presented with with disseminated disseminated rather rather than than local local disease, disease, andand were were often often taking taking concomitant concomitant immunosuppressants immunosuppressants such such as as methotrexate methotrexate or corticosteroids. or corticosteroids.

Avoid Avoid Olumiant Olumiant in patients in patients with with anan active, active, serious serious infection, infection, including including localized localized infections. infections.

Consider Consider the the risks risks andand benefits benefits of treatment of treatment prior prior to initiating to initiating Olumiant Olumiant in patients: in patients: • with • with chronic chronic or recurrent or recurrent infection infection • who • who have have been been exposed exposed to TB to TB • with • with a history a history of aof serious a serious or an or opportunistic an opportunistic infection infection • who • who have have resided resided or traveled or traveled in areas in areas of endemic of endemic tuberculosis tuberculosis or endemic or endemic mycoses; mycoses; or or • with • with underlying underlying conditions conditions that that may may predispose predispose them them to infection. to infection.

Closely Closely monitor monitor patients patients forfor infections infections during during and and after after Olumiant Olumiant treatment. treatment.

Interrupt Interrupt Olumiant Olumiant if aifpatient a patient develops develops aa serious serious infection, infection, an opportunistic an opportunistic infection, infection, or or sepsis. sepsis.

DoDo not not resume resume Olumiant Olumiant until until thethe infection infection is controlled. is controlled.

The The impact impact ofofOlumiant Olumianton onchronic chronicviral viralhepatitis hepatitisreactivation reactivation is is unknown.

Screen unknown.

Screenfor forviral viralhepatitis hepatitisininaccordance accordancewith withclinical clinical guidelines guidelines before beforeinitiating initiatingOlumiant.

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MALIGNANCY MALIGNANCYAND ANDLYMPHOPROLIFERATIVE LYMPHOPROLIFERATIVEDISORDERS: DISORDERS: Malignancies Malignancieswere wereobserved observedininOlumiant Olumiantclinical clinicalstudies. studies.

Consider Consider the therisks risksand andbenefits benefitsofofOlumiant Olumiantprior priorto toinitiating initiating therapy therapy inin patients patientswith withaaknown knownmalignancy malignancyother otherthan thanaa successfully successfullytreated treatednon-melanoma non-melanomaskin skincancer cancer(NMSC) (NMSC)or or when when considering consideringcontinuing continuingOlumiant Olumiantininpatients patientswho whodevelop develop a malignancy. a malignancy.NMSCs NMSCswere werereported reportedininpatients patientstreated treatedwith with Olumiant.

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Periodic Periodicskin skinexamination examinationisisrecommended recommendedfor for patients patients who whoare areatatincreased increasedrisk riskfor forskin skincancer. cancer.

THROMBOSIS: THROMBOSIS:Thrombosis, Thrombosis,including includingDVT DVTand andPE, PE,has hasbeen been observed observed atatananincreased increasedincidence incidenceininOlumiant-treated Olumiant-treated patients patients compared comparedtotoplacebo. placebo.InInaddition, addition,arterial arterialthrombosis thrombosis events events inin the theextremities extremitieshave havebeen beenreported reportedininclinical clinicalstudies studies with with Olumiant.

Olumiant.Many Manyofofthese theseadverse adverseevents eventswere wereserious seriousand and some some resulted resultedinindeath. death.There Therewas wasno noclear clearrelationship relationshipbetween between platelet platelet count countelevations elevationsand andthrombotic thromboticevents. events.Use UseOlumiant Olumiant with with caution cautionininpatients patientswho whomay maybe beatatincreased increasedrisk riskof of thrombosis. thrombosis.

IfIfclinical clinicalfeatures featuresofofDVT/PE DVT/PEor orarterial arterialthrombosis thrombosis occur, occur, evaluate evaluatepatients patientspromptly promptlyand andtreat treatappropriately. appropriately.

GASTROINTESTINAL GASTROINTESTINALPERFORATIONS: PERFORATIONS:Gastrointestinal Gastrointestinal perforations perforationshave havebeen beenreported reportedininOlumiant Olumiantclinical clinicalstudies, studies, although although the therole roleofofJAK JAKinhibition inhibition ininin these these events events not known. inhibition events isisnot not known. inhibition these eventsisis notknown. known.

Tuberculosis Tuberculosis – Before – Before initiating initiating Olumiant Olumiant evaluate evaluate and and test test Use Use Olumiant Olumiant with with caution caution in in patients patients who who may may be be at at increased increased patients patients for latent for latent or active or active infection infection andand treat treat patients patients with with risk risk for for gastrointestinal gastrointestinalperforation perforation(e.g., (e.g.,patients patientswith withaahistory history latent latent TB with TB with standard standard antimycobacterial antimycobacterial therapy. therapy.

Olumiant Olumiant of of diverticulitis). diverticulitis).

Promptly Promptly evaluate evaluate patients patients who who present present with with should should not not be given be given to patients to patients with with active active TB.TB. Consider Consider anti-TB anti-TB new new onset onset abdominal abdominal symptoms symptoms for for early early identification identification of of therapy therapy prior prior to initiating to initiating Olumiant Olumiant in patients in patients with with a history a history ofof gastrointestinal gastrointestinalperforation. perforation. latent latent or active or active TB in TBwhom in whom an adequate an adequate course course of of treatment treatment cannot cannot be confirmed, be confirmed, andand forfor patients patients with with a negative a negative test test forfor LABORATORY LABORATORYABNORMALITIES: ABNORMALITIES: latent latent TB but TB but whowho have have riskrisk factors factors forfor TBTB infection. infection.

Monitor Monitor patients patients for TB for during TB during Olumiant Olumiant treatment. treatment.

Neutropenia Neutropenia– –Olumiant Olumianttreatment treatmentwas wasassociated associatedwith with an an increased increased incidence incidence of of neutropenia neutropenia (absolute (absolute neutrophil neutrophil Viral Viral Reactivation Reactivation – Viral – Viral reactivation, reactivation, including including cases cases ofof count count [ANC] [ANC]<1000 <1000cells/mm cells/mm33)33)compared comparedto toplacebo. placebo.Avoid Avoid herpes herpes virus virus reactivation reactivation (e.g., (e.g., herpes herpes zoster), zoster), were were reported reported initiation or interrupt Olumiant treatment in patients with initiation or interrupt Olumiant treatment in patients with in clinical in clinical studies studies withwith Olumiant.

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If aIfpatient a patient develops develops herpes herpes 33 33 an ANC <1000 cells/mm an ANC <1000 cells/mm .

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Evaluate at at baseline baseline and and thereafter thereafter zoster, zoster, interrupt interrupt Olumiant Olumiant treatment treatment until until thethe episode episode resolves. resolves. according according totoroutine routinepatient patientmanagement. management.

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Lymphopenia––Absolute Lymphopenia Absolutelymphocyte lymphocyte count count (ALC) (ALC) <500 <500 cells/mm33were werereported reportedininOlumiant Olumiant clinical trials. cells/mm clinical trials.

Lymphocytecounts countsless lessthan thanthe thelower lower limit normal limit ofof normal Lymphocyte wereassociated associatedwith withinfection infectionininpatients patients treated with treated with were Olumiant,but butnot notplacebo. placebo.Avoid Avoidinitiation initiation interrupt oror interrupt Olumiant, Olumianttreatment treatmentininpatients patientswith with ALC <500 cells/ anan ALC <500 cells/ Olumiant mm33. .Evaluate Evaluateatatbaseline baselineand andthereafter thereafter according according toto mm routinepatient patientmanagement. management. routine Anemia––Decreases Decreasesininhemoglobin hemoglobin levels levels toto <8<8 g/dL g/dL Anemia werereported reportedininOlumiant Olumiantclinical clinicaltrials. trials.

Avoid Avoid were initiationor orinterrupt interruptOlumiant Olumianttreatment treatment inin patients patients initiation withhemoglobin hemoglobin<8 <8g/dL. g/dL.Evaluate Evaluateatat baseline baseline and and with thereafteraccording accordingtotoroutine routinepatient patient management. management. thereafter LiverEnzyme EnzymeElevations Elevations– –Olumiant Olumiant treatment treatment was was Liver associatedwith withincreased increasedincidence incidence ofof liver liver enzyme enzyme associated elevationcompared comparedtotoplacebo. placebo.Increases Increases toto ≥5x ≥5x and and elevation ≥10xupper upperlimit limitofofnormal normalwere wereobserved observed forfor both both ≥10x ALTand andAST ASTininpatients patientsininOlumiant Olumiant clinical clinical trials. trials.

ALT Evaluateatatbaseline baselineand andthereafter thereafter according according toto routine routine Evaluate patientmanagement. management.Promptly Promptlyinvestigate investigate the the cause cause patient ofliver liverenzyme enzymeelevation elevationtotoidentify identify potential potential cases cases ofof of drug-inducedliver liverinjury. injury.IfIfincreases increases inin ALT ALT oror AST AST are are drug-induced observedand anddrug-induced drug-inducedliver liverinjury injury isis suspected, suspected, observed interruptOlumiant Olumiantuntil untilthis thisdiagnosis diagnosis isis excluded. excluded. interrupt

current current immunization immunization guidelines guidelines prior prior to initiating to initiating Olumiant Olumiant therapy. therapy.

ADVERSE ADVERSE REACTIONS REACTIONS Adverse Adverse reactions reactions (≥1%) (≥1%) include: include: upper upper respiratory respiratory tract tract infections infections (16.3%, (16.3%, 14.7%, 14.7%, 11.7%), 11.7%), nausea nausea (2.7%, (2.7%, 2.8%, 2.8%, 1.6%), 1.6%), herpes herpes simplex simplex (0.8%, (0.8%, 1.8%, 1.8%, 0.7%), 0.7%), and and herpes herpes zoster zoster (1.0%, (1.0%, 1.4%, 1.4%, 0.4%) 0.4%) for for Olumiant Olumiant 2 mg, 2 mg, baricitinib baricitinib 4 mg, 4 mg, andand placebo, placebo, respectively. respectively.

USE USE IN IN SPECIFIC SPECIFIC POPULATIONS POPULATIONS PREGNANCY PREGNANCY AND AND LACTATION: LACTATION: No No information information is is available available to to support support thethe useuse of Olumiant of Olumiant in pregnancy in pregnancy or or lactation. lactation.

Advise Advise women women notnot to breastfeed to breastfeed during during treatment treatment with with Olumiant.

Olumiant.

HEPATIC HEPATIC AND AND RENAL RENAL IMPAIRMENT: IMPAIRMENT: Olumiant Olumiant is is notnot recommended recommended in patients in patients with with severe severe hepatic hepatic impairment impairment or in orpatients in patients with with moderate moderate or severe or severe renal renal impairment. impairment.

Please Please seesee thethe following following pages pages for for Brief Brief Summary Summary of of Prescribing Prescribing Information, Information, including including Boxed Boxed Warning Warning about about Serious Serious Infections, Infections, Malignancies, Malignancies, andand Thrombosis.

Thrombosis.

LipidElevations Elevations––Treatment Treatmentwith withOlumiant Olumiant was was Lipid BABA HCP HCP ISI ISI 01JUN2018 01JUN2018 associatedwith withincreases increasesininlipid lipidparameters, parameters, including including associated totalcholesterol, cholesterol,low-density low-densitylipoprotein lipoprotein cholesterol, cholesterol, total andhigh-density high-densitylipoprotein lipoproteincholesterol. cholesterol.

Assess Assess and lipidparameters parametersapproximately approximately12 12weeks weeks following following lipid Olumiantinitiation. initiation.Manage Managepatients patients according according toto clinical clinical Olumiant guidelines guidelinesfor forthe themanagement managementofofhyperlipidemia. hyperlipidemia.

VACCINATIONS:Avoid Avoiduse useofoflive livevaccines vaccines with with VACCINATIONS: Olumiant.Update Updateimmunizations immunizationsininagreement agreement with with Olumiant.

References: References:1.1.Olumiant Olumiant[package [package insert]. insert].

Indianapolis, Indianapolis, IN:IN: EliEli Lilly Lilly andand Company; Company; 2018.

2018.

2. Genovese 2. Genovese MC,MC, Kremer Kremer J, Zamani J, Zamani O, etO, al.et al.

Baricitinib Baricitinibininpatients patientswith withrefractory refractory rheumatoid rheumatoid arthritis. arthritis.

N Engl N Engl J Med. J Med. 2016;374:1243-1252.

2016;374:1243-1252.

3. Genovese 3. Genovese MC,MC, Kremer Kremer J, J, Zamani ZamaniO,O,etetal.al.Baricitinib Baricitinibininpatients patients with with refractory refractory rheumatoid rheumatoid arthritis. arthritis.

N Engl N Engl J Med. J Med. 2016; 2016; 374(suppl):1-30.

374(suppl):1-30.

Olumiant®isisa aregistered registeredtrademark trademark owned licensed Lilly Company, its subsidiaries or affiliates.

Olumiant® owned oror licensed byby EliEli Lilly andand Company, its subsidiaries or affiliates.

PP-BA-US-0627 11/2018©Lilly PP-BA-US-0627 11/2018 PP-BA-US-052409/2018 09/2018 ©Lilly USA, LLC 2018. rights reserved.

PP-BA-US-0524 USA, LLC 2018.

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OLUMIANT® (baricitinib) TABLETS BRIEF SUMMARY OF PRESCRIBING INFORMATION Consult the package insert for complete prescribing information.

Vaccinations—Avoid use of live vaccines with Olumiant. Update immunizations in agreement with current immunization guidelines prior to initiating Olumiant therapy.

ADVERSE REACTIONS

WARNING: SERIOUS INFECTIONS, MALIGNANCY, AND THROMBOSIS SERIOUS INFECTIONS: Patients treated with Olumiant are at risk for developing serious infections that may lead to hospitalization or death.

Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt Olumiant until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before initiating Olumiant and during therapy. Treatment for latent infection should be considered prior to Olumiant use.

• Invasive fungal infections, including candidiasis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with Olumiant should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Olumiant including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES: Lymphoma and other malignancies have been observed in patients treated with Olumiant.

THROMBOSIS: Thrombosis, including deep venous thrombosis and pulmonary embolism, has been observed at an increased incidence in patients treated with Olumiant compared to placebo. In addition, there were cases of arterial thrombosis. Many of these adverse events were serious and some resulted in death. Patients with symptoms of thrombosis should be promptly evaluated.

INDICATIONS AND USAGE Olumiant® (baricitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies.

Limitation of use: Use of Olumiant in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

WARNINGS AND PRECAUTIONS Serious Infections—Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving Olumiant. The most common serious infections reported with Olumiant included pneumonia, herpes zoster, and urinary tract infection. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, and cytomegalovirus, and BK virus were reported with Olumiant. Some patients have presented with disseminated rather than local disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Avoid use of Olumiant in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating Olumiant in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Olumiant.

Interrupt Olumiant if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Olumiant should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and Olumiant should be interrupted if the patient is not responding to therapy. Do not resume Olumiant until the infection is controlled.

Tuberculosis—Evaluate and test patients for latent or active infection prior to administration of Olumiant. Patients with latent tuberculosis (TB) should be treated with standard antimycobacterial therapy before initiating Olumiant.

Olumiant should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of Olumiant in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

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, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies with Olumiant. If a patient develops herpes zoster, interrupt Olumiant treatment until the episode resolves.

The impact of Olumiant on chronic viral hepatitis reactivation is unknown. Patients with evidence of active hepatitis B or C infection were excluded from clinical trials. Patients who were positive for hepatitis C antibody but negative for hepatitis C virus RNA were permitted to enroll. Patients with positive hepatitis B surface antibody and hepatitis B core antibody, without hepatitis B surface antigen, were permitted to enroll; such patients should be monitored for expression of hepatitis B virus (HBV) DNA. Should HBV DNA be detected, consult with a hepatologist. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with Olumiant.

Malignancy and Lymphoproliferative Disorders—Consider the risks and benefits of Olumiant treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing Olumiant in patients who develop a malignancy. Malignancies were observed in clinical studies of Olumiant.

Non-melanoma skin cancers—Non-melanoma skin cancers (NMSCs) have been reported in patients treated with Olumiant. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Thrombosis—Thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), has been observed at an increased incidence in patients treated with Olumiant compared to placebo. In addition, arterial thrombosis events in the extremities have been reported in clinical studies with Olumiant. Many of these adverse events were serious and some resulted in death. There was no clear relationship between platelet count elevations and thrombotic events. Olumiant should be used with caution in patients who may be at increased risk of thrombosis. If clinical features of DVT/PE or arterial thrombosis occur, patients should be evaluated promptly and treated appropriately.

Gastrointestinal Perforations—Events of gastrointestinal perforation have been reported in clinical studies with Olumiant, although the role of JAK inhibition in these events is not known.

Olumiant should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Laboratory Abnormalities Neutropenia—Treatment with Olumiant was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] less than 1000 cells/mm3) compared to placebo. Avoid initiation or interrupt Olumiant treatment in patients with an ANC less than 1000 cells/mm3. Evaluate at baseline and thereafter according to routine patient management.

Lymphopenia—Absolute lymphocyte count (ALC) less than 500 cells/mm3 were reported in Olumiant clinical trials. Lymphocyte counts less than the lower limit of normal were associated with infection in patients treated with Olumiant, but not placebo.

Avoid initiation or interrupt Olumiant treatment in patients with an ALC less than 500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management.

Anemia—Decreases in hemoglobin levels to less than 8 g/dL were reported in Olumiant clinical trials. Avoid initiation or interrupt Olumiant treatment in patients with hemoglobin less than 8 g/dL. Evaluate at baseline and thereafter according to routine patient management.

Liver Enzyme Elevations—Treatment with Olumiant was associated with increased incidence of liver enzyme elevation compared to placebo. Increases to greater than or equal to 5x and greater than or equal to 10x upper limit of normal (ULN) were observed for both ALT and AST in patients in Olumiant clinical trials.

Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and druginduced liver injury is suspected, interrupt Olumiant until this diagnosis is excluded.

Lipid Elevations—Treatment with Olumiant was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Assessment of lipid parameters should be performed approximately 12 weeks following Olumiant initiation.

Manage patients according to clinical guidelines for the management of hyperlipidemia.

OLUMIANT® (baricitinib)

BA HCP BS 01JUN2018

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 predict the rates observed in a broader patient population in clinical practice.

The following data include six randomized, double-blind, placebo-controlled studies (three Phase 2, three Phase 3) and a long-term extension study. All patients had moderately to severely active RA. Patients were randomized to placebo (1070 patients), Olumiant 2 mg (479 patients), or baricitinib 4 mg (997 patients).

Patients could be switched to baricitinib 4 mg from placebo or Olumiant 2 mg from as early as Week 12 depending on the study design. All patients initially randomized to placebo were switched to baricitinib 4 mg by Week 24.

During the 16-week treatment period, adverse events leading to discontinuation of treatment were reported by 35 patients (11.4 events per 100 patient-years) treated with placebo, 17 patients (12.1 events per 100 patient-years) with Olumiant 2 mg, and 40 patients (13.4 events per 100 patient-years) treated with baricitinib 4 mg.

During 0 to 52 week exposure, adverse events leading to discontinuation of treatment were reported by 31 patients (9.2 events per 100 patient-years) with Olumiant 2 mg, and 92 patients (10.2 events per 100 patient-years) treated with baricitinib 4 mg.

Overall Infections—During the 16-week treatment period, infections were reported by 253 patients (82.1 events per 100 patient-years) treated with placebo, 139 patients (99.1 events per 100 patient-years) treated with Olumiant 2 mg, and 298 patients (100.1 events per 100 patient-years) treated with baricitinib 4 mg.

During 0 to 52 week exposure, infections were reported by 200 patients (59.6 events per 100 patients-years) treated with Olumiant 2 mg, and 500 patients (55.3 events per 100 patient-years) treated with baricitinib 4 mg.

In the 0 to 52 week exposure population, the most commonly reported infections with Olumiant were viral upper respiratory tract infection, upper respiratory tract infection, urinary tract infection, and bronchitis.

Serious Infections—During the 16-week treatment period, serious infections were reported in 13 patients (4.2 events per 100 patientyears) treated with placebo, 5 patients (3.6 events per 100 patient-years) treated with Olumiant 2 mg, and 11 patients (3.7 events per 100 patient-years) treated with baricitinib 4 mg.

During 0 to 52 week exposure, serious infections were reported in 14 patients (4.2 events per 100 patient-years) treated with Olumiant 2 mg and 32 patients (3.5 events per 100 patient-years) treated with baricitinib 4 mg.

In the 0 to 52 week exposure population, the most commonly reported serious infections with Olumiant were pneumonia, herpes zoster, and urinary tract infection.

Tuberculosis—During the 16-week treatment period, no events of tuberculosis were reported.

During 0 to 52 week exposure, events of tuberculosis were reported in 0 patients treated with Olumiant 2 mg and 1 patient (0.1 per 100 patient-years) treated with baricitinib 4 mg.

Cases of disseminated tuberculosis were also reported.

Opportunistic Infections (excluding tuberculosis)—During the 16-week treatment period, opportunistic infections were reported in 2 patients (0.6 per 100 patient-years) treated with placebo, 0 patients treated with Olumiant 2 mg and 2 patients (0.7 per 100 patientyears) treated with baricitinib 4 mg.

During 0 to 52 week exposure, opportunistic infections were reported in 1 patient (0.3 per 100 patient-years) treated with Olumiant 2 mg and 5 patients (0.6 per 100 patient-years) treated with baricitinib 4 mg.

Malignancy—During the 16-week treatment period, malignancies excluding non-melanoma skin cancers (NMSC) were reported in 0 patients treated with placebo, 1 patient (0.7 per 100 patient-years) treated with Olumiant 2 mg, and 1 patient (0.3 per 100 patientyears) treated with baricitinib 4 mg.

During the 0 to 52 week treatment period, malignancies excluding NMSC were reported in 2 patients (0.6 per 100 patient-years) treated with Olumiant 2 mg and 6 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg.

Venous Thrombosis—During the 16-week treatment period, venous thromboses (deep vein thrombosis or pulmonary embolism) were reported in 0 patients treated with placebo, 0 patients treated with Olumiant 2 mg, and 5 patients (1.7 per 100 patient-years) treated with baricitinib 4 mg.

During the 0 to 52 week treatment period, venous thromboses were reported in 2 patients (0.6 per 100 patient-years) treated with Olumiant 2 mg and 7 patients (0.8 per 100 patient-years) treated with baricitinib 4 mg.

Arterial Thrombosis—During the 16-week treatment period, arterial thromboses were reported in 1 patient treated with placebo (0.3 per 100 patient-years), 2 patients (1.4 per 100 patient-years) treated with Olumiant 2 mg, and 2 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg.

During the 0 to 52 week treatment period, arterial thromboses were reported in 3 patients (0.9 per 100 patient-years) treated with Olumiant 2 mg and 3 patients (0.3 per 100 patient-years) treated with baricitinib 4 mg.

Laboratory Abnormalities Neutropenia—During the 16-week treatment period, neutrophil counts below 1000 cells/mm3 occurred in 0% of patients treated with placebo, 0.6% of patients treated with Olumiant 2 mg, and 0.3% of patients treated with baricitinib 4 mg. There were no neutrophil counts below 500 cells/mm3 observed in any treatment group.

Platelet Elevations—During the 16-week treatment period, increases in platelet counts above 600,000 cells/mm3 occurred in 1.1% of patients treated with placebo, 1.1% of patients treated with Olumiant 2 mg, and 2.0% of patients treated with baricitinib 4 mg. Mean platelet count increased by 3000 cells/mm3 at 16 weeks in patients treated with placebo, by 15,000 cells/mm3 at 16 weeks in patients treated with Olumiant 2 mg and by 23,000 cells/mm3 in patients treated with baricitinib 4 mg.

Liver Enzyme Elevations—Events of increases in liver enzymes greater than or equal to 3x ULN were observed in patients treated with Olumiant.

• During the 16-week treatment period, ALT elevations greater than or equal to 3x ULN occurred in 1.0% of patients treated with placebo, 1.7% of patients treated with Olumiant 2 mg, and 1.4% of patients treated with baricitinib 4 mg.

• During the 16-week treatment period, AST elevations greater than or equal to 3x ULN occurred in 0.8% of patients treated with placebo, 1.3% of patients treated with Olumiant 2 mg, and 0.8% of patients treated with baricitinib 4 mg.

• In a phase 3 study of DMARD naive patients, during the 24-week treatment period, ALT and AST elevations ≥3x ULN occurred in 1.9% and 0% of patients treated with methotrexate monotherapy, 1.9% and 1.3% of patients treated with baricitinib 4 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib 4 mg plus methotrexate.

Lipid Elevations—In controlled clinical trials, Olumiant treatment was associated with dose-related increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. Elevations were observed at 12 weeks and remained stable thereafter. During the 12-week treatment period, changes in lipid parameters are summarized below: • Mean LDL cholesterol increased by 8 mg/dL in patients treated with Olumiant 2 mg and by 14 mg/dL in patients treated with baricitinib 4 mg.

• Mean HDL cholesterol increased by 7 mg/dL in patients treated with Olumiant 2 mg and by 9 mg/dL in patients treated with baricitinib 4 mg.

• The mean LDL/HDL ratio remained stable.

• Mean triglycerides increased by 7 mg/dL in patients treated with Olumiant 2 mg and by 15 mg/dL in patients treated with baricitinib 4mg.

Creatine Phosphokinase (CPK)—Olumiant treatment was associated with increases in CPK within one week of starting Olumiant and plateauing after 8 to 12 weeks. At 16 weeks, the mean change in CPK for Olumiant 2 mg and baricitinib 4 mg was 37 IU/L and 52 IU/L, respectively.

Creatinine—In controlled clinical trials, dose-related increases in serum creatinine were observed with Olumiant treatment. At 52 weeks, the mean increase in serum creatinine was less than 0.1 mg/dL with baricitinib 4 mg. The clinical significance of the observed serum creatinine increases is unknown.

Other Adverse Reactions—Other adverse reactions are summarized in the following table.

DR

Str (OA as

Oth bio

US

Pre

Ris ma at e res No 5 a bar stil pos we

pre bac

Da Ani to 1 gre tox

day of m Em No ora

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Add

Adverse Reactions occurring in greater than or equal to 1% of Olumiant 2 mg and baricitinib 4 mg Treated Patients in Placebo-Controlled Trials

Events Upper respiratory tract infectionsa Nausea Herpes simplexb Herpes zoster a

b

Placebo n=1070 (%) 11.7 1.6 0.7 0.4

Weeks 0-16 Olumiant 2 mg n=479 (%) 16.3 2.7 0.8 1.0

Baricitinib 4 mg n=997 (%) 14.7 2.8 1.8 1.4

Includes acute sinusitis, acute tonsillitis, chronic tonsillitis, epiglottitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinobronchitis, sinusitis, tonsillitis, tracheitis, and upper respiratory tract infection.

Includes eczema herpeticum, genital herpes, herpes simplex, ophthalmic herpes simplex, and oral herpes.

Additional adverse drug reactions occurring in fewer than 1% of patients: acne.

OLUMIANT® (baricitinib)

BA BA HCP BS 01JUN2018

OL

zations in agreement with current immunization guidelines prior

er widely varying conditions, adverse reaction rates observed e clinical studies of another drug and may not predict the rates

ontrolled studies (three Phase 2, three Phase 3) and a long-term s were randomized to placebo (1070 patients), Olumiant 2 mg

miant 2 mg from as early as Week 12 depending on the study itinib 4 mg by Week 24. scontinuation of treatment were reported by 35 patients 1 events per 100 patient-years) with Olumiant 2 mg, and mg. uation of treatment were reported by 31 patients (9.2 events per 100 patient-years) treated with baricitinib 4 mg. e reported by 253 patients (82.1 events per 100 patient-years) ated with Olumiant 2 mg, and 298 patients (100.1 events per

tients (59.6 events per 100 patients-years) treated with ted with baricitinib 4 mg. rted infections with Olumiant were viral upper respiratory tract nchitis. ons were reported in 13 patients (4.2 events per 100 patienttreated with Olumiant 2 mg, and 11 patients (3.7 events per

14 patients (4.2 events per 100 patient-years) treated with with baricitinib 4 mg. rted serious infections with Olumiant were pneumonia, herpes

ulosis were reported. d in 0 patients treated with Olumiant 2 mg and 1 patient

eatment period, opportunistic infections were reported in ated with Olumiant 2 mg and 2 patients (0.7 per 100 patient-

ed in 1 patient (0.3 per 100 patient-years) treated with ricitinib 4 mg. ng non-melanoma skin cancers (NMSC) were reported in ted with Olumiant 2 mg, and 1 patient (0.3 per 100 patient-

NMSC were reported in 2 patients (0.6 per 100 patient-years) ated with baricitinib 4 mg. mboses (deep vein thrombosis or pulmonary embolism) were ant 2 mg, and 5 patients (1.7 per 100 patient-years) treated with

e reported in 2 patients (0.6 per 100 patient-years) treated with ricitinib 4 mg. mboses were reported in 1 patient treated with placebo (0.3 per umiant 2 mg, and 2 patients (0.7 per 100 patient-years) treated

e reported in 3 patients (0.9 per 100 patient-years) treated with ricitinib 4 mg.

elow 1000 cells/mm3 occurred in 0% of patients treated with nts treated with baricitinib 4 mg. There were no neutrophil counts

latelet counts above 600,000 cells/mm3 occurred in 1.1% of g, and 2.0% of patients treated with baricitinib 4 mg. Mean ed with placebo, by 15,000 cells/mm3 at 16 weeks in patients with baricitinib 4 mg. an or equal to 3x ULN were observed in patients treated

r equal to 3x ULN occurred in 1.0% of patients treated with patients treated with baricitinib 4 mg. or equal to 3x ULN occurred in 0.8% of patients treated with patients treated with baricitinib 4 mg. eatment period, ALT and AST elevations ≥3x ULN occurred , 1.9% and 1.3% of patients treated with baricitinib 4 mg b 4 mg plus methotrexate. ociated with dose-related increases in lipid parameters erol. Elevations were observed at 12 weeks and remained stable ters are summarized below: h Olumiant 2 mg and by 14 mg/dL in patients treated with

DRUG INTERACTIONS Strong OAT3 Inhibitors—Baricitinib exposure is increased when Olumiant is co-administered with strong Organic Anion Transporter 3 (OAT3) inhibitors (such as probenecid). Olumiant is not recommended for use in patients taking strong OAT3 inhibitors, such as probenecid.

Other JAK Inhibitors or Biologic DMARDs—Olumiant has not been studied in combination with other JAK inhibitors or with biologic DMARDs. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary—The limited human data on use of Olumiant in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage. In animal embryo-fetal development studies, oral baricitinib administration to pregnant rats and rabbits at exposures equal to and greater than approximately 20 and 84 times the maximum recommended human dose (MRHD), respectively, resulted in reduced fetal body weights, increased embryolethality (rabbits only), and dose-related increases in skeletal malformations.

No developmental toxicity was observed in pregnant rats and rabbits treated with oral baricitinib during organogenesis at approximately 5 and 13 times the exposure at the MRHD, respectively. In a pre- and post-natal development study in pregnant female rats, oral baricitinib administration at exposures approximately 43 times the MRHD resulted in reduction in pup viability (increased incidence of stillborn pups and early neonatal deaths), decreased fetal birth weight, reduced fetal body weight gain, decreased cytotoxic T cells on post-natal day (PND) 35 with evidence of recovery by PND 65, and developmental delays that might be attributable to decreased body weight gain. No developmental toxicity was observed at an exposure approximately 9 times the exposure at the MRHD. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are 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 miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Animal Data: In an embryofetal development study in pregnant rats, dosed orally during the period of organogenesis from gestation days 6 to 17, baricitinib was teratogenic (skeletal malformations that consisted of bent limb bones and rib anomalies) at exposures equal to or greater than approximately 20 times the MRHD (on an AUC basis at maternal oral doses of 10 mg/kg/day and higher). No developmental toxicity was observed in rats at an exposure approximately 5 times the MRHD (on an AUC basis at a maternal oral dose of 2 mg/kg/day).

In an embryofetal development study in pregnant rabbits, dosed orally during the period of organogenesis from gestation days 7 to 20, embryolethality, decreased fetal body weights, and skeletal malformations (rib anomalies) were observed in the presence of maternal toxicity at an exposure approximately 84 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day).

Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both early and late resorptions.

No developmental toxicity was observed in rabbits at an exposure approximately 12 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

In a pre- and post-natal development study in pregnant female rats dosed orally from gestation day 6 through lactation day 20, adverse findings observed in pups included decreased survival from birth to post-natal day 4 (due to increased stillbirths and early neonatal deaths), decreased birth weight, decreased body weight gain during the pre-weaning phase, increased incidence of malrotated forelimbs during the pre-weaning phase, and decreased cytotoxic T cells on PND 35 with recovery by PND 65 at exposures approximately 43 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Developmental delays (that may be secondary to decreased body weight gain) were observed in males and females at exposures approximately 43 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). These findings included decreased forelimb and hindlimb grip strengths, and delayed mean age of sexual maturity. No developmental toxicity was observed in rats at an exposure approximately 9 times the MRHD (on an AUC basis at a maternal oral dose of 5 mg/kg/day).

Lactation Risk Summary—No information is available on the presence of Olumiant in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Baricitinib is present in the milk of lactating rats. Due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. Because of the potential for serious adverse reactions in nursing infants, advise an Olumiant-treated woman not to breastfeed.

Data—A single oral dose of 25 mg/kg radiolabeled baricitinib was administered to lactating female Sprague-Dawley rats on post-partum day 13. Drug exposure was approximately 45-fold greater in milk than in plasma based on AUC0-t values.

Pediatric Use—The safety and effectiveness of Olumiant in pediatric patients have not been established.

Geriatric Use—Of the 3100 patients treated in the four phase 3 studies, a total of 537 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Olumiant is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Impairment—No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The use of Olumiant has not been studied in patients with severe hepatic impairment and is therefore not recommended.

Renal Impairment—Renal function was found to significantly affect baricitinib exposure. Olumiant is not recommended for use in patients with estimated GFR of less than 60 mL/min/1.73 m2.

OVERDOSAGE Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days have been administered in clinical trials without doselimiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours.

In case of an overdose, it is recommended that the patient should be monitored for signs and symptoms of adverse reactions.

Patients who develop adverse reactions should receive appropriate treatment.

Additional information can be found at www.Olumiant.com

h Olumiant 2 mg and by 9 mg/dL in patients treated with

umiant 2 mg and by 15 mg/dL in patients treated with

increases in CPK within one week of starting Olumiant K for Olumiant 2 mg and baricitinib 4 mg was 37 IU/L and

reatinine were observed with Olumiant treatment. At 52 weeks, citinib 4 mg. The clinical significance of the observed serum

e following table.

an or equal to 1% of Olumiant 2 mg s in Placebo-Controlled Trials

acebo =1070 (%) 11.7 1.6 0.7 0.4

Weeks 0-16 Olumiant 2 mg n=479 (%) 16.3 2.7 0.8 1.0

Baricitinib 4 mg n=997 (%) 14.7 2.8 1.8 1.4

aryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, , and upper respiratory tract infection. ic herpes simplex, and oral herpes.

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2018, Eli Lilly and Company. All rights reserved.

acne.

BA HCP BS 01JUN2018 BA HCP BS 01JUN2018

OLUMIANT® (baricitinib)

BA HCP BS 01JUN2018

MSP ARTÍCULO / DE OPINIÓN

PUNTO DE VISTA DEL PACIENTE…

Por: Alexa Borroto Bechara Psicóloga Escolar Paciente de Still’s Disease Directora Ejecutiva Be Brave by Fundación Bechara fundacionbechara@gmail.com

T

enía apenas veinte años cuando me cambió la vida. De la noche a la mañana pasé de ser una joven saludable, activa e independiente, a estar completamente inmóvil y depender totalmente de otros sin entender qué le ocurría a mi cuerpo. Me desperté un jueves, en marzo del dos mil doce con la rodilla derecha sumamente inflamada, preguntándome qué me estaría pasando pues no me había caído, ni había sufrido ninguna lesión. En menos de cuarenta y ocho horas tenía mis pulmones y todas las coyunturas de mi cuerpo severamente inflamadas. Luego de estar hospitalizada por una semana, y haber sido atendida por más de diez especialistas, el reumatólogo me diagnosticó artritis reumatoide.

Rápidamente, los médicos me explicaron que, para poder estabilizar la condición severa, tenía que comenzar una especie de quimioterapia, un medicamento biológico y altas dosis de cortisona. Me dieron de alta del hospital y me dijeron que tenía que tratar de volver a mi vida normal. Sin poder caminar, vestir, ni lavar mis dientes sin ayuda, volver a mi vida normal era el reto más grande que había enfrentado en mi vida. Como joven curiosa, me comencé a cuestionar algunas preguntas: por qué esto surgió tan severa y rápidamente, qué debía hacer para estabilizarme y cómo los médicos pretendían que yo volviese a hacer mi vida tan rápido. Este es solo el comienzo de mi historia…

A través de mi experiencia, me he dado cuenta del rol tan esencial que tienen los médicos en la vida de sus pacientes. Las condiciones autoinmunes reumáticas son condiciones crónicas, de por vida y muy impredecibles. Por tanto, requieren mucho manejo de dolor y -en especial- manejo de emociones. En los ojos del paciente, los médicos tienen el poder de capacitarnos con las herramientas necesarias para remover dolor, curar o estabilizar una enfermedad. Como paciente, busco a mi médico por su conocimiento y experiencia, pero lo busco -aún más- porque confío en que me va a ayudar a sentirme mejor.

Sin embargo, muchos médicos tienen el

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efecto opuesto en Ayudar al sus pacientes y, en paciente a En los ojos del paciente, vez de empoderarla adquisición de los médicos tienen el los, los incapacitan. su medicamento poder de capacitarnos Estos médicos paespecializado. Al con las herramientas san tiempo mínimo tener más comucon sus pacientes, nicación con los necesarias para no les contestan planes médicos y remover dolor, curar preguntas básicas, saber los difereno estabilizar una ni les proveen infortes medicamentos enfermedad. Como mación necesaria aceptados por paciente, busco a para tener un estilo cada plan, los méde vida saludable. dicos pueden facimi médico por su A través de los litar la adquisición conocimiento y años, he tenido que de los mismos que experiencia, pero visitar anualmente son tan costosos lo busco -aún másmúltiples doctores y difícil de aprobar. porque confío en que de distintas espeDe igual forma, cialidades, tanto las secretarias me va a ayudar a en Estados Unidos pueden informarsentirme mejor. como en Puerto les a los pacientes Rico. Algunos de essobre tarjetas de tos han sido ángeles copagos de los en mi vida y me han medicamentos y brindado un trato de primera. Sin embarcómo conseguir los mejores descuentos go, otros me han hecho pasar momentos disponibles dependiendo del caso. muy difíciles y me han causado ansiedad, frustración e inquietud.

Educar al paciente sobre qué hacer en una emergencia o desastre natuComo paciente, les aconsejaría a los ral como el huracán María. Luego de este médicos que trabajan con pacientes con desastre, muchos pacientes tuvieron gran condiciones autoinmunes: dificultad en conseguir sus medicamentos especializados y almacenar adecuadamente Al momento de dar un diagnóstico, es los mismos por la falta de electricidad. Los esencial ser compasivo y empático. médicos deberían aconsejarles a sus pacienAunque el médico está acostumbrado a tes y ser específicos en cómo prepararse trabajar con estas condiciones diariamenpara estos momentos. Por ejemplo, en mi te, para el paciente y sus familiares es experiencia, yo compré una nevera insulada algo completamente nuevo. Por lo tanto, grande con mucho hielo, específicamente el médico debería tomarse el tiempo para para los medicamentos. De igual forma, brindarle a su paciente suficiente inforhablé con mi farmacia especializada y mis mación sobre el pronóstico, síntomas, médicos para que me proveyeran medicaposibles medicamentos y efectos secunmentos de muestra que tenían en exceso darios. Así ayudará al paciente a procesar para estar cubierta por más tiempo. esta información.

Disminuir el tiempo de espera. Como Capacitar a sus pacientes a entender paciente, es frustrante tener que estar su condición. Actualmente, en el intervarias horas esperando a que el médico net hay mucha información falsa y errónea atienda cuando sufres constante dolor. que muchas veces confunde al paciente.

Por lo tanto, aconsejaría que los médicos El médico podría darle al paciente distinsean más estrictos con sus pacientes y tos enlaces de páginas de internet, fundarequerir puntualidad. ciones sin fines de lucro o videos donde el paciente pueda acceder y aprender más Digitalizar los récords para agilizar sobre su condición y sus medicamentos. el proceso, tener la información del De igual manera, definir términos y explipaciente más accesible y ser más eficiencar la condición en palabras sencillas de te en la cadena entre médico, paciente y acuerdo al paciente y su edad. farmacia especializada.

4

1

2

5

6

El ser portavoz de las condiciones autoinmunes a través del proyecto Be Brave de la Fundación Bechara me ha enseñado -además- la importancia de que los médicos estén al día con los últimos avances de investigación en la medicina.

Dado que las condiciones autoinmunes reumáticas son bien diversas y se presentan de manera diferente en cada paciente, es esencial que los médicos estén al tanto de los tratamientos más recientes.

Es por esto que, como parte de nuestra misión, Be Brave brinda seminarios médicos de educación continua anualmente en reumatología. Hemos logrado ser un eslabón esencial, hemos logrado unir a investigadores, médicos y pacientes para promover el diagnóstico temprano y los tratamientos innovadores de los pacientes con estas condiciones. Exhortamos a los médicos a visitar nuestra página de internet www.fundaciobechara.org para que puedan participar, enriquecer su conocimiento y ofrecer una mejor calidad de vida a sus pacientes.

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XELJANZ delivered powerful reductions in the signs and symptoms of RA and PsA1-4 RA: ORAL Solo (DMARD-IR patients) ACR20 response rate for XELJANZ 5 mg BID (n=243) at month 3 (primary endpoint) was 59% vs 26% with placebo (n=122); P<0.00011,2 PsA: OPAL Broaden (csDMARD-IR patients) ACR20 response rate for XELJANZ 5 mg BID + csDMARD (n=107) at month 3 (primary endpoint) was 50% vs 33% with placebo + csDMARD (n=105); P≤0.051,4,a See study designs on the following pages.

Not an actual patient. Pill not to scale.

a

Nonresponder imputation was applied to missing sign/symptom data.1,4

INDICATIONS

Rheumatoid Arthritis • XELJANZ®/XELJANZ® XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Psoriatic Arthritis • XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Ulcerative Colitis • XELJANZ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC).

• Limitations of Use: Use of XELJANZ in combination with biologic therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

XELJANZ XR is not approved for use in UC.

IMPORTANT SAFETY INFORMATION

Reported infections include: SERIOUS INFECTIONS • Active tuberculosis, which may present with pulmonary or extrapulmonary disease.

Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use. methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than is controlled. localized, disease.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The first and only FDA-approved oral JAK inhibitor for 3 indications: rheumatoid arthritis, psoriatic arthritis, ulcerative colitis1

An estimated

150,000 patients

in the US have been treated with XELJANZ for RA and PsA2,b â&#x20AC;˘ More than 146,000 patients for RA and more than 4,000 patients for PsA Based on US data source: IQVIA Lifelink Patient Data, including Rx, Dx, and Specialty Pharmacy, December 2018.2

b

A MARK OF EXPERIENCE

1

XELJANZ has >6 years of JAKi market experience in RA1

Supported by a comprehensive

Among US rheumatologists,

clinical trial program,

the 3rd most prescribed self-administered RA specialty treatmentc since 2015 (behind adalimumab and etanercept)2,d

evaluating efficacy and safety in six phase 3 clinical trials in RA and two phase 3 clinical trials in PsA1

Specialty treatment includes abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, sarilumab, tocilizumab, and tofacitinib.2

c

Internal calculations by Pfizer based on IQVIA database, US National Prescription Audit (NPA), of total prescription (TRx) products indicated for RA, November 2018.2

d

IMPORTANT SAFETY INFORMATION (cont'd)

The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections, or with chronic or recurrent infection.

In the UC population, XELJANZ 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

The risks and benefits of treatment with XELJANZ/XELJANZ XR should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection, or those who have lived or traveled in areas of endemic TB or mycoses. Viral reactivation including herpes virus and hepatitis B reactivation have been reported.

Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infection.

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated nonmelanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy.

Malignancies (including solid cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg twice daily dosing in the UC long-term extension study.

Other malignancies were observed in clinical studies and the post-marketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. NMSCs have been reported in patients treated with XELJANZ. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

ACR=American College of Rheumatology; BID=twice daily; csDMARD=conventional synthetic disease-modifying antirheumatic drug; DMARD=disease-modifying antirheumatic drug; Dx=diagnosis; FDA=US Food and Drug Administration; IR=inadequate responder; JAK=Janus kinase; JAKi=Janus kinase inhibitor; PsA=psoriatic arthritis; RA=rheumatoid arthritis; Rx=prescription; UC=ulcerative colitis.

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

Learn more about the Mark of XELJANZ at XELJANZHCP.com See ACR response rates on the previous pages.

Study Designs ORAL Solo (Study RA-I)3

A 6-month, randomized, double-blind, placebo-controlled, multicenter trial in which 610 patients with moderately to severely active RA who had an inadequate response or toxicity to a DMARD of any type received XELJANZ 5 mg BID or 10 mg BID or placebo.

Stable low-dose oral glucocorticoids allowed. All DMARDs were washed out before baseline visit, except stable doses of antimalarial agents were permitted (XELJANZ 5 mg 19%; placebo 12%). The 3 coprimary endpoints were ACR20 response rate, HAQ-DI change, and rate of DAS28-4(ESR) <2.6 at month 3. Nonresponder imputation was applied to missing sign/symptom data.

OPAL Broaden (Study PsA-I)1,2,4 A 12-month, randomized, double-blind, double-dummy, active-controlled, placebocontrolled, multicenter, phase 3 trial in which 422 adult patients with active PsA who had inadequate response to at least one csDMARD and were TNFi-naïve received either XELJANZ 5 mg BID, 10 mg BID, adalimumab 40 mg SC q 2 wk, or placebo. At month 3, all patients randomized to placebo were advanced to XELJANZ 5 mg BID or 10 mg BID in a blinded manner based on their initial randomization sequence. Across all treatment arms, all patients were required to receive a stable dose of one csDMARD (also known as a nonbiologic DMARD, which included methotrexate, sulfasalazine, and leflunomide).

Stable low-dose oral glucocorticoids were allowed. Study PsA-I was not designed to demonstrate noninferiority or superiority of XELJANZ to adalimumab.

IMPORTANT SAFETY INFORMATION (cont'd)

GASTROINTESTINAL PERFORATIONS (cont'd) There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).

HYPERSENSITIVITY Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/XELJANZ XR and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

LABORATORY ABNORMALITIES Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with an ANC less than 1000 cells/mm3.

For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ/ XELJANZ XR dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia: Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. If drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

Lipid Elevations: Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. Manage patients with hyperlipidemia according to clinical guidelines.

Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy.

VACCINATIONS Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy.

PATIENTS WITH GASTROINTESTINAL NARROWING Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation.

HEPATIC and RENAL IMPAIRMENT Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended.

For patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 5 mg twice daily, reduce to XELJANZ 5 mg once daily.

For UC patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 10 mg twice daily, reduce to XELJANZ 5 mg twice daily.

ADVERSE REACTIONS The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in patients with rheumatoid arthritis (RA) with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infection, nasopharyngitis, diarrhea, headache, and hypertension. The safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile observed in RA patients.

Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials for ulcerative colitis were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

USE IN PREGNANCY Available data with XELJANZ/XELJANZ XR use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy. In animal studies, tofacitinib at 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryofetal findings. The relevance of these findings to women of childbearing potential is uncertain. Consider pregnancy planning and prevention for females of reproductive potential.

ACR=American College of Rheumatology; BID=twice daily; csDMARD=conventional synthetic disease-modifying antirheumatic drug; DAS28-4(ESR)=Disease Activity Score for 28-joint counts based on erythrocyte sedimentation rate; DMARD=disease-modifying antirheumatic drug; HAQ-DI=Health Assessment Questionnaire–Disability Index; PsA=psoriatic arthritis; q 2 wk=every 2 weeks; RA=rheumatoid arthritis; SC=subcutaneously; TNFi=tumor necrosis factor inhibitor.

References: 1. XELJANZ/XELJANZ XR [prescribing information]. New York, NY: Pfizer Inc; October 2018. 2. Data on file. Pfizer Inc, New York, NY. 3. Fleischmann R, Kremer J, Cush J, et al; for the ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495-507.

4. Mease P, Hall S, FitzGerald O, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med. 2017;377(16):1537-1550.

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

PP-XEL-USA-4358-01 © 2019 Pfizer Inc. All rights reserved. Printed in USA/April 2019

XELJANZ® (tofacitinib)/XELJANZ® XR (tofacitinib) BRIEF SUMMARY OF PRESCRIBING INFORMATION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease.

Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with XELJANZ/XELJANZ XR should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virusassociated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

INDICATIONS AND USAGE Rheumatoid Arthritis XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Psoriatic Arthritis XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Ulcerative Colitis XELJANZ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC).

• Limitations of Use: Use of XELJANZ in combination with biologic therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal

herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.

In the UC population, XELJANZ treatment with 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily.

Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).

Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ/ XELJANZ XR in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ/XELJANZ XR should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.

Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are recommended.

Tuberculosis Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ/ XELJANZ XR. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan and Korea.

Malignancy and Lymphoproliferative Disorders Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. During the 2 PsA controlled clinical studies there were

3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ. During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1220 patients, 0 cases of solid cancer or lymphoma were observed in XELJANZ-treated patients. In the long-term extension study, malignancies (including solid cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg twice daily.

In Phase 2B, controlled dose-ranging trials in denovo renal transplant patients, all of whom received induction therapy with basiliximab, highdose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated posttransplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.

Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids.

XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Hypersensitivity Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/ XELJANZ XR. Some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections • Malignancy and Lymphoproliferative Disorders • Gastrointestinal Perforations • Laboratory Abnormalities 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 predict the rates observed in a broader patient population in clinical practice.

Rheumatoid Arthritis The clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily.

The recommended dose for XELJANZ XR is 11 mg once daily.

The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials.

In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that

follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long- term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.

The most common serious adverse reactions were serious infections.

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.

Overall Infections In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patientyears) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.

Tuberculosis In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).

Opportunistic Infections (excluding tuberculosis) In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patientyears for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patientyears) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient- years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.

The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.

Laboratory Abnormalities Lymphopenia In the controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

Confirmed lymphocyte counts less than 500 cells/ mm3 were associated with an increased incidence of treated and serious infections.

Neutropenia In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.

Liver Enzyme Elevations Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.

In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.

In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.

Lipid Elevations In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

• Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.

• Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.

Serum Creatinine Elevations In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment.

The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocolspecified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in the table below.

Common Adverse Reactions* in Clinical Trials of XELJANZ for theTreatment of Rheumatoid Arthritis With or Without Concomitant DMARDs (0-3 Months) XELJANZ XELJANZ 5 mg 10 mg Twice Placebo Twice Daily Daily** N = 1336 (%)

N = 1349 (%)

N = 809 (%)

Upper respiratory tract infection

4

4

3

Preferred Term

Nasopharyngitis

4

3

3

Diarrhea

4

3

2

Headache

4

3

2

Hypertension

2

2

1

N reflects randomized and treated patients from the seven clinical trials. * reported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo. ** the recommended dose of XELJANZ for the treatment of rheumatoid arthritis is 5 mg twice daily.

Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Infections and infestations: Diverticulitis Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal) Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients. The safety experience in these patients was consistent with Studies RA-I through V. Psoriatic Arthritis XELJANZ 5 mg twice daily and 10 mg twice daily were studied in 2 double-blind Phase 3 clinical trials in patients with active psoriatic arthritis (PsA).

Study PsA-I (NCT01877668) had a duration of 12 months and enrolled patients who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker.

Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.

Study PsA-II (NCT01882439) had a duration of 6 months and enrolled patients who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo controlled period.

In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. All patients in the clinical trials were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (9.5%) patients aged 65 years or older and 66 (13.9%) patients with diabetes at baseline.

The safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile observed in rheumatoid arthritis patients.

Ulcerative Colitis XELJANZ has been studied in patients with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose ranging UC-V) and an open-label long term extension study (UC-IV). Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

Induction Trials (Study UC-I, UC-II, and UC-V): Common adverse reactions reported in ≥2% of patients treated with XELJANZ 10 mg twice daily and ≥1% greater than that reported in patients receiving placebo in the 3 induction trials were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.

Maintenance Trial (Study UC-III): Common adverse reactions reported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported in patients receiving placebo are shown in the table below.

Common Adverse Reactions* in UC Patients during the Maintenance Trial (Study UC-III) XELJANZ XELJANZ 5 mg 10 mg Placebo Twice Daily Twice Daily Preferred Term

N = 198 (%)

N = 196 (%)

N = 198 (%)

Nasopharyngitis

10

14

6

Elevated cholesterol levels**

5

9

1

Headache

9

3

6

Upper respiratory tract infection

7

6

4

Increased blood creatine phosphokinase

3

7

2

Rash

3

6

4

Diarrhea

2

5

3

Herpes zoster

1

5

1

Gastroenteritis

3

4

3

Anemia

4

2

2

Nausea

1

4

3

* reported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported for placebo. ** includes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed more often in patients treated with XELJANZ 10 mg twice daily. Four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer.

Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC. Postmarketing Experience Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed).

DRUG INTERACTIONS The table below includes drugs with clinically important drug interactions when administered concomitantly with XELJANZ/XELJANZ XR and instructions for preventing or managing them.

Clinical Relevant Interactions Affecting XELJANZ and XELJANZ XR When Coadministered with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/ XELJANZ XR is recommended

Moderate CYP3A4 Inhibitors Coadministered with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/ XELJANZ XR is recommended

Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact

Decreased exposure to tofacitinib and may result in loss of or reduced clinical response

Intervention

Coadministration with XELJANZ/ XELJANZ XR is not recommended

Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact

Risk of added immunosuppression; coadministration with biologic DMARDs or potent immunosuppressants has not been studied in patients with rheumatoid arthritis, psoriatic arthritis, or UC.

Intervention

Coadministration with XELJANZ/ XELJANZ XR is not recommended

USE IN SPECIFIC POPULATIONS All information provided in this section is applicable to XELJANZ and XELJANZ XR as they contain the same active ingredient (tofacitinib).

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XELJANZ/XELJANZ XR during pregnancy. Patients should be encouraged to enroll in the XELJANZ/XELJANZ XR pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972.

Risk Summary Available data with XELJANZ/ XELJANZ XR use in pregnant women are insufficient

to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy (see Clinical Considerations). In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dose of 5 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively (see Data).

The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data Animal Data In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats).

Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).

In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/ skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).

In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).

Lactation Risk Summary There are no data on the presence of tofacitinib in human milk, the effects on a breastfed infant, or the effects on milk production. Tofacitinib is present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults treated with XELJANZ/XELJANZ XR, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of XELJANZ or 36 hours after the last dose of XELJANZ XR (approximately 6 elimination half-lives).

Data Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.

Females and Males of Reproductive Potential Contraception Females In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dose of 5 mg twice daily and 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryofetal findings. However, there is uncertainty as to how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential.

Infertility Females Based on findings in rats, treatment with XELJANZ/XELJANZ XR may result in reduced fertility in females of reproductive potential.

It is not known if this effect is reversible.

Pediatric Use The safety and effectiveness of XELJANZ/XELJANZ XR in pediatric patients have not been established.

Geriatric Use Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older.

The frequency of serious infection among XELJANZtreated subjects 65 years of age and older was higher than among those under the age of 65.

Of the 1156 XELJANZ treated patients in the UC program, a total of 77 patients (7%) were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they responded differently from younger patients.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Use in Diabetics As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.

Renal Impairment Moderate and Severe Impairment XELJANZ-treated patients with moderate or severe renal impairment had greater tofacitinib blood concentrations than XELJANZ-treated patients with normal renal function. Therefore, dosage adjustment of XELJANZ is recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis).

• Rheumatoid arthritis and psoriatic arthritis patients with moderate or severe renal impairment receiving XELJANZ XR should switch to XELJANZ and adjust the dosage.

Mild impairment No dosage adjustment is required in patients with mild renal impairment.

Hepatic Impairment Severe Impairment XELJANZ/XELJANZ XR has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended.

Moderate Impairment XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib blood concentration than XELJANZ-treated patients with normal hepatic function. Higher blood concentrations may increase the risk of some adverse reactions. Therefore, dosage adjustment of XELJANZ is recommended in patients with moderate hepatic impairment.

• Rheumatoid arthritis and psoriatic arthritis patients receiving XELJANZ XR should switch to XELJANZ and adjust the dosage.

Mild Impairment No dosage adjustment of XELJANZ/XELJANZ XR is required in patients with mild hepatic impairment.

Hepatitis B or C Serology The safety and efficacy of XELJANZ/XELJANZ XR have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

OVERDOSAGE There is no specific antidote for overdose with XELJANZ/XELJANZ XR. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

In a study in subjects with end stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)].

However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus limits the value of hemodialysis for treatment of overdose with XELJANZ/XELJANZ XR. This brief summary is based on XELJANZ®/ XELJANZ® XR (tofacitinib) Prescribing Information LAB-0445-16.0 Issued: October 2018 © 2018 Pfizer Inc. All rights reserved. October 2018

MSP ARTÍCULO / DE REVISIÓN

Por: Frances M. Colón Pratts, Pharm.D. CDE Catedrática Auxiliar, Clínica Farmacéutica, Clínica Educadora Certificada en Diabetes NOVA Southeastern University, Colegio de Farmacéuticos de Puerto Rico

DIABETES EN PUERTO RICO: DATOS SOBRE LA PREVALENCIA, INCIDENCIA Y MORTALIDAD

58

PALABRAS CLAVES

KEYWORDS

Puerto Rico, diabetes, diabetes tipo 2, diabetes tipo 1, prevalencia, incidencia, mortalidad.

Puerto Rico, diabetes, type 2 diabetes, type 1 diabetes, prevalence, incidence, mortality.

Revista Puertorriqueña de Medicina y Salud Pública

LA MORTALIDAD POR DIABETES EN PUERTO RICO MUESTRA UNA TENDENCIA ASCENDENTE RESUMEN La diabetes es una condición crónica que afecta la función endocrina del páncreas. Según la Organización Mundial de la Salud, en el 2014, la prevalencia mundial estimada para la diabetes fue de un 8.5% en adultos. Se han identificado varios factores de riesgos modificables y no modificables para desarrollar diabetes y, varios de ellos, afectan directamente a la población puer torriqueña. El objetivo primordial de este ar tículo es examinar la literatura disponible sobre la epidemiología de la diabetes en Puer to Rico y brindar una sinopsis de los hallazgos.

Se llevó a cabo una revisión de la literatura a través de las bases de datos electrónicas de Medline y LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), en donde se seleccionaron artículos concernientes a la epidemiología de la diabetes en Puerto Rico. De igual manera, fueron evaluados datos reportados por el Departamento de Salud de Puerto Rico, la Federación Internacional de Diabetes, el Centro para el Control y la Prevención de Enfermedades.

La prevalencia autorreportada de diabetes en adultos puertorriqueños para el año 2017 fue de un 15% y mostró tener mayor prevalencia en adultos de 65 años o mayores, particularmente en las mujeres. La diabetes es considerada la tercera causa de muerte en Puerto Rico y la mortalidad por esta afección muestra una tendencia ascendente en el país.

Datos sobre la prevalencia, incidencia y mor talidad asociada a la diabetes son indispensables al desarrollar nuevos programas y mejorar políticas públicas existentes dirigidas a la prevención y tratamiento de la condición en la isla.

Revista Puertorriqueña de Medicina y Salud Pública

59

MSP ARTÍCULO / DE REVISIÓN

60

2016

15

2015

13.8

2014

14.8

2013

14.3 13.8

2012

Prevalencia (%)

15.2

2011

Diabetes is a chronic condition that affects the endocrine function of the pancreas. According to the World Health Organization, in 2014, the estimated global prevalence for diabetes was 8.5% in adults. Several modifiable and non-modifiable risk factors have been identified to develop diabetes, and several of them directly affect the Puerto Rican population. The primary objective of this article is to examine the available literature on the epidemiology of diabetes in Puerto Rico and provide a synopsis of the findings.

A review of the literature was carried out through the electronic databases of Medline and LILACS (Latin American and Caribbean Literature in Health Sciences), where articles concerning the epidemiology of diabetes in Puerto Rico were selected. Similarly, data reported by the Department of Health of Puerto Rico, the International Diabetes Federation, the Center for Disease Control and Prevention were evaluated.

The self-reported prevalence of diabetes in Puerto Rican adults for the year 2017 was 15% and showed a higher prevalence in adults 65 years of age or older, particularly in women. Diabetes is considered the third cause of death in Puerto Rico and mortality from this condition shows an upward trend in the country.

Data on the prevalence, incidence and mortality associated with diabetes are essential when developing new programs and improving existing public policies aimed at the prevention and treatment of the condition on the island

2017

ABSTRACT

13.4

12

13

14

15

16

Gráfica 1: Prevalencia (ajustada en función a la edad) de diabetes en Puerto Rico según BRFSS, 2011-2017.

Referencia: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Population Health.

Chronic Disease Indicators (CDI) Data [online]. 2016 [accessed Mar 11, 2019]. URL: https://nccd.cdc.gov/cdi

INTRODUCCIÓN La diabetes es una condición crónica que afecta la función endocrina del páncreas. Esta podría clasificarse de manera general en: diabetes tipo 1, diabetes tipo 2, diabetes gestacional y diabetes provocada por otras razones (ej. diabetes inducida por medicamentos).1 Según la Organización Mundial de la Salud (OMS), en el 2014, la prevalencia global estimada de

Revista Puertorriqueña de Medicina y Salud Pública

la diabetes fue de 8.5% en adultos con 18 años de edad o más y estimó que, para el año 2016, 1.6 millones de personas murieron a causa de la diabetes, siendo la sexta causa de muerte a nivel global.2,3 En los Estados Unidos, la prevalencia estimada de diabetes se reportó en el 9.4% de la población para el año 2015.4 Entre las personas de origen hispano en los Estados Unidos, los puertorriqueños ocupan la segunda posición de más alta prevalencia de diabetes, con un 12%, antecedidos por los mexicanos, con un 13.8%.4 En este mismo año, la incidencia de diabetes en adultos de 18 años o más fue de 1.5 millones de casos, más de la mitad ocurrieron en personas entre las edades de 45 a 64 años.4 La incidencia fue mayor en las personas negras no hispanas (9 personas de cada 1,000) y las hispanas (8.4 personas de cada 1,000).4 La diabetes fue la séptima causa de muerte en los Estados Unidos en el año 2015.4 Se han identificado varios factores de riesgos modificables y no modificables para desarrollar diabetes y, varios de ellos, afectan directamente a la población puertorriqueña. Ser hispano es un factor de riesgo no modificable para desarrollar diabetes tipo 2.1 Tener sobrepeso u obesidad y la inactividad física son factores modificables asociados a un aumento en el riesgo de padecer de diabetes.1 Según los resultados (ajustados en función de la edad) reportados por el Sistema de Vigilancia de Factores de Riesgo del Comportamiento o “Behavioral Risk Factor Surveillance System”

LA DIABETES ES UNA CONDICIÓN CRÓNICA QUE AFECTA LA FUNCIÓN ENDOCRINA DEL PÁNCREAS. ESTA PODRÍA CLASIFICARSE DE MANERA GENERAL EN: DIABETES TIPO 1, DIABETES TIPO 2, DIABETES GESTACIONAL Y DIABETES PROVOCADA POR OTRAS RAZONES

el Centro para el Control y la Prevención de Enfermedades (CDC), la OMS y la Asociación Americana de Diabetes (ADA, por sus siglas en inglés). La búsqueda se realizó de manera electrónica y a través de las bases de datos electrónicas de Medline y LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), utilizando términos como: “epidemiología”, “prevalencia”, “incidencia”, “Puerto Rico”, “diabetes”, “diabetes tipo 2”, “diabetes tipo 1” y “mortalidad”. Los artículos e información más relevantes fueron seleccionados.

El “Puerto Rico-BRFSS o PR-BRFSS” es una herramienta clave para estimar la prevalencia de casos de diabetes en Puerto Rico. Se trata de una encuesta nacional realizada desde el año 1995 anualmente por el CDC a través del Departamento de Salud de Puerto Rico. En esta encuesta se indaga por vía tele-

(BRFSS) para el año 2017, el 32.6% de los puertorriqueños autorreportó ser obeso y el 34.8% tener sobrepeso, datos más altos en comparación con el grupo de puertorriqueños que autorreportó encontrarse en su peso normal (31%).5 Por otro lado, datos obtenidos en este cuestionario indican que, para este mismo año, el 53% de los puertorriqueños encuestados reportaron no haber realizado ejercicio durante el último mes; mientras que, el 79.9% reportó no realizar actividad física aeróbica de 150 minutos o más por semana (datos ajustados en función de la edad).5

METODOLOGÍA Y HERRAMIENTAS DE RECOLECCIÓN DE DATOS Se llevó a cabo una revisión de la literatura que recoge los datos epidemiológicos de diabetes en Puerto Rico. La revisión incluyó datos reportados por el Departamento de Salud de Puerto Rico, la Federación Internacional de Diabetes,

fónica el autorreporte del diagnóstico de diabetes en adultos de 18 años o más no institucionalizados en relación a si los entrevistados responden “sí” a la siguiente pregunta: “¿Alguna vez algún médico le informó que tenía diabetes?”

RESULTADOS Prevalencia de diabetes en Puerto Rico según BRFSS Conforme con BRFSS, la prevalencia (ajustada en función de la edad) reportada de diabetes en adultos en Puerto Rico para el año 2017 fue de 15%.5 Siendo ligeramente mayor en las mujeres (18%) que en los hombres (16.4%), ver gráfica 2. La mayor prevalencia se reportó en personas de 65 años o más (36.9%), seguido por el grupo de personas de 55 a 64 años (27.9%), los de 45 a 54 años (18.5%) y los de 35 a 44 años (5.7%). Por otra parte, se observó una prevalencia cruda mayor en aquellos que alcanzaron una educación menor a escuela superior

Prevalencia (%)

20 15 10 5 0

Año

2011

2012

2013

Mujeres

2014

2015

2016

2017

Hombres

Gráfica 2: Prevalencia (ajustada en función a la edad) de Diabetes por Género en Puerto Rico según BRFSS, 2011-2017. Referencia: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Population Health. Chronic Disease Indicators (CDI) Data [online]. 2016 [accessed Mar 11, 2019]. URL: https://nccd.cdc.gov/cdi.

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4,000

4,222

MSP ARTÍCULO / DE REVISIÓN

Gráfica 4: Muertes por diabetes en Puerto Rico, 2005-2012 Fuente: Departamento de Salud.

2014). Resumen General de la Salud en Puerto Rico. San Juan, Puerto Rico.

(29.4%) y en aquellos con un ingreso menor de 15,000 dólares.5 Un 2.7% reportó haber sido informado por su médico sobre el diagnóstico de prediabetes. Es importante señalar que Puerto Rico es la jurisdicción de los Estados Unidos con la más alta prevalencia de casos de diabetes, según lo reporta este estudio; seguido por los estados de West Virginia (15.25%), Mississippi (14.2%) y Alabama (14.1%).5 De acuerdo con este estudio, en los últimos años, Puerto Rico siempre ha tenido una de las prevalencias más altas de diabetes de los Estados Unidos y sus territorios, ocupando el primer o segundo puesto.5 En la gráfica 4, mostramos los datos de prevalencia de diabetes en Puerto Rico.

Según la Federación Internacional de Diabetes, Puerto Rico es el país con mayor prevalencia de diabetes en adultos entre las edades de 18 a 99 años, en comparación con otras regiones de América del Sur y Centroamérica; reportando una prevalencia de 12.8% en el 2017, estimando que 1 de cada 6 adultos en Puerto Rico padece de diabetes.6

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PREVALENCIA DE DIABETES POR REGIÓN Según datos del Departamento de Salud, para el año 2008, las regiones de mayor prevalencia de diabetes en Puerto Rico en adultos de 18 años o más, fueron: la subregión de Aguadilla (13.8%), la región de Ponce (13.4%), la región de Arecibo (13.2%) y la región de Mayagüez (13.0%).7 Por otra parte, un estudio cuyo objetivo principal fue crear estimados de prevalencia de diabetes por municipios en Puerto Rico en adultos de 20 años o más, reveló que, para el año 2009, la prevalencia (ajustada en función de la edad), fue mayor para los siguientes municipios: Arecibo (15.8%), Barceloneta (15.4%), Ciales (15.2%), Quebradilla (15.1%), Lajas (15%) y Maunabo (15%) .8 Para la región metropolitana compuesta por San Juan, Carolina y Caguas, la prevalencia (ajustada en función de la edad) autorreportada de diabetes fue de 14% para el año 2017.5 Esta prevalencia fue mayor a la reportada en el año 2016 (13.2%).5

Revista Puertorriqueña de Medicina y Salud Pública

700 600 500

394 432

400 265

300 172

200 100 0

0

2

Menores 10-14 de10 años años

0 15-19 años

3

4

5

20-24 años

25-29 años

30-34 años

16

35-39 años

39

58

40-44 años

45-49 años

106

50-54 años

55-59 años

60-64 años

65-69 años

70-74 años

Gráfica 5: Muertes por diabetes en Puerto Rico por grupo de edad, 2012. Fuente: Departamento de Salud. (2014). Resumen General de la Salud en Puerto Rico. San Juan, Puerto Rico.

INCIDENCIA DE DIABETES TIPO 1 La incidencia de diabetes aumentó de 13.1 a 18.7 casos por cada 100,000 niños anualmente, entre 1985 a 1994, en pacientes menores de 15 años.9 La edad promedio para el diagnóstico de diabetes tipo 1 fue 8.6 años y 8.4 años, en niñas y niños respectivamente.9 Por otro lado, la OMS inició un proyecto en 1990 cuyo objetivo principal fue investigar y monitorear los patrones de incidencia de diabetes tipo 1 en niños de 14 años o menos, conocido como “Multinational Project for Childhood Diabetes” (DiaMond). En este, se muestra que Puerto Rico es el territorio con la más alta incidencia de diabetes tipo 1, con 17.4 casos por cada 100,000 habitantes por año, de América Central y el Caribe, entre 1900 a 1994. La incidencia en niños y niñas fue de 16.2 y 18.7 casos por cada 100,000 habitantes por año, respectivamente.10

PREVALENCIA DE DIABETES TIPO 2 Se estima que del 90 al 95% de los casos de diabetes, son de tipo

2.11 En adición, se conoce que el riesgo de diabetes tipo 2 aumenta a medida que se envejece. Como dato curioso, se muestran datos publicados sobre la prevalencia diabetes tipo 2 en jóvenes puertorriqueños. La prevalencia estimada de diabetes tipo 2 en niños y/o jóvenes menores de 20 años entre 1995 a 2003 fue de 13.5 casos por cada 100,000 habitantes por año.11 La diabetes tipo 2 mostró tener mayor prevalencia en el grupo de jóvenes entre las edades de 15 a 19 años y en niñas (69%).11

MORTALIDAD ASOCIADA A DIABETES En los últimos años, los casos de muertes asociadas a la diabetes han ido en ascenso. El número de muertes en los años 2009 a 2012, es mayor en hombres en comparación con las mujeres.12 La diabetes se ha mantenido como la tercera causa de muerte en Puerto Rico, antecedida por el cáncer y enfermedades de corazón.12,13 Sin embargo, en el 2015, la diabetes fue la séptima causa de muerte de los Estados Unidos.4 En el 2013, la diabetes fue responsable del 10.7% de las muertes en Puerto Rico.12,13

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MSP ARTÍCULO / DE REVISIÓN

DISCUSIÓN La prevalencia de la diabetes en Puerto Rico ha ido en acenso durante los últimos años y muestra ser mayor en adultos de 65 años o más, particularmente en las mujeres.

Incluso, esta prevalencia es mayor a la reportada para los Estados Unidos. La enfermedad afecta de manera negativa la calidad de vida de aquellos que la padecen y afecta indirectamente otros sectores de la sociedad (ej. familiares, sistema de salud, entre otros). Las complicaciones que surgen a raíz de la condición contribuyen grandemente a la mortalidad y morbilidad en Puerto Rico.

Las complicaciones macrovasculares han sido identificadas como la causa principal de muerte en los pacientes diabéticos; mientras que, complicaciones microvasculares como la enfermedad renal terminal, de igual manera, contribuyen a la mortalidad. La diabetes es considerada la tercera causa de muerte en Puerto Rico, lo que es alarmante, ya que a nivel mundial y en los Estados Unidos la diabetes es la sexta y séptima causa de muerte, respectivamente. En adición, la diabetes es la causa principal de fallo renal, amputaciones no traumáticas de las extremidades inferiores y nuevos casos de ceguera en los adultos.

CONCLUSIONES Los puertorriqueños poseen factores no modificables que los predisponen al padecimiento de la diabetes; sin embargo, factores como el sobrepeso, la obesidad y la inactividad física podrían ser puntos claves en la prevención de la enfermedad. Entender la epidemiología de la diabetes en Puerto Rico es esencial para reconocer y concientizar sobre el impacto de esta condición en nuestro sistema de salud. Datos sobre la prevalencia, incidencia y mortalidad asociada a la diabetes son indispensables al desarrollar nuevos programas y mejorar políticas públicas existentes dirigidas a la prevención y tratamiento de la condición en nuestro país.

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REFERENCIAS: American Diabetes Association. 2.

Classification and diagnosis of diabetes: standards of medical care in diabetes 2019. Diabetes Care. 2019;42(Suppl. 1): S13–S28.

Diabetes key facts. World Health Organization website. https://www.who.int/ news-room/fact-sheets/detail/diabetes.

Published [October 30, 2018]. Accessed [March 9, 2019].

The top 10 causes of death. World Health Organization website. https://www.who. int/news-room/fact-sheets/detail/thetop-10-causes-of-death. Published [May 24, 2018]. Accessed [March 9, 2019].

National Diabetes Statistic Report: Estimates of Diabetes and Its Burden in the United States, 2017. Centers for Disease Control and Prevention website. https:// www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report. pdf. Accessed [March 9, 2019].

Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Population Health. BRFSS Prevalence & Trends Data [online]. 2015. https://www. cdc.gov/brfss/brfssprevalence/. Accessed [Feb 28, 2019].

EN LOS ESTADOS UNIDOS, LA PREVALENCIA ESTIMADA DE DIABETES SE REPORTÓ EN EL 9.4% DE LA POBLACIÓN PARA EL AÑO 2015. ENTRE LAS PERSONAS DE ORIGEN HISPANO EN LOS ESTADOS UNIDOS, LOS PUERTORRIQUEÑOS OCUPAN LA SEGUNDA POSICIÓN DE MÁS ALTA PREVALENCIA DE DIABETES, CON UN 12%, ANTECEDIDOS POR LOS MEXICANOS, CON UN 13.8%

Revista Puertorriqueña de Medicina y Salud Pública

IDF Diabetes Atlas, 8th ed, 2017. International Diabetes Federation website. file:///C:/Users/fc294/Downloads/Atlas8e-regional-fact-sheet-18-99-SACA.pdf.

Accessed [March 9, 2019].

Instituto de Estadística de Puerto Rico, Estado Libre Asociado de Puerto Rico.

Nuevas Estadísticas de Diabetes. http:// www.edicion.pr.gov/agencias/diabetes/ Documents/Diabetes/DIABETES%20 EN%20PUERTO%20RICO.pdf. Accessed [Marc 9, 2019].

Tierney EF, Burrows NR, Barker LE, et al.

Small area variation in diabetes prevalence in Puerto Rico. Rev Panam Salud Publica. 2013; 33 (6): 398-406.

Frazer de Llado T, Gonzalez de Pijem L, Hawn B. Incidence of IDDM in children living in Puerto Rico. Diabetes Care. 1998; 21(5): 744-748.

Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care. 2000; 23(10): 1516-26.

Perez-Perdomo R, Perez-Cardona C, Allende-Vigo M, Rivera-Rodriguez M, Rodriguez-Lugo L. Type 2 diabetes mellitus among young in Puerto Rico, 2003. P R Health Sci J. 2005; 24(2):111-7.

Sánchez Hernandez E, Rosado Santiago N, Sanchez Alemán S, et al. Resumen General de la Salud en Puerto Rico.

Departamento de Salud. (2014). San Juan, Puerto Rico. http://www.salud.gov.pr/ Estadisticas-Registros-y-Publicaciones/ Estadisticas%20Vitales/Informe%20 de%20la%20Salud%20en%20PUerto%20Rico%202014.pdf. Accessed [March 9, 2019].

Sanchez Hernandez E, Morales González J, Alcover Fernández L, Torres Concepción K. Informe Anual de la Salud 2016. Departamento de Salud y Secretaría Auxiliar de Planificación y Desarrollo de Puerto Rico. http:// www.salud.gov.pr/Estadisticas-Registros-y-Publicaciones/Estadisticas%20Vitales/Informe%20de%20 la%20Salud%20en%20Puerto%20 Rico%202016.pdf. Published [December, 2016]. Accessed [March 12,2019].

No-see, no-handle needle No reconstitution required No need to dial a dose 1,2

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

Limitations of Use: Not recommended as first-line therapy for patients inadequately controlled on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans. Prescribe only if potential benefits outweigh potential risks. Has not been studied in patients with a history of pancreatitis; consider another antidiabetic therapy. Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. Not a substitute for insulin. Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. Not for patients with pre-existing severe gastrointestinal disease.

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

It is unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

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

Please see Important Safety Information for Trulicity, including Boxed Warning about possible thyroid tumors including thyroid cancer, on following pages and accompanying Brief Summary of Prescribing Information. Please see Instructions for Use included with the pen.

Preparation2 •

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

•

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

The key administration steps

Disposal2

2

•

1

Uncap the pen

2

Place and unlock

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

3

Press and hold

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

Select Important Safety Information •

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

•

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

Yes, I think I can do this

*

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

•

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

•

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

•

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

•

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

•

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

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

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

Please see Instructions for Use included with the pen.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Please see Instructions for Use included with the pen.

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

Trulicity is available by prescription only.

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

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

2015;9(5):1071-1079.

PP-DG-US-1990 02/2019 ©Lilly USA, LLC 2019. All rights reserved.

TRULICITY® (dulaglutide)

ADVERSE REACTIONS

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

INDICATIONS AND USAGE

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

TRULICITY® (dulaglutide)

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

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

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

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

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

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

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

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

Additional information can be found at www.TRULICITY.com

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

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SUPLEMENTO ESPECIAL

REVISIÓN ACTUALIZADA EN EL MANEJO DE HIPERLIPIDEMIA DEL PACIENTE DIABÉTICO

CIRUGÍA METABÓLICA COMO ALTERNATIVA PARA LA DIABETES TIPO 2

CAUSAS SECUNDARIAS DE LA DIABETES

PELLETS COMO REEMPLAZO HORMONAL

MSP ARTÍCULO / ORIGINAL

Por: José M. García Mateo, MD, FACE Diplomate of the American Board of Endocrinology, Diabetes and Metabolism Diplomate of the American Board of Clinical Lipidology Presidente Electo de la Sociedad Puertorriqueña de Endocrinología y Diabetología

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PALABRAS CLAVES

KEYWORDS

Riesgo, aterogénico, estatina, colesterol, eventos.

Risk, atherogenic, statin, cholesterol, events.

Revista Puertorriqueña de Medicina y Salud Pública

LAS ESTADÍSTICAS DE ESTADOS UNIDOS ESTIMAN QUE LA ENFERMEDAD CARDIOVASCULAR Y CEREBROVASCULAR ES DE 2 A 4 VECES MÁS COMÚN EN ADULTOS DIABÉTICOS

RESUMEN El diagnóstico de diabetes ha alcanzado proporciones epidémicas, pues las mejorías en los criterios han permitido una detección más temprana. La enfermedad cardiovascular es la causa principal de morbilidad y mortalidad en pacientes diabéticos. El manejo de la hiperlipidemia característica aterogénica en los pacientes con diabetes ha demostrado una disminución significativa en eventos y mortalidad cardiovascular en estudios aleatorios. Estos hechos han llevado a la publicación de guías de manejo para el tratamiento de dislipidemia, las cuales fueron actualizadas recientemente y serán revisadas en este artículo.

ABSTRACT The diagnosis of diabetes has reached epidemic proportions as diagnosis criteria has improved leading to an earlier detection of the disease. Cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients. The management of the characteristic dyslipidemia in diabetic patients has shown in randomized clinical trials a decrease in cardiovascular events and mortality especially with statin therapy. These facts lead to the publication of clinical guidelines in the management of dyslipidemia in diabetic patients that were updated recently and will be summarized in this article.

INTRODUCCIÓN La diabetes se caracteriza por un alto nivel de glucosa, resultado de defectos en la capacidad del cuerpo para producir o usar insulina. El Centro para el Control de Enfermedades de los Estados Unidos (CDC, por sus siglas en inglés), estima que el 9.3% de la población en los 50 estados tiene diabetes; aunque, en Puerto Rico, esta incidencia sobrepasa el 16%. La enfermedad cardiovascular es más común en los pacientes diabéticos.

Las estadísticas de Estados Unidos estiman que la enfermedad cardiovascular y cerebrovascular es de 2 a 4 veces más común en adultos diabéticos. Todas las entidades profesionales expertas en el manejo de pacientes diabéticos (Asociación Americana de Diabetes, Asociación Americana del Corazón, etc.) consideran que la diabetes tipo 2 es parte de un síndrome cardiometabólico, ya que aproximadamente el 70% también sufre de obesidad, hipertensión e hiperlipidemia.

La dislipidemia más común con la diabetes es la combinación de un nivel alto de triglicéridos y un nivel bajo de colesterol bueno o de alta densidad (HDL). El colesterol de baja densidad o malo (LDL) puede encontrarse normal o alto y se caracteriza por ser una molécula más pequeña, que es -a su vezmás aterogénica.

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MSP ARTÍCULO / ORIGINAL

LDL-C >190 mg/dL(>4.9 mmol/L) No risk assessment, high-intensivty statin (Class I)

Primary Prevention: Assess ASCVD Risk in Each Age Group Emphasize Adherence to Healthy Lifestyle

Diabetes mellitus and age 40-75 y Moderate-intensity statin (Class I)

Age 0 -19 y Lifestyle to prevent or reduce ASCVD risk Diagnosis of Familial Hypercholesterolemia statin

Age 20 - 39 y Estimate lifetime risk to encourage lifestyle to reduce ASCVD risk Consider statin if family history premature ASCVD and LDL - C >160 mg/dL (24.1 mmol/L)

ASCVD Risk Enhancers: • Family history of premature ASCVD • Persistently elevated LDL-C>160 mg/dL (>4.1 mmol/L) • Chronic Kidney disease • Metabolic syndrome • Conditions specific to women (e.g., preeclampsia, premature menopause) • Inflammatory diseases (especially rheumatoid arthritis, psoriasis, HIV) • Ethnicity (e.g., South Asian ancestry)

Age 40 - 75 y and LDL - C >70 - <190 mg/dL (>1.8 - <4.9 mmol/mL) Without diabetes mellitus 10-years ASCVD risk percent begins risk discssion

Age>75 y Clinical assessment, Risk discussion

<5% Low Risk

5% - <7.5% Borderline Risk

>7.5% - <20% Intermediate Risk

>20% High Risk

Risk discussion: Emphasize lifestyle to reduce risk factors (Class I)

Risk discussion: If risk enhancers present then risk discussion regarding moderate intensity statin therapy (Class IIb)

Risk discussion: If risk estimate + risk enhancers favor statin, initiate moderate intensity statin to reduce LDL-C by 30% - 49% (Class I)

Risk discussion: Initiate statin to reduce LDL-C > 50% (Class I)

Lipid / Biomarkers: • Persistently elevated triglycerides (>175 mg/dL, (>2.0 mmol)) In selected individuals if measured: • hs - CR>2.0 mg/L • Lp(a) levels > 50 mg/dL or >125 nmol/L • apoB >130 mg/dL • Ankie-brachial index (ABI) <0.9

If risk desicion is uncertain: Consider measuring CAC in selected adults: CAC= zero (lowers risk, consider no statin, uniess diabetes, family history of premature CHD, or cigarette smoking are present) CAC =1.99 favors statin (especially after age 55) CAC = 100+and/or >75th percentile, initiate statin therapy

FIGURA 1

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Diabetes mellitus ans age 40-75 y Risk assessment consider high-intensity (Class IIa)

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ESTUDIOS RECIENTES RESPECTO AL DIAGNÓSTICO Teniendo en cuenta que la dislipidemia no presenta síntomas, el diagnóstico se realiza por medio de la prueba del perfil lipídico. El nivel de los lípidos puede ser afectado por la edad, sexo y antecedentes familiares.

Factores de estilo de vida como una dieta inadecuada, la baja actividad física o fumar, también afectan estos niveles. Un aumento de glucosa en la sangre también puede contribuir a la dislipidemia con el aumento de triglicéridos y otras partículas aterogénicas (apoB o partículas de LDL).

Varios estudios aleatorios controlados han demostrado que la reducción de niveles de lípidos, específicamente la lipoproteína de densidad baja o LDL-C (por sus siglas en inglés), disminuye estadísticamente los eventos y mortalidad cardiovascular en las poblaciones con alto riesgo de estos, en especial los diabéticos. Aunque varias modalidades para reducir el colesterol han demostrado estos resultados, la información más contundente es con el uso de inhibidores de reductasa HMGCoA o estatinas.

Estas han evidenciado que, en pacientes con enfermedad aterosclerótica documentada o de mayor riesgo como los diabéticos, son de beneficio cardiovascular, independientemente del nivel de LDL-C de base (alto, bajo o normal). Además, existen estudios con pacientes diabéticos, exclusivamente, que demuestran los mismos resultados.

Estos hechos han llevado al desarrollo de guías terapéuticas para el manejo de hiperlipidemias en pacientes diabéticos que se actualizaron recientemente por varias entidades: Asociación Americana de Diabetes (ADA), Colegio Americano de Cardiología / Asociación Americana del Corazón (ACC/AHA), Asociación Nacional de Lípidos (NLA) y la Asociación Americana de Endocrinólogos Clínicos (AACE), entre otras. La Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED) reconoce a estas entidades para el manejo de hiperlipidemia en la población diabética de Puerto Rico.

GUÍAS DE MANEJO PARA EL TRATAMIENTO DE DISLIPIDEMIA Existen diferencias entre las recomendaciones de diferentes sociedades, pero el propósito es el mismo: disminuir el nivel de colesterol aterogénico y reducir los eventos cardiovasculares. Aunque las guías de manejo se han dirigido hacia recomendar cierta intensidad de dosis de estatina, dependiendo del riesgo del paciente, se ha mantenido el uso de parámetros

numéricos (antes llamados metas) para mantener una comunicación adecuada entre profesionales y pacientes y se enfatiza en la última actualización de dichas guías. Esto es, gracias a recientes estudios, donde se muestran pacientes con enfermedad aterosclerótica cardiovascular documentada ya tratados con terapia de estatina a dosis máximas toleradas y, que no han obtenido un nivel de LDL-C o nonHDL-C óptimo ( < 70 mg/dL y < 100 mg/dL respectivamente).

En estos casos, el uso de terapias combinadas con diferentes mecanismos de acción a las estatinas, han logrado bajar esos niveles y -a su vez- obtener beneficio en eventos cardiovasculares. La población de pacientes diabéticos está bien representada en dichos estudios. Las terapias utilizadas en estos ensayos clínicos son el inhibidor de absorción intestinal de colesterol, ezetimibe y los inhibidores de la enzima PCSK9.

El estudio IMPROVE IT con ezetimibe demostró un 7% de reducción en eventos cardiovasculares con el uso de ezetimibe, añadido a terapia con estatina de intensidad moderada (simvastatina 20 mg). Los estudios FOURIER y ODYSSEY OUTCOMES, con evolocumab y alirocumab respectivamente, demostraron que estos inhibidores de PCSK9 disminuyen a más del 50% el LDL-C y, a su vez, obtuvieron un 15% de reducción en eventos mayores cardiovasculares.

La población diabética en estos tres estudios demostró mayor beneficio comparado a los no diabéticos.

Las recomendaciones discutidas en las Figuras 1, 2 y 3 enfatizan el uso de estatinas como primera línea a una intensidad ajustada al riesgo cardiovascular, el nivel de base de LDL-C y la tolerancia del paciente a ser tratado. En el paciente diabético

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se enfatiza una terapia más agresiTable 10.2-recommendations for statin and combination treatment in adults with diabetes va cuando coexiste la enfermedad ASCVD or aterosclerótica en esta población, Recommended statin intensity and Age 10-year ASCVD combination treatment* ya que su riesgo estimado de evenrisk>20% tos y mortalidad es mayor. Por estas <40 years No Nonet • In patients with ASCVD, if LDL cholesterol>70 mg/dL razones, la AACE define al paciente Yes High despite maximally tolerated statin dose, consider adding additional LDL-lowering therapy diabético con enfermedad ateroscle(such as ezetimibe or PCSK9 inhibitor) rótica cardiovascular documentada como de “riesgo extremo”. Si no es >40 years No Moderate • In patients with ASCVD, if LDL cholesterol>70 mg/dL Yes posible llegar a unos niveles óptimos High despite maximally tolerated statin dose, consider adding additional LDL-lowering therapy recomendados de LDL-C o non HDL-C, (such as ezetimibe or PCSK9 inhibitor) entonces se añade una terapia con ASCVD, atherosclerotic cardiovascular disease, PCSK9, proprotein convertase subtilisin/Kexin type 9. *In addition to lifestyle diferente mecanismo de acción; therapy. For patients who do not tolerate the intended intensity of statin, the maximally tolerated statin dose should be específicamente con ezetimibe o los used. Moderate-intensity statin may be considered based on risk-benefit profile and presence of ASCVD risk factors. ASCVD inhibidores de PCSK9 si el beneficio risk factorsincluide LDL cholesterol >100 mg/dL (2.6 mmol/L), high bolld pressure, smoking, chronic kidney disease, en riesgo cardiovascular sobrepasa albuminuria, and family hostory of premature ASCVD. High-intensity statin may be years with prevalent ASCVD were not well represented in clinical trials of non-statin-based LDL reduction. Before initiating combination lipid-lowering therapy, las interacciones, efectos adversos y consider the potential for further ASCVD risk reduction, drug-specific adverse effect, and patient preferences. los costos de estas.

El uso de ezetimibe está siendo considerado como la terapia de elección para combinar con estatina por su vía FIGURA 2 oral cuando sea necesario; experiencia prolongada en su eficacia, seguridad y la disponibilidad de formulación genérica, lo cual mejora el costo. El uso de inhibidores necesitan, ayudando a obtener niveles recomendados de PCSK9 se limita a pacientes con enfermedad aterosde LDL-C. Para mejorar el acceso a los inhibidores de clerótica cardiovascular documentada y aquellos con PCSK9, recientemente hubo una reducción significativa niveles de LDL-C de base muy elevados como hipercoen el costo de evolocumab y se espera que ocurra lo lesterolemia familiar, donde el uso de estatina con o sin mismo con alirocumab. ezetimibe no ha logrado reducciones a En cuanto a la dislipidemia, caniveles óptimos recomendados. racterística aterogénica de los diaRecientemente, evolocumab fue béticos, donde predomina el nivel El nivel de los lípidos puede ser aprobado para el uso en pacientes con alto de triglicéridos, el colesterol hiperlipidemia primaria no familiar y la de densidad alta (HDL-C) el ateroafectado por la edad, sexo y reducción de eventos cardiovasculaprotector bajo y la abundancia de antecedentes familiares. Facres. Se prevé presentar el alirocumab partículas pequeñas de LDL-C (LDL tores de estilo de vida como próximamente para que sea aprobado particles), se especulaba que el uso debido a sus resultados positivos para una dieta inadecuada, la baja de terapias dirigidas a la reducción reducir eventos cardiovasculares. Los de triglicéridos y el aumento de actividad física o fumar, tampacientes diabéticos se caracterizan HDL-C tendrían un efecto favorable bién afectan estos niveles. por tener alta incidencia de polifarcardiovascular en esta población. macia, enfermedad crónica renal e Los estudios realizados que evaluahipotiroidismo. Por tanto, poseen riesgo de efectos ron dichas terapias como fibratos, niacina y ácidos secundarios por estatinas, mayormente relacionados grasos omega 3 (O3FA) no demostraron ningún benea síntomas músculo-esqueletales. El uso de estas teficio para los pacientes, incluyendo aquellos con conrapias -que no son estatinas- son excelentes opciones dición de diabetes. La combinación de dichas terapara estos pacientes intolerantes a estas drogas o con pias con estatinas, aunque pueden ayudar a obtener tolerancia a una intensidad de estatina inferior a lo que un mejor perfil lipídico, no ha demostrado beneficio

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SUPLEMENTO ESPECIAL

SUPLEMENTO ESPECIAL

ASCVD Risk Factor Modifications Algorthm DYSLIPIDEMIA

HYPERTENSION

LIFESTYLE THERAPY (Including Medically Assisted Weight Loss)

LIPID PANEL: Assess ASCVD Risk

Goal: systolic < 130, Diatolic <80 mm Hg

STATIN THERAPY If TG > 500 mg/dL, Fibrates, Rx-grade omega-3 fatty acids, niacin If statin-intolerant Try alternate statin, lower statin dose or frequency, or add nonstatin LDL-C-lowering therapies RISK LEVELS LDL-C (mg/dL)

Repeat lipid panel, assess adquacy, tolrance of therapy

HIGH

VERY HIGH

EXTREME

DESIRABLE LEVELS

DESIRABLE LEVELS

DESIRABLE LEVELS

<100

<70

<55

Non-HDL-C (mg/dL)

<130

<100

<80

TG (mg/dL)

<150

<150

<150

APO B (mg/dL)

<90

<80

<70

If not at desirable levels:

To lower LDL-C: To lower Non-HDL-C, TG: To lower Apo B. LDL-P: To lower LDL-C in FH:**

Intensify therapies to attain goals according to risk levels HIGH: DM but no other major risk and/or age <40 VERY HIGH: DM + major ASCVD risk(s)(HTN,Farm Hx, low HDL-C, smoking, CKD3,4)*

EXTREME: DIM plus established clinical CVD

Intensify lifestyle therapy (weight loss, physical activity, dietary changes) and glycemic control.

Consider additional therapy Intensify statin, add ezetimibe, PCSK9i, colesevelam, or niacin Intensify statin and/or add Rx-grade OM3 fatty acid, fibrate, and/or niacin Intensify statin and/or add ezetimibe, PCSK9i, colesevelam, and/or niacin Statin + PCSK9i

Assess adequacy & tolerance of therapy with focused laboratory evaluations and patient follow-up

ACEi or ARB

For initial blood pressure >150/100 mm Hg: DUAL THERAPY Calcium Channel Blocker

ACEi or + B-blocker ARB Thiazide If not at goal (2-3 months) Add calcium channel blocker, B-blocker or thiazide If not at goal (2-3 months) Add next agent from the adove group, repeat If not at goal (2-3 months) Additional choices (a-blockers, cntral agents, vasodilators, aldosterona antagonist) Achievement or target blood pressure is critical

FIGURA 3

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SUPLEMENTO ESPECIAL

En el paciente diabético debemos optimizar los niveles de presión sanguínea, reducir el peso corporal, promover una dieta saludable, aumentar la actividad física, mejorar el control glucémico y educar sobre la condición cardiovascular basado en la evidencia. El uso de esta combinación solo está recomendado por juicio clínico en pacientes selectos.

Recientemente, en un estudio se escogieron aleatoriamente pacientes con enfermedad aterosclerótica cardiovascular documentada y pacientes diabéticos de aproximadamente 50 años de edad con múltiples factores de riesgo cardiovascular a utilizar 4 gramos diarios de una presentación del O3FA eicosapentoic acid (EPA) o placebo para evaluar su beneficio cardiovascular. El resultado fue una mejora significativa de un 25% en eventos cardiovasculares mayores. Esta terapia demostró resultados diferentes prometedores que pueden estar asociados al tipo de EPA purificado utilizado. Se esperan resultados de estudios en progreso con terapias similares basadas en O3FA para tratar de apoyar estos datos antes de determinar cualquier recomendación definitiva.

CONCLUSIONES En conclusión, el manejo de hiperlipidemia en pacientes diabéticos -como en otras poblaciones de alto riesgo cardiovascular- ha evolucionado en los últimos años. La prevención primaria está apoyada de forma concluyente con el uso de estatinas mayormente de intensidad moderada y con más presencia en pacientes diabéticos sobre los 40 años de edad, independientemente del nivel de base de colesterol. La prevención secundaria está aprobada en pacientes diabéticos desde edades más tempranas y se recomienda una agresividad mayor en la intensidad de la estatina a usar con el propósito de obtener niveles mucho más bajos de lo antes recomendado y disminuir eventos cardiovasculares y mortalidad.

En varios casos puede existir la necesidad de utilizar terapias adicionales a estatinas que ayuden a obtener estos valores óptimos de colesterol con apoyo de la información clínica para reducir eventos cardiovasculares. Es importante reconocer al paciente diabético como uno de alto riesgo cardiovascular y, además de controlar su colesterol, como se ha discutido en este resumen, tenemos que optimizar los niveles de presión sanguínea, 78

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reducir el peso corporal, promover una dieta saludable, aumentar la actividad física, mejorar el control glucémico y educar sobre la condición y su seguimiento. Es la ley actualmente manejar la diabetes como lo que en realidad es: un síndrome cardiometabólico.

REFERENCIAS: Grundy SM, et al. 2018: Cholesterol Clinical Practice Guidelines.

Journal of the American College of Cardiology (2018), doi: https://doi.org/10.1016/j.jacc.2018.11.003.

AACE Guidelines for the Management of Dyslipidemia and Prevention of Cardiovascular disease. ENDOCRINE PRACTICE Vol 23 (Suppl 2) April 2017 Jacobson T, et al. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Par t 1—Full Repor t. J Clin Lipidology. Volume 9, Issue 2, Pages 129–169 Randomised trial of cholesterol lowering in 4 4 4 4 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-9.

Hear t Protection Study Collaborative Group. Lancet 2003;361:2005–2016 Colhoun HM et al. Colaborative Ator vastatin Diabetes Study.

Lancet. 2004;264:685-696.

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:17 13-22.

Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy af ter acute coronar y syndromes. N Engl J Med. 2015;372:2387-97 Scwar tz, et al. Alirocumab and Cardiovascular Outcomes af ter Acute Coronar y Syndrome. N Eng J Med. 2018; 379: 2097-2107 The Effects of n3 Fatty Acid Supplement in Diabetes. The ASCEND Study Group. N Engl J Med 2018; 379:1540-1550 Bhatt, D, etal. Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT). N Engl J Med 2019; 380:11-22

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CIRUGÍA METABÓLICA COMO ALTERNATIVA PARA LA DIABETES TIPO 2

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KEY WORDS

Diabetes tipo 2, cirugía metabólica, cirugía bariátrica, paciente diabético, epidemia global.

Type 2 diabetes, metabolic surgery, bariatric surgery, diabetic patient.

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Por: Ana Santos, MD Cirujana, Directora de la División de Cirugía Bariátrica en el Hospital Menonita de Cayey desde 2001

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RESUMEN La diabetes tipo 2 se considera ya una epidemia global. En Puerto Rico, específicamente, es la tercera causa de muerte, con más de 400,000 pacientes diagnosticados y un aumento de cifras en la población infantil. Muchos pacientes optan por la terapia tradicional, basada en un cambio de estilo de vida que incluye una dieta balanceada y ejercicios, con la medicación prescrita por su médico, ya sean orales o la insulina. Sin embargo, aquellos pacientes diabéticos que también enfrentan un problema de obesidad han encontrado una alternativa eficiente en la cirugía bariátrica, que les ha permitido -incluso- abandonar la mayoría de sus medicamentos.

De hecho, cuando el índice de masa corporal es superior a 35, las indicaciones de la Asociación Americana de Diabetes se sustentan en muy buena evidencia científica. Es por ello que, la cirugía metabólica, es uno de los tratamientos más recomendados para tratar la diabetes tipo 2 entre los casos de obesidad. Con la introducción de enfoques laparoscópicos mínimamente invasivos, modelos de atención multidisciplinarios y centros especializados de gran volumen, ha habido una reducción dramática de la mortalidad. Además, los análisis económicos también han demostrado que los tratamientos quirúrgicos para la diabetes son rentables.

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ABSTRACT Type 2 diabetes is already considered a global epidemic. And in Puerto Rico, specifically, it is the third cause of death, with more than 400,000 patients diagnosed and an increase in numbers in child population. Many patients opt for traditional therapy, based on changes in lifestyle, which include a balanced diet and exercise, with the use of medication, either oral or insulin. However, the patients who also face an obesity problem have found an efficient alternative in bariatric surgery, which has allowed them to abandon most of their medications.

In fact, when the body mass index is higher than 35, the indications of the American Diabetes Association are based on very reliable scientific evidence. This is the reason why metabolic surgery is one of the most recommended treatments for Type 2 diabetes amongst the obese population. With the introduction of laparoscopic, minimally invasive approaches, multidisciplinary care models and specialized centers of large volume, there has been a dramatic reduction in mortality. In addition, economic analyzes have also shown that surgical treatments for diabetes are cost-effective.

INTRODUCCIÓN La diabetes tipo 2 se considera ya una epidemia global. En Puerto Rico, específicamente, es la tercera causa de muerte, con más de 400,000 pacientes diagnosticados y un aumento de cifras en la población infantil.

De acuerdo al Behavioral Risk Factor Surveillance System (BRFSS), que recopila estadísticas sobre enfermedades crónicas a través de los Centros de Control y Prevención de Enfermedades de Estados Unidos, Puerto Rico ha sido uno de los territorios con mayor incidencia de diabetes en todo Estados Unidos y esto ha ocurrido de manera consistente desde 1996.

En medio de este panorama, muchos pacientes optan por la terapia tradicional, basada en un cambio de estilo de vida, que incluye una dieta balanceada y ejercicios junto a la medicación prescrita por su médico, ya sean orales o la insulina. Sin embargo, aquellos pacientes diabéticos que también enfrentan un problema de obesidad han encontrado una alternativa eficiente en la cirugía metabólica que les ha permitido -incluso- abandonar la mayoría de sus medicamentos.

Aproximadamente el 5% de la población de los Estados Unidos es mórbidamente obesa. En Puerto Rico, específicamente, la prevalencia de obesidad y sobrepeso en adultos es de un 67%, según datos ofrecidos recientemente por el Foro de Obesidad en Puerto Rico, un esfuerzo realizado por el Departamento de Salud en la isla. Y la diabetes, de hecho, es uno de los problemas asociados que acarrea la obesidad.

Aunque esta enfermedad, en gran parte, sigue siendo tratada con la dieta y la terapia con medicamentos, generalmente responde bien a la cirugía bariátrica1.

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LA CIRUGÍA BARIÁTRICA La cirugía metabólica se define como el uso de operaciones gastrointestinales con la intención de tratar la diabetes tipo 2 y la obesidad. Es un procedimiento que se comenzó a evaluar hace casi un siglo, después de que informes que datan de la década de 1920 mostraran que las operaciones gastrointestinales para las úlceras y cáncer podían causar una mejora dramática de la diabetes. Después de la llegada de la cirugía bariátrica en la década de 1950, se notificaron cada vez más las observaciones de la remisión de la diabetes después de la cirugía gastrointestinal.

Pero, ¿cómo, exactamente, la cirugía mejora la diabetes? Modificando diversos mecanismos de fisiología gastrointestinal, implicados en la regulación metabólica. Dado su papel en la regulación metabólica, el tracto gastrointestinal constituye un objetivo clínicamente y biológicamente significativo para el manejo de la diabetes tipo 2. Y, de hecho, cuando el índice de masa corporal es superior a 35, las indicaciones de la Asociación Americana de Diabetes se sustentan en muy buena evidencia científica. Es por ello que la cirugía metabólica es uno de los tratamientos más recomendados para tratar la diabetes tipo 2 entre los obesos.

De acuerdo a 11 ensayos recientes, seleccionados de manera aleatoria, así como estudios que comparan la cirugía en personas con sobrepeso/obesidad con diabetes tipo 2, muestran que la cirugía metabólica produce una mejoría sustancial en el control glucémico, reduce el uso de medicamentos, disminuye el riesgo de una enfermedad cardiovascular y minimiza los ataques cardíacos, accidentes cerebrovasculares, probabilidades de cáncer y mortalidad general, mayor pérdida de peso y mejora la calidad de vida.

En el estudio “Bariatric surgery: a systematic review and meta-analysis”, uno de sus autores, el cirujano bariátrico Henry Buchwald, quien también ha sido líder en este campo durante 40 años y se ha desempeñado como presidente de la Sociedad Americana de Cirugía Bariátrica

SUPLEMENTO ESPECIAL SUPLEMENTO ESPECIAL

La elegibilidad de los pacientes para la cirugía metabólica debe ser evaluada por un equipo multidisciplinario, que debe incluir cirujano, internista, nutricionistas y especialistas en diabetes

y de la Federación Internacional de Cirugía para la Obesidad en Estados Unidos, mostró en un meta-análisis que cerca del 85% de los pacientes obesos mórbidos con diabetes del tipo dos permanecían euglicémicos (con un nivel normal de azúcar en la sangre) a más de 14 años de seguimiento, con remisión de esta patología en más del 75%; lo que fue más frecuente en el bypass gástrico (83,7%) y en menor proporción en las técnicas como la banda gástrica (47,9%).

Cabe destacar que, una persona que tenga un índice de masa corporal (IMC) de 30 o mayor, ya es candidato a la cirugía metabólica, pues ya se encuentra en un grado de obesidad.

De hecho, en el artículo “Potential of Surgery for Curing Type 2 Diabetes Mellitus”, de los doctores Franceso Rubino y Michel Gagner, hablan específicamente de cómo el bypass gástrico ha resultado favorable para pacientes diabéticos con un IMC de 30 a 35. Así que, con la existencia de la data científica sobre el éxito en la cirugía bariátrica, en los obesos, la pregunta lógica es si los diabéticos que solo tienen sobrepeso -o un IMC de 25 a 29- pudieran tener, además, el tratamiento quirúrgico como alternativa. Cuando la diabetes no está bien controlada o requiere más de dos medicamentos, debe existir una comunicación directa entre el paciente y endocrinólogo para decidir si constituye una alternativa.

Claro está, después de la operación, es de suma importancia que cada paciente se comprometa con llevar una vida más sana, con la alimentación adecuada y la actividad física necesaria para garantizar su bienestar. Una proporción sustancial de pacientes -aproximadamente el 60%- dependiendo del procedimiento, experimenta una normalización duradera de los niveles de azúcar en la sangre sin la necesidad de un tratamiento farmacológico continuo, de acuerdo a datos ofrecidos en la más reciente Cumbre de Cirugía Metabólica.

La elegibilidad de los pacientes para la cirugía metabólica debe ser evaluada por un equipo multidisciplinario, que debe incluir cirujano, internista, nutricionistas y especialistas en diabetes. Este tipo de intervención es cubierta por la mayoría de los planes médicos, gracias a la ley 212 del año 2008, con la que se establece como mandatorio en todo ofrecimiento de contrato de seguros de salud, que se incluya dentro de la póliza el pago de la cubierta de servicios clínicos, para el tratamiento de la obesidad mórbida y el síndrome metabólico con la cirugía bariátrica siempre y cuando un médico y hospital especializado en cirugía bariátrica lo estipule necesario bajo referido.

RIESGOS DE MORTALIDAD Y COSTO-EFECTIVIDAD Con la introducción de enfoques laparoscópicos mínimamente invasivos, modelos de atención multidisciplinarios y centros especializados de gran volumen, ha habido una reducción dramática de la mortalidad y la morbilidad de la cirugía bariátrica en las últimas dos décadas. La cirugía laparoscópica también permite una recuperación temprana de la cirugía y minimiza la estancia hospitalaria.

Los análisis económicos también han demostrado que los tratamientos quirúrgicos para la diabetes son rentables. De acuerdo a la data recopilada y presentada en la más reciente cumbre de cirugía metabólica, el año de vida ajustado por calidad (QALY) es aproximadamente de $3,500 a $6,500, muy por debajo de $50,000/QALY. CONCLUSIONES El seguimiento a la operación deberá incluir evaluaciones con el cirujano y el nutricionista al menos cada seis meses. Además, es fundamental tener claridad en que, con esta intervención, el paciente se está adentrando a un nuevo estilo de vida, donde es fundamental cuidar cuerpo y mente al mismo tiempo. Solo así, se potencia el éxito de la intervención.

REFERENCIAS: Rubino F, Gagner M. Potential of Surger y for Curing Type 2 Diabetes Mellitus. Ann Surg 2002; 236:554-9.

American Diabetes Association. Standards of medical care in diabetes 2009. Diabetes Care 2009-32: S13-61.

Buchwald H, Avidor Y, Braunwald E, Jensen M, Pories W, Fahrbach K et al. Bariatric surger y: a systematic review and meta-analysis.

JAMA 2004; 292:1724-37.

Lanzarini S., Enrique, Csendes J. Attila, Lembach Hanns, Molina Y. Juan Carlos, Papapietro V. Karin, Araya Q. Verónica Cirugía metabólica: ¿una nueva alternativa para el tratamiento de la diabetes mellitus tipo 2?, www.redclinica.cl, Rev Hosp Clín Univ Chile 201 Surgical Treatment for Type 2 Diabetes, Summary of Recommendations and Guidelines from the 2nd Diabetes Surgery Summit (DSS-II) Gráficas: Surgical Treatment for Type 2 Diabetes, Summar y of Recommendations and Guidelines from the 2nd Diabetes Surger y Summit (DSS-II)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Particularly close monitoring may be required.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

NDC 0002‑8824‑27 NDC 0002‑8501‑01

PATIENT COUNSELING INFORMATION: See FDA‑approved patient labeling.

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

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

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

HI U500 HCP BS 27SEP2016

Humulin R U-500 (insulin human injection)

Humulin R U-500 (insulin human injection)

HI U500 HCP BS 27SEP2016

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

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

HI U500 HCP BS 27SEP2016

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

10:38 11:58 AM AM

MSP ARTÍCULO / DE REVISIÓN

Por: Michelle Mangual, MD Directora del Programa de Fellowship de Endocrinología, Diabetes y Metabolismo del Hospital Municipal de San Juan y endocrinóloga en el Centro de Diabetes de Puerto Rico. Board Certified en Medicina Interna, Endocrinología y en Lipidología Clínica

RESUMEN Las principales causas secundarias de la diabetes son la enfermedad del páncreas exocrino, las endocrinopatías, los fármacos u otros productos químicos e infecciones. Los mecanismos que causan la diabetes secundaria se relacionan con la fisiología y fisiopatología de la secreción de insulina y su acción en los tejidos diana. El objetivo y las modalidades de tratamiento para la diabetes secundaria son similares a los de las formas de diabetes tipo 1 y tipo 2.

ABSTRACT The main secondary causes of diabetes are disease of the exocrine pancreas, endocrinopathies, drugs or other chemicals and infections. The mechanisms that cause secondary diabetes relate to the physiology and pathophysiology of the secretion of insulin and its action on target tissues. The goal and modalities of treatment for secondary diabetes are similar to those for the type 1 and type 2 forms of diabetes.

CAUSAS SECUNDARIAS DE LA DIABETES PALABRAS CLAVES

KEY WORDS

Diabetes postrasplante, fibrosis quística, hiperglucemia, pancreas exocrino, resistencia a insulina.

Postrasplant diabetes, cystic fibrosis, hyperglycemia, exocrine pancreas, insulin resistance.

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INTRODUCCIÓN La diabetes tipo 2 representa más del 90% de los casos de diabetes en los Estados Unidos, Canadá y Europa. Por otro lado, la diabetes tipo 1 representa del 5 a 10%, y el resto se debe a otras causas. Otros tipos de diabetes, también conocidos como diabetes secundaria, son causados por otras enfermedades o medicamentos.

Dependiendo del proceso primario involucrado; por ejemplo, destrucción de las células beta pancreáticas o desarrollo de resistencia periférica a la insulina), estos tipos de diabetes se comportan de manera similar a la diabetes tipo 1 o tipo 2.

Las causas más comunes de la diabetes secundaria son las siguientes: • Enfermedades del páncreas que destruyen las células beta pancreáticas (p. ej., hemocromatosis, pancreatitis, fibrosis quística, cáncer pancreático) • Síndromes hormonales que interfieren con la secreción de insulina (p. ej., feocromocitoma) • Síndromes hormonales que causan resistencia a la insulina periférica (p. ej., acromegalia, síndrome de Cushing, feocromocitoma, glucagonoma) • Medicamentos (p. ej., fenitoína, glucocorticoides, estrógenos, tiazidas, agonistas B-adrenérgicos)

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ENFERMEDADES DEL PÁNCREAS EXOCRINO Cualquier proceso que dañe de manera difusa el páncreas puede causar diabetes. Los procesos adquiridos incluyen pancreatitis, traumatismo, infección, pancreatectomía y carcinoma pancreático. Con la excepción de la causada por el cáncer, el daño al páncreas debe ser extenso para que ocurra la diabetes y los adrenocarcinomas que afectan solo a una pequeña porción del páncreas se han asociado con diabetes. Esto implica un mecanismo distinto a la simple reducción de la masa de células β. En caso de que sea lo suficientemente extensa, la fibrosis quística y la hemocromatosis también dañarán las células β y afectarán la secreción de insulina. Además, la pancreatopatía fibrocíclica puede ir acompañada de dolor abdominal que se irradia a la espalda y se pueden identificar calcificaciones pancreáticas en el examen de rayos X. En autopsia se ha encontrado fibrosis pancreática y cálculos de calcio en los conductos exocrinos.

La diabetes relacionada con la fibrosis quística (DRFQ) es la comorbilidad más frecuente en personas con fibrosis quística, la cual se presenta en aproximadamente el 20% de los adolescentes y entre el 40-50% de adultos con esta condición1. La diabetes en esta población, comparado con individuos con diabetes tipo 1 o tipo 2, está asociada con peor estado nutricional, más enfermedad pulmonar inflamatoria grave y mayor mortalidad. La insuficiencia insulínica es el defecto primario en la CFRD. La función de células β determinada genéticamente y la resistencia a la insulina asociada con infección e inflamación puede también contribuir al desarrollo de la CFRD. Anomalías más leves de la tolerancia a la glucosa es incluso más común y ocurren a edades más tempranas que la CFRD. Aún no se ha determinado si los individuos con intolerancia a la glucosa deben ser tratados con reemplazo de insulina. A pesar de que la detección de intolerancia a la glucosa antes de los 10 años puede identificar aquellos pacientes a riesgo

para la progresión a CFRD, no se ha establecido ningún beneficio con respecto al peso, estatura, BMI o función pulmonar.

La mortalidad por CFRD ha disminuido significativamente con el tiempo y la brecha en la mortalidad entre pacientes con fibrosis quística con y sin diabetes se ha reducido considerablemente. Los estudios clínicos sobre el tratamiento de CFRD son limitados. El estudio más grande comparó tres regímenes: insulina aspart antes de las comidas, repaglinida u oral placebo en pacientes con fibrosis quística con diabetes o tolerancia anormal a la glucosa. Todos los participantes tuvieron pérdida de peso en el año anterior al tratamiento. Sin embargo, en el grupo tratado con insulina, este patrón se invirtió y los pacientes ganaron 0.39 unidades de BMI (P= 0.02). El grupo tratado con repaglinida tuvo un aumento de peso inicial, pero esto no se mantuvo hasta los 6 meses. El grupo placebo continuó perdiendo peso2. La insulina sigue siendo la terapia más utilizada para la CFRD. Con la evidencia disponible hasta el momento, la Asociación Americana de Diabetes (ADA) recomienda que se debe comenzar el cernimiento anual para la CFRD a la edad de 10 años en todos los pacientes con fibrosis quística, el cual debe realizarse con un OGTT 3.

DIABETES MELLITUS POSTRASPLANTE La hiperglucemia es muy común durante el período temprano postrasplante. El 90% de los pacientes con aloinjerto renal presentan hiperglucemia en las primeras semanas después del trasplante. En la mayoría de los casos, la hiperglucemia inducida por estrés o esteroides se resuelve en el momento del alta 4 . Si bien el uso de terapias inmunosupresoras contribuye en gran medida al desarrollo de la diabetes mellitus postrasplante (DMPT), los riesgos de rechazo del trasplante son mayores que los riesgos de la DMPT y la función del médico es tratar la hiperglucemia de manera adecuada, independientemente del tipo de inmunosupresión. Los factores de riesgo para la DMPT incluyen tanto los riesgos generales de diabetes como la edad, los antecedentes familiares de diabetes, los factores específicos del

SUPLEMENTO ESPECIAL SUPLEMENTO ESPECIAL

trasplante y el uso de agentes inmunosupresores. Mientras que la hiperglucemia postrasplante es un factor de riesgo importante para el desarrollo de la DMPT, un diagnóstico formal de DMPT se realiza de manera óptima una vez que el paciente está estable con inmunosupresión de mantenimiento y en ausencia de infección aguda5. El OGTT se considera la prueba estándar para el diagnóstico de DMPT. Pocos estudios han informado sobre el uso a corto y largo plazo de agentes antihiperglucémicos en el contexto de DMPT. La mayoría de los estudios han reportado que los pacientes de trasplante con hiperglucemia y DMPT después del trasplante tienen mayores tasas de rechazo, infección y re-hospitalización. La terapia con insulina es el agente de elección para el tratamiento de la hiperglucemia y la diabetes en el entorno hospitalario. Después del alta, los pacientes con diabetes preexistente podrían volver a su régimen antes del trasplante si estos se encontraban en un buen control antes del trasplante. Mientras que, las personas con un control previo deficiente o con hiperglucemia persistente, deben continuar la insulina junto a un monitoreo frecuente de la glucemia en el hogar para determinar cuándo pueden ser necesarias reducciones de las dosis de insulina y cuándo puede ser apropiado cambiar a hipoglucemiantes orales. Ningún estudio hasta la fecha ha establecido qué agentes no insulínicos son más seguros o más eficaces en la DMPT; la elección del agente generalmente se realiza en función del perfil de efectos secundarios de la medicación y las posibles interacciones con el régimen de inmunosupresión del paciente5.

Es posible que se requieran ajustes de la dosis del agente antihiperglucémico debido a la disminución de la tasa de filtración glomerular, una complicación relativamente común en los pacientes de trasplante. Un pequeño estudio piloto a corto plazo informó que la metformina era segura para uso en pacientes con trasplante renal, pero su seguridad no se ha determinado en otros tipos de trasplante de órganos 6. Las tiazolidinedionas se han utilizado con éxito en pacientes con trasplantes de hígado y riñón. Los

LA FUNCIÓN DE CÉLULAS β DETERMINADA GENÉTICAMENTE Y LA RESISTENCIA A LA INSULINA ASOCIADA CON INFECCIÓN E INFLAMACIÓN PUEDE TAMBIÉN CONTRIBUIR AL DESARROLLO DE LA CFRD. inhibidores de la dipeptidil peptidasa 4 no interactúan con los fármacos inmunosupresores y han demostrado seguridad en ensayos clínicos pequeños.

de forma permanente las células β pancreáticas. Tales reacciones a los medicamentos, -afortunadamenteson raras. También hay muchos medicamentos y hormonas que pueden afectar la acción de la insulina como el ácido nicotínico y glucocorticoides.

Se ha informado que los pacientes que reciben interferón α desarrollan diabetes asociada con los anticuerpos de las células de los islotes y, en ciertos casos, una deficiencia grave de insulina.

REFERENCIAS: Moran A, Pillay K, Becker D, Granados A, Hameed S, Acerini CL. ISPAD Clinical Practice Consensus Guidelines 2018: management of cystic fibrosis-related diabetes in children and adolescents.

Pediatr Diabetes 2018;19

ENDOCRINOPATÍAS Varias hormonas; por ejemplo, hormona de crecimiento, cortisol, glucagón, epinefrina, antagonizan la acción de la insulina. Las cantidades excesivas de estas hormonas como la acromegalia, síndrome de Cushing, glucagonoma, feocromocitoma, respectivamente, pueden causar diabetes. Esto generalmente ocurre en individuos con defectos preexistentes en la secreción de insulina y la hiperglucemia generalmente se resuelve cuando se resuelve el exceso de hormonas. La hiperglucemia generalmente es resuelta después de que el tumor es removido.

Moran A, Pekow P, Grover P, et al.; Cystic Fibrosis Related Diabetes Therapy Study Group. Insulin therapy to improve BMI in cystic fibrosis–related diabetes without fasting hyperglycemia: results of the Cystic Fibrosis Related Diabetes Therapy Trial. Diabetes Care 2009;32: 1783-1788

DIABETES INDUCIDA POR MEDICAMENTOS O SUSTANCIAS QUÍMICAS Muchas drogas pueden perjudicar la secreción de insulina. Aunque, es posible que estos medicamentos no causen diabetes por sí mismos, pero pueden precipitar la diabetes en personas con resistencia a la insulina. En tales casos, la clasificación no está clara porque se desconoce la secuencia o la importancia relativa de la disfunción de las células β y la resistencia a la insulina. Ciertas toxinas como el vacor (un veneno para ratas) y la pentamidina intravenosa pueden destruir

Wallia A, Illuri V, Molitch ME. Diabetes care af ter transplant: definitions, risk factors, and clinical management. Med Clin Nor th Am 2016;100: 535-550

Standards of Medical Care in Diabetes.

Diabetes Care 2019 Jan; 42 (Supplement 1) Chakkera HA, Weil EJ, Castro J, et al.

Hyperglycemia during the immediate period af ter kidney transplantation. Clin J Am Soc Nephrol 2009;4: 853-859

Kurian B, Joshi R, Helmuth A. Effectiveness and long-term safety of thiazolidinediones and metformin in renal transplant recipients. Endocr Pract 2008; 14:979–984 Budde K, Neumayer H-H, Fritsche L, Sulowicz W, Stompor T, Eckland D. The pharmacokinetics of pioglitazone in patients with impaired renal function. Br J Clin Pharmacol 2003; 55:368-374

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MSP ARTÍCULO / ORIGINAL Por: Paola Mansilla Letelier, MD Endocrinóloga e Internista

PELLETS COMO REEMPLAZO HORMONAL

PALABRAS CLAVES

KEY WORDS

Terapia hormonal, hipogonadismo, pellets, testosterona, cáncer de próstata.

Hormone therapy, hypogonadism, pellets, testosterone, prostate cancer.

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MSP ARTÍCULO / ORIGINAL

En algunos casos el paciente no necesariamente necesita reemplazo de testosterona, sino corregir el problema de base

RESUMEN En los últimos años, la terapia hormonal ha logrado su acogida como la nueva fuente de la juventud. Sin embargo, al recurrir a manos inexpertas, estas terapias pueden ser el detonante para problemas aún mayores. Es importante que el clínico reconozca y sepa hacer el diagnóstico adecuado de hipogonadismo antes de empezar cualquier tipo de reemplazo de testosterona. Pacientes que no tienen un diagnóstico claro de hipogonadismo pueden resultar con daños permanentes en el eje pituitárico-hipotalámico y otras enfermedades como cáncer de próstata.

ABSTRACT In recent years, hormone therapy has achieved its acceptance as the new source of youth. However, by resorting to inexperienced hands, these therapies can be the trigger for even greater problems. It is important that the clinician recognize and know how to make the proper diagnosis of hypogonadism before starting any type of testosterone replacement. Patients who do not have a clear diagnosis of hypogonadism can result with permanent damage to the pituitary-hypothalamic axis and other diseases such as prostate cancer.

En los últimos años, la terapia hormonal ha logrado su acogida como la nueva fuente de la juventud. ¿Tiene problemas de cansancio, falta de energía, pérdida de cabello o problemas de peso? La terapia hormonal aparenta ser la solución a todos estos problemas. Sin embargo, -lamentablemente- al recurrir a manos inexpertas, estas terapias pueden ser el detonante a problemas aún mayores.

Los primeros reemplazos hormonales fueron utilizados en mujeres post-menopáusicas en la década del 30. Posteriormente, en el año 1972, Testopel® fue aprobada por la FDA para hombres con hipogonadismo. Desde entonces, muchas otras terapias -en varias formulaciones- fueron aprobadas para esta misma condición.

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Sin embargo -debido a anuncios y promociones inadecuadas- el uso inapropiado de estas terapias y otras que dicen ser bioidénticas, han tenido un impacto en la salud de muchos hombres que buscan este tipo de reemplazo para problemas de erección, aumento de musculatura, efecto “anti-aging”, incrementar su deseo sexual o mejorar su rendimiento físico en eventos deportivos.

Por esta razón, es importante que el clínico reconozca y sepa hacer el diagnóstico adecuado de hipogonadismo antes de empezar cualquier tipo de reemplazo de testosterona, pues esta es la única indicación actual para su utilización, según las guías existentes. Pacientes que no tienen un diagnóstico claro de hipogonadismo pueden resultar con daños permanentes en el eje pituitárico-hipotalámico y otras enfermedades como cáncer de próstata, según se ha visto.

SÍNTOMAS DE TESTOSTERONA BAJA En jóvenes -usualmente- la testosterona baja se caracteriza por un pobre desarrollo de los testículos, pobre desarrollo de la voz masculina, carencia de vello facial, dificultad para ganar masa muscular, desarrollo del tejido mamario, entre otros. En el adulto mayor, los síntomas suelen ser menos específicos.

Estos pueden presentar cambios de humor y pérdida de apetito sexual (libido), el cual no se debe confundir con problemas de erección; ya que este último, no necesariamente está relacionado a niveles bajos de testosterona.

PACIENTES INDICADOS PARA LA TERAPIA DE TESTOSTERONA La terapia hormonal de testosterona no está indicada para todos los pacientes. Solo aquellos con problemas reales de hipogonadismo primario (testicular) o secundario (pituitáricohipotalámico) son los que poseen indicación para la misma. La manera correcta de hacer este diagnóstico es bajo la dirección de un endocrinólogo; este realiza pruebas hormonales para determinar en qué área se encuentra el problema y corregirlo.

DIAGNÓSTICO DE HIPOGONADISMO El diagnóstico de hipogonadismo se realiza mediante pruebas del eje pituitario-hipotalámico, las cuales incluyen las hormonas foliculoestimulante (FSH) y luteinizante (HL). Además, pruebas de niveles de testosterona. Si el paciente refleja deficiencia de testosterona entre las 8 y las 10 de la mañana en dos o más

SUPLEMENTO ESPECIAL SUPLEMENTO ESPECIAL Pacientes que no tienen un diagnóstico claro de hipogonadismo pueden resultar con daños permanentes en el eje pituitáricohipotalámico y otras enfermedades como cáncer de próstata

ocasiones, entonces es diagnosticado con la condición y se procede al reemplazo hormonal con testosterona. De igual modo, es importante reconocer que, en algunos casos como en la obesidad, apnea del sueño, VIH, entre otras, se puede dar una aparente disminución en la testosterona total. En este caso, el paciente no necesariamente necesita reemplazo de testosterona, sino corregir el problema de base; por ejemplo, bajar de peso.

adecuada, se ha visto daño temporal o permanente del eje hipotalámico-pituitario; lo cual provoca dependencia de por vida a esta hormona. Pacientes que tengan indicación y que estén bajo reemplazo hormonal, deben ser evaluados periódicamente con niveles de testosterona para evitar sobretratamiento y sus efectos adversos.

CONCLUSIONES REEMPLAZO DE TESTOSTERONA El reemplazo de testosterona se realiza mediante distintas formulaciones: inyecciones intramusculares, parchos, geles, pellets o pequeñas tabletas que pueden colocarse en las encías.

Aquellos hombres que utilizan geles, parchos o tabletas deben lavarse las manos después de colocarse el reemplazo como medida preventiva; ya que este puede absorberse fácilmente a través de la piel de otra persona y tener efectos perjudiciales, sobre todo en féminas o niños.

PELLETS DE TESTOSTERONA. SU FUNCIÓN Los pellets de testosterona son aproximadamente del tamaño de un grano de arroz y son implantados de forma subcutánea en el área de la cadera o en los glúteos. Estos contienen testosterona cristalizada, la cual es liberada de forma gradual a lo largo de seis meses aproximadamente. La dosis adecuada puede cambiar, debido a que cada paciente puede absorber la hormona de manera distinta y su volumen de distribución cambia. En el caso de los pellets, la dosis puede ser difícil de ajustar, ya que hay que hacer nuevas incisiones para poder implantar o remover estos compuestos. Por otro lado, en aquellos pacientes que están sobretratados o que tienen niveles de testosterona por encima del nivel normal, se hace casi imposible poder removerlos. Esto, debido a que, en muchos casos, se ha creado tejido fibrótico alrededor, lo cual hace difícil la remoción. Debido a esto, este tipo de terapia no está recomendada según las guías del “Endocrine Society”.

EFECTOS ADVERSOS DEL REEMPLAZO HORMONAL DE TESTOSTERONA Entre los efectos adversos se encuentran el acné, el conteo elevado de glóbulos rojos, el agrandamiento de la próstata y un aumento en el riesgo de infartos cerebrales o ataques cardíacos, especialmente en hombres mayores de 60 años. En paciente que han usado por años la testosterona sin indicación

Es importante recalcar que la terapia hormonal, sea cual fuese su administración, requiere la evaluación de un endocrinólogo especialista en la condición. La única indicación actual de la terapia es el hipogonadismo. Lamentablemente, el impacto de los anuncios sobre el uso de testosterona como terapia “anti-aging” o su uso inadecuado para tratar la obesidad, los problemas de erección o el deseo sexual, ha hecho que cada día se utilice inadecuadamente esta terapia.

Cambios pequeños en el estilo de vida como la higiene del sueño, la buena alimentación y el ejercicio, aunque sea en intervalos cortos, pueden mejorar los estados de ánimo y la liberación de endorfinas. Estas sustancias mejoran el insomnio, el estrés, la libido y otros problemas que presentan a diario los pacientes y que, tienden a confundirse con posible deficiencia de testosterona. El reemplazo de testosterona puede ser adecuado para algunos, pero la importancia de hacer un diagnóstico certero es vital para evitar efectos adversos.

REFERENCIAS: Patient education: Androgen replacement in men (The Basics). Recuperado de https://www.uptodate.com/contents/androgen-replacement-in-men-the-basics?search=hypogonadism&topicRef=7462&source=related_link Shalender Bhasin, Juan P. Brito, Glenn R., Cunningham Frances, J. Hayes Howard, N. Hodis Alvin, M. Matsumoto, Peter J., Snyder Ronald, S. Swerdloff, Frederick C., Wu Maria, A. Yialamas. (2018) Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline The Journal of Clinical Endocrinology & Metabolism, 2018; 103(5):1715-1744. Recuperado dehttps://medlineplus.gov/spanish/ency/article/000390.htm Testospel. Recuperado de https://www.drugs.com/pro/testopel.html Testosterone treatment of male hypogonadism. Recuperado de https:// www.uptodate.com/contents/testosterone-treatment-of-male-hypo-

Revista Puertorriqueña de Medicina y Salud Pública

99

THESE ARE PATIENTS WITH

METASTATIC GASTRIC,

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

PATIENTS WHO, IN THE FACE OF ADVERSITY,

REMAIN DETERMINED.

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

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

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

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

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

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

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

”We have some unfinished business.”

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

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

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

”I ’m ready to do

what it takes.”

METASTATIC COLORECTAL CANCER INDICATION

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

INDICATIONS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Non-Small Cell Lung Cancer CYRAMZA in combination with docetaxel, is indicated for treatment of metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. Colorectal Cancer CYRAMZA in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown.

In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel.

Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event.

Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation.

In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

CYRAMZA® (ramucirumab) injection

CYRAMZA RB-P HCP BS 27MAR2017 - 9.5 x 11.5

RB-P HCP BS 27MAR2017

Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients.

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Gastric Cancer Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal.

CYRAMZA Administered as a Single Agent Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1 provides the frequency and severity of adverse reactions in Study 1.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1

Adverse Reactions (MedDRA) System Organ Class

CYRAMZA (8 mg/kg) N=236

Placebo N=115

All Grades (Frequency %)

Grade 3-4 (Frequency %)

All Grades (Frequency %)

Grade 3-4 (Frequency %)

14

1

9

2

6

3

2

1

9

0

3

0

16

8

8

3

Gastrointestinal Disorders Diarrhea Metabolism and Nutrition Disorders Hyponatremia Nervous System Disorders Headache Vascular Disorders Hypertension

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions.

In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 61 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months.

In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 2 provides the frequency and severity of adverse reactions in Study 2.

Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2 Adverse Reactions (MedDRA) System Organ Class Blood and Lymphatic System Disorders Neutropenia Thrombocytopenia Gastrointestinal Disorders Diarrhea Gastrointestinal hemorrhage events Stomatitis CYRAMZA® (ramucirumab) injection

CYRAMZA plus Paclitaxel (N=327) All Grades Grade ≥3 (Frequency %) (Frequency %)

Placebo plus Paclitaxel (N=329) All Grades Grade ≥3 (Frequency %) (Frequency %)

54 13

41 2

31 6

19 2

32 10 20

4 4 1

23 6 7

2 2 1 RB-P HCP BS 27MAR2017

PRINTER VERSION 1 OF 3

Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2 (Cont.)

CYRAMZA plus Paclitaxel (N=327) All Grades Grade ≥3 (Frequency %) (Frequency %) General Disorders and Administration Site Disorders Adverse Reactions (MedDRA) System Organ Class

Fatigue/Asthenia Peripheral edema Metabolism and Nutrition Disorders Hypoalbuminemia Renal and Urinary Disorders Proteinuria Respiratory, Thoracic, and Mediastinal Disorders Epistaxis Vascular Disorder Hypertension

Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Placebo plus Paclitaxel (N=329) All Grades Grade ≥3 (Frequency %) (Frequency %)

57 25

12 2

44 14

6 1

11

1

5

1

17

1

6

0

31

0

7

0

25

15

6

3

Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel).

Non-Small Cell Lung Cancer CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months.

In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation.

Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colonystimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.

Table 3 provides the frequency and severity of adverse reactions in Study 3.

Adverse Reactions (MedDRA) System Organ Class

Blood and Lymphatic System Disorders Febrile neutropenia 16 Neutropenia 55 Thrombocytopenia 13 Gastrointestinal Disorders Stomatitis/Mucosal inflammation 37 Eye Disorders Lacrimation increased 13 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 Peripheral edema 16 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 Vascular Disorders Hypertension 11

10 46 5

10 40 <1

7

19

2

<1

5

0

14 0

50 9

11 <1

<1

7

<1

6

5

2

CYRAMZA RB-P HCP BS 27MAR2017 - 9.5 x 11.5

Adverse Reactions (MedDRA) System Organ Class

CYRAMZA plus FOLFIRI N=529

Placebo plus FOLFIRI N=528

All Grades (Frequency %)

Grade ≥3 (Frequency %)

All Grades (Frequency %)

Grade ≥3 (Frequency %)

Neutropenia

59

38

46

23

Thrombocytopenia

28

3

14

<1

Blood and Lymphatic System Disorders

Gastrointestinal Disorders Decreased appetite

37

2

27

2

Diarrhea

60

11

51

10

Gastrointestinal hemorrhage events

12

2

7

1

Stomatitis

31

4

21

2

20

<1

9

0

6

1

2

0

17

3

5

<1

33

0

15

0

13

1

5

<1

26

11

9

3

General Disorders and Administration Site Disorders Peripheral edema Metabolism and Nutrition Disorders Hypoalbuminemia Renal and Urinary Disorders Proteinuriaa Respiratory, Thoracic, and Mediastinal Disorders Epistaxis Skin and Subcutaneous Tissue Disorders

Vascular Disorders

Placebo plus docetaxel (N=618) All Grades Grade 3-4 (Frequency %) (Frequency %)

16 49 3

CYRAMZA® (ramucirumab) injection

Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 4

Palmar-plantar erythrodysesthesia syndrome

Table 3: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 CYRAMZA plus docetaxel (N=627) All Grades Grade 3-4 (Frequency %) (Frequency %)

Colorectal Cancer CYRAMZA Administered in Combination with FOLFIRI Study 4 was a multinational, randomized, double-blind study conducted in patients with metastatic colorectal cancer with disease progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients received either CYRAMZA 8 mg/kg intravenously plus FOLFIRI intravenously every 2 weeks or placebo plus FOLFIRI intravenously every 2 weeks.

Study 4 excluded patients with an ECOG PS of 2 or greater, uncontrolled hypertension, major surgery within 28 days, and those who experienced any of the following during first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event; Grade 4 hypertension; Grade 3 proteinuria; a Grade 3-4 bleeding event; or bowel perforation.

Demographics and baseline characteristics for the treated population were similar between treatment arms (n=1057). Median age was 62 years; 57% of patients were men; 76% were White and 20% were Asian; 48% had ECOG PS 0.

The data described in this section reflect exposure to CYRAMZA plus FOLFIRI in 529 patients in Study 4. Patients received a median of 8 doses (range 1-68) of CYRAMZA; the median duration of exposure was 4.4 months, and 169 (32% of 529) patients received CYRAMZA for at least six months. The most common adverse reactions (all grades) observed in CYRAMZA plus FOLFIRI-treated patients at a rate of ≥30% and ≥2% higher than placebo plus FOLFIRI were diarrhea, neutropenia, decreased appetite, epistaxis, and stomatitis. Twenty percent of patients treated with CYRAMZA plus FOLFIRI received granulocyte colony-stimulating factors. Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%).

The most common adverse reactions leading to discontinuation of any component of CYRAMZA plus FOLFIRI as compared to placebo plus FOLFIRI, were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).

The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).

Table 4 provides the frequency and severity of adverse reactions in Study 4.

RB-P HCP BS 27MAR2017

Hypertension a

Includes 3 patients with nephrotic syndrome in the CYRAMZA plus FOLFIRI treatment group.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus FOLFIRI-treated patients in Study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).

Thyroid stimulating hormone (TSH) levels were evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus FOLFIRI-treated patients) with normal baseline TSH levels. Patients underwent periodic TSH laboratory assessments until 30 days after the last dose of study treatment. Increased TSH levels were observed in 53 (46%) patients treated with CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI. Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZAtreated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

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 CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38.

CYRAMZA® (ramucirumab) injection

RB-P HCP BS 27MAR2017

PRINTER VERSION 2 OF 3

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36).

Of the 529 patients who received CYRAMZA plus FOLFIRI in Study 4, 209 (40%) were 65 and over, while 51 (10%) were 75 and over. Overall, no differences in safety or effectiveness were observed between these subjects and younger subjects.

Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.

Table 5: CYRAMZA Dose Reductions for Proteinuria Initial CYRAMZA Dose 8 mg/kg 10 mg/kg

First Dose Reduction to: 6 mg/kg 8 mg/kg

Second Dose Reduction to: 5 mg/kg 6 mg/kg

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to paclitaxel, docetaxel, or the components of FOLFIRI, refer to the current prescribing information.

PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event.

• Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment.

• Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA. Additional information can be found at www.CYRAMZAHCP.com.

DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule Gastric Cancer The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel.

Non-Small Cell Lung Cancer The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity.

Colorectal Cancer The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. Continue CYRAMZA until disease progression or unacceptable toxicity.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride).

For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose (see Table 5) once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose (see Table 5) once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. ®

CYRAMZA (ramucirumab) injection

CYRAMZA RB-P HCP BS 27MAR2017 - 9.5 x 11.5

RB-P HCP BS 27MAR2017

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2017, Eli Lilly and Company. All rights reserved.

RB-P HCP BS 27MAR2017 PP-RB-US-0989 CYRAMZA® (ramucirumab) injection

RB-P HCP BS 27MAR2017

PRINTER VERSION 3 OF 3

2019

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

Fecha

Actividad

1 de marzo 2019

1er Congreso de Salud Mental de PR

Puerto Rico

Lugar

Coordinador o Contacto

Comentarios

San Juan Marriot Hotel San Juan, PR

Pedro Del Valle 787-562-1516 pldvalle@hotmail.com

CONGRESO

2 de marzo 2019

Simposio Ortopédico de Columna- SPOT

El San Juan Hotel San Juan, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología (SPOT) 787-723-6751 asis.spot@gmail.com

SIMPOSIO

7 al 9 de Marzo 2019

Convención Anual Academia Médica del Sur

Ponce Hilton Hotel Ponce, PR

Academia Médica del Sur 787-843-0610 academiamedicadel sur@gmail.com

CONVENCIÓN

8 al 10 de marzo 2019

Convención anual-American College of Physicians

Hotel la Concha San Juan, PR

RIVS Marketing 787-548-0047 info@rivsmarketing.com

9 de Marzo 2019

Be Brave Rheumatic Updates and Research Trends

Fraternidad AFDA El Condado, Calle Cervantes #2 San Juan, PR

Fundación Bechara & Asociación de Reumatólogos de PR 787-512-2223 www.fundacionbechara.org

CONFERENCIAS

15 al 17 de marzo 2019

Conferencia de Primavera- Colegio de Químicos de PR

Ponce Hilton Hotel Ponce, PR

Alterna Communications 787-239-4885 Sheileen Velázquez

CONFERENCIAS

19 al 20 de marzo 2019

Jornada- Iniciativa de Servicios de Salud en los Centros de Salud Primaria 330 para el Uso Problemático de Sustancias en Puerto Rico

Hotel Marriot Isla Verde, PR

Virginia de los Reyes 787-409-8465

CONFERENCIA

29 al 31 de marzo 2019

Cursos Obligatorios- San Juan

Club Rotario Río Piedras San Juan, PR

High Education Health 787-964-6394 heh@hehpr.com/ www.hehpr.com

5 al 6 de abril 2019

Pulmonary and Critical Care Congress 2019- Sociedad Puertorriqueña de Neumología

Ponce Hilton Hotel Ponce, PR

Business Planners Merna Morales 787-706-0442 bplanner21@gmail.com

CONVENCIÓN

6 de abril 2019

Congress 2019 Neurology & Pregnancy-Academia Puertorriqueña de Neurología

Sheraton Convention Center Hotel San Juan, PR

AMEC 787-289-8989 amecpr@gmail.com

CONGRESO

6 al 7 de abril 2019

Convención Anual Academia de Patología y Medicina de Laboratorio de PR

Sheraton Convention Center Hotel San Juan, PR

Serra & Serra Group 787-640-5776 patologospr@serrayserra.com

CONVENCIÓN

6 de abril 2019

Convención anual Asociación de Psiquiatras de Bayamón

Hotel la Concha San Juan, PR

AMEC 787-289-8989 amecpr@gmail.com

CONVENCIÓN

25 al 27 abril 2019

Convención Anual Academia de Médicos de Familia de PR

Sheraton Convention Center Hotel San Juan, PR

SDMS 787-731-3325 info@sdmsgroup.com

CONVENCIÓN

106

Revista Puertorriqueña de Medicina y Salud Pública

Fecha

Actividad

Lugar

Coordinador o Contacto

Comentarios

27 al 28 de abril 2019

Pain Mangement Academy Annual Convention 2019

Sheraton Convention Center Hotel San Juan, PR

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

CONVENCIÓN

27 de abril 2019

Curso Avanzado sobre Dosificación, Metas Terapéuticas y Administración del Cannabis Medicinal

Recinto de Ciencias Médicas San Juan, PR

Medical Cannabis Training Institute 787-589-8050 info@mctipr.com

CURSO

27 de abril 2019

Simposio Ortopédico de Medicina Deportiva- SPOT

El San Juan Hotel San Juan, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología (SPOT) 787-723-6751 asis.spot@gmail.com

SIMPOSIO

26 al 27 de abril 2019

Simposio Internacional sobre Latinos y Enfermedad de Alzheimer

San Juan, PR

Universidad de Puerto Rico (RCM) División de Educación Continua 787-250-1312 http://mghcme.org/alzheimers

SIMPOSIO

27 de abril 2019

2019 Insomnia Update

Casa del Médico del Oeste Mayagüez, PR

Japri Planners 787-612-5775 787-961-2502 japriplanners@hotmail.com

CURSO

28 de abril 2019

Educación Continuada- Síndrome Hermansky Pudlak & Fibrosis Pulmonar

Marriot Hotel Isla Verde, PR

Sociedad Torácica Americana y Red de HPS 1-855-754-1040

CURSO

3 al 5 de Mayo 2019

2da Cumbre Asociaciones Psiquátricas de Puerto Rico

Wyndham Rio Mar Hotel Río Grande, PR

Educational Partners (787) 646-0780 vperez@epcpr.com

CONVENCIÓN

3 al 5 de mayo 2019

14th Annual Meeting of Infectious Diseases- Sociedad de Enfermedades Infecciosas de Puerto Rico

Embassy Suites Dorado del Mar Dorado, PR

Enid Rivera 804-774-6326 enidrm27@gmail.com

CONVENCIÓN

3 al 4 de mayo 2019

American College of Cardiology, PR Chapter- Annual Convention 2019

Intercontinental Hotel Isla Verde, PR

ACC-PR Chapter Aixa Vélez 787-649-7681 www.accpuertorico.org

CONVENCIÓN

4 al 5 de mayo 2019

Convención Anual Sociedad Radiológica (SOCRAD)

Wyndham Rio Mar Rio Grande, PR

Serra & Serra Group 787-640-5776 info@socrad.com

CONVENCIÓN

4 de mayo 2019

A Practical Approach Optimizing the Glycemic Control in the Outpatient with Type 2 Diabetes Course- American College of Physicians

Hyatt Place San Juan, PR

RiVS Marketing 787-548-0047 info@rivsmarketing.com

CURSO

9 al 10 de mayo 2019

Puerto Rico Clinical Research Summit 2019

Sheraton Convention Center Hotel San Juan, PR

Consorcio de Investigación Clínica de PR http://prsciencetrust.org /prcr-summit-2019/

CONVENCIÓN

17 al 19 de mayo 2019

Convención Anual Asociación d e Reumatólogos de PR

Wyndham Rio Mar Rio Grande, PR

Serra & Serra Group 787-640-5776 reumatologospr@serrayserra.com

CONVENCIÓN

16 al 18 de mayo 2019

American College of Surgeons, PR Chapter- Annual Convetion 2019

Escuela de Medicina UPR & Vivo Beach Club Isla Verde, PR

ACS-PR Chapter Aixa Vélez 787-649-7681 www.facs.org

CONVENCIÓN

17 al 18 de mayo 2019

Second Biannual Transgender Health Care Summit

La Concha Resort Hotel San Juan, PR

Educational Partners (787) 646-0780 vperez@epcpr.com

CUMBRE

24 al 27 de mayo 2019

SPED Annual Convention

Hotel El Conquistador Fajardo, PR

Educational Partners (787) 646-0780 vperez@epcpr.com

CONVENCIÓN

31 de mayo al 2 de junio 2019

Cursos Obligatorios- Mayagüez

Club de Leones Mayagüez, PR

High Education Health 787-964-6394 heh@hehpr.com/ www.hehpr.com

CURSOS

6 al 8 de junio 2019

Convención Anual de la Sociedad de Médicos Podiatras de PR

Hotel El Convento San Juan, PR

Sociedad de Médicos Podiatras de PR Aixa Vélez 787-649-7681

CONVENCIÓN

Revista Puertorriqueña de Medicina y Salud Pública

107

Fecha

108

Actividad

Lugar

Coordinador o Contacto

Comentarios

7 al 8 de junio 2019

Caribbean Congress on Emergency Medicine- Colegio de Emergenciólogos de PR

Sheraton Convention Center Hotel San Juan, PR

RiVS Marketing 787-548-0047 info@rivsmarketing.com

7 al 9 de junio 2019

Cursos Obligatorios- San Juan

Club Rotario Río Piedras San Juan, PR

High Health Education 787-964-6394 heh@hehpr.com/www.hehpr.com

CURSO

6 al 9 de junio de 2019

Convención Anual-Sociedad Puertorriqueña de Oftalmología

St. Regis Bahía Beach Hotel Rio Grande, PR

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

CONVENCIÓN

15 de junio 2019

Personalized Medicine Medicine for the Prevention and Treatment of Colorrectal Cancer- Coalición de Cáncer Colorrectal de PR

Embassy Suites Hotel Isla Verde & Mayagüez Resort Hotel

IC PLANNERS Ivette Colón 787-504-3655 ivettecolon@icplannerspr.com

SIMPOSIO

20 al 22 de junio 2019

Sociedad Dermatológica de PR- 2019 Summer Meeting

Caribe Hilton Hotel San Juan, PR

RN ProEvents 787-368-7939 rafinieto@rnproevents.com

CONVENCIÓN

21 al 23 de junio 2019

Convención anual Asociación Puertorriqueña de Medicina Física y Rehabilitación

Meliá Coco Beach Resort Rio Grande, PR

Serra & Serra Group 787-640-5776 asocfisiatraspr@serrayserra.com

CONVENCIÓN

21-23 de junio 2019

Convención anual Sociedad Puertorriqueña de Cardiología Intervencional

Falta Confirmar lugar**

Enid Rivera 804-774-6326 enidrm27@gmail.com

CONVENCIÓN

22 de junio 2019

Simposio Ortopédico de Trauma- SPOT

El San Juan Hotel San Juan, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología (SPOT) 787-723-6751 asis.spot@gmail.com

SIMPOSIO

12 al 14 de julio 2019

Convención anual- Sociedad Puertorriqueña de Cardiología

Sheraton Convention Center Hotel San Juan, PR

Sociedad Puertorriqueña de Cardiología 787-620-2228 socprcardio@gmail.com

CONVENCIÓN

28 al 30 de junio 2019

Convención anual Academia de Medicina General de PR

Sheraton Convention Center Hotel San Juan, PR

SR Consultants and Events 939-292-4115 srconsultantsandevents@gmail.com

CONVENCIÓN

1 al 4 de agosto 2019

Convención Caribe Gyn 2019

Ponce Hilton Hotel Ponce, PR

Germaine Quiñones 787-608-1477 caribegyn2015@gmail.com

CONVENCIÓN

2 al 3 de agosto 2019

ASCO Annual Convention 2019

Caribe Hilton Hotel San Juan, PR

Total Health Conferencing Sarah Louden (561)-663-1628 www.totalhealthconferencing.com

CONVENCIÓN

24 de agosto 2019

Asociación de Gastroenterología y Hepatología Pediátrica de PR

Sheraton Convention Center Hotel San Juan, PR

IC PLANNERS Ivette Colón 787-504-3655 ivettecolon@icplannerspr.com

SIMPOSIO

24 de agosto 2019

Convención Anual- Facultad Médica del Hospital Panamericano

Hotel Verdanza Isla Verde, PR

Japri Planners 787-612-5775 787-961-2502 japriplanners@hotmail.com

CONVENCIÓN

24 de agosto 2019

Update in GI Cancer Symposium- Asociación Puertorriqueña de Gastroenterología

Caribe Hilton Hotel San Juan, PR

RiVS Marketing 787-548-0047 info@rivsmarketing.com

SIMPOSIO

30 de agosto al 2 de septiembre 2019

Convención Anual Sociedad Puertorriqueña de Ortopedia y Traumatología (SPOT)

Wyndham Rio Mar Hotel Rio Grande, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología (SPOT) 787-723-6751 asis.spot@gmail.com

CONVENCIÓN

31 de agosto al 2 de septiembre 2019

Convención Anual Sociedad de Médicos Pediatras Región Oeste (AMPRO)

Mayagüez Resort & Casino Mayagüez, PR

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

CONVENCIÓN

Revista Puertorriqueña de Medicina y Salud Pública

CONGRESO

Fecha

Actividad

Lugar

Coordinador o Contacto

Comentarios

7 de septiembre 2019

Update in the Treatment of Liver Diseases- Asociación Puertorriqueña de Gastroenterología

Hotel La Concha San Juan, PR

RiVS Marketing 787-548-0047 info@rivsmarketing.com

SIMPOSIO

13 al 15 de septiembre 2019

Cursos Obligatorios- Mayagüez

Club de Leones Mayagüez, PR

High Education Health 787-964-6394 heh@hehpr.com/www.hehpr.com

CURSO

21 de septiembre 2019

Excellence in Nursing- Sociedad Puertorriqueña de Asistentes de Gastroenterología

Caribe Hilton Hotel San Juan, PR

RiVS Marketing 787-548-0047 info@rivsmark ting.com

CONVENCIÓN

20 al 22 de agosto 2019

8th Respiratory Congress- Coalición de Asma y otras Condiciones Respiratorias Crónicas de PR

Sheraton Convention Center Hotel San Juan, PR

IC Planners 787-504-3655 ivettecolon@icplannerspr.com

CONGRESO

26 al 28 de septiembre 2019

Puerto Rico Urological Association Annual Convention 2019

Sheraton Convention Center Hotel San Juan, PR

Puerto Rico Urological Association Aixa Vélez 787-649-7681 www.pruanet.org

CONVENCIÓN

5 de octubre 2019

4TH EP Symposium- ACC PR Chapter

Ponce Hilton Hotel Ponce, PR

ACC-PR Chapter. Aixa Vélez 787-649-7681 www.accpuertorico.org

SIMPOSIO

11 al 14 de octubre 2019

Convención anual de la Sociedad de Médicos Graduados de la Escuela de Medicina RCM

San Juan Marriot Resort San Juan, PR

Sociedad de Médicos Graduados de la Escuela de Medicina RCM 787-758-2525 ext. 2038

CONVENCIÓN

26 de octubre 2018

Asociación de Médicos Alergistas de PR

Embassy Suites Hotel San Juan, PR

IC PLANNERS Ivette Colón 787-504-3655 ivettecolon@icplannerspr.com

CONVENCIÓN

25 al 27 de octubre 2019

Convención anual- Puerto Rico HIV Treaters Association

Embassy Suites Dorado de Mar Dorado, PR

Educational Partners (787) 646-0780 vperez@epcpr.com

CONVENCIÓN

8 al 10 de Noviembre 2019

Convención Anual Asociación Médica de Pediatras Región Este (AMPRE)

San Juan Marriot Stellaris Resort San Juan, PR

Business Planners Merna Morales 787-706-0442 bplanner21@gmail.com

CONVENCIÓN

1 al 3 de noviembre 2019

Cursos Obligatorios- San Juan

Club Rotario de Río Piedras San Juan, PR

High Education Health 787-964-6394 heh@hehpr.com/www.hehpr.com

CURSO

22 al 24 de Noviembre 2019

Convención Sociedad Puertorriqueña de Neumología

Wyndham Rio Mar Rio Grande, PR

Business Planners Merna Morales 787-706-0442 bplanner21@gmail.com

CONVENCIÓN

12 al 15 de diciembre 2019

SPED AACE Congress

Caribe Hilton Hotel San Juan, PR

Educational Partners (787) 646-0780 vperez@epcpr.com

CONGRESO

13 al 15 de diciembre 2019

Convención anual- Colegio de Médicos Cirujanos de Puerto Rico

Centro de Convenciones San Juan, PR

Colegio de Médicos Cirujanos de PR 787-751-5979

CONVENCIÓN

SI QUIERE CONOCER MÁS ACERCA DE LAS CONVENCIONES QUE SE LLEVARÁN A CABO EN LA ISLA, VISÍTENOS EN MEDICINAYSALUDPUBLICA.COM

Revista Puertorriqueña de Medicina y Salud Pública

109

2019

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

Fecha

Actividad

Internacional

Lugar

Coordinador o Contacto

Comentarios

New Orleans, USA

ACC (847)-996-5822 acc@experient-inc.com

Hawaii Convention Center Honolulu, Hawaii

Society of Gynecologic Oncology www.sgo.org

CONVENCIÓN

ENDO 2019-Endocrine Society Annual Meeting

New Orleans, USA

Endocrine Society www.endocrine.org

CONVENCIÓN

23 al 28 de marzo 2019

Society of Interventional Radiology 2019 Meeting

Austin Convention Center Austin, Texas USA

Society of Interventional Radiology www.sirmeeting.org

CONVENCIÓN

20 al 22 de marzo de 2019

Congreso Internacional de Cáncer en la Mujer

San José, Costa Rica

Colegio Médicos Cirujanos de Costa Rica 22102200/22102202

CONGRESO

3 al 6 de abril 2019

17 th World Congress of Endoscopy Surgery

Baltimore Convention Center Baltimore, MD USA

Sages Education & Research Foundation www.sages2019.org

CONGRESO

6 al 9 de abril 2019

27 th European Congress of Psychiatry-EPA 2019

Varsovia, Polonia

European Phsychiatry Association epa-congress.org

CONGRESO

11 al 13 de abril 2019

American College of PhysiciansInternal Medicine Annual Meeting 2019

Pennsylvania Convention Center Philadelphia, PA USA

American College of Physicians (ACP) anualmeeting.acponline.org

CONVENCIÓN

11 al 13 de abril 2019

Annual Regional Anesthesiology and Acute Pain Medicine Meeting 2019

Caesar’s Palace Las Vegas, Nevada USA

American Society of Regional Anesthesia and Pain Medicine (ASRA) www.asra.com

CONVENCIÓN

12 al 13 de abril de 2019

XIX Simposio Internacional de Alergia e Neumología

Hotel Almirante Cartagena Colombia

Clínica Respiratoria y de Alergias 57-304-6511777

SIMPOSIO

24 al 28 de abril 2019

28 th Annual Scientific & Clinical Congress-American College of Endocrinology

Los Angeles Convention Center & JW Marriot Los Angeles, CA USA

American College of Endocrinology www.aace.com

CONGRESO

25 al 26 de abril de 2019

Congreso Internacional de Cirugía Oculoplástica

Lima, Perú

Sociedad peruana de oftalmología 51-1-4402698

CONGRESO

27 al 30 de abril 2019

Pan -American Congress of Rheumatology 2019

Quito, Ecuador

PANTAR www.congreso-pantar.com

CONGRESO

2 AL 5 de mayo 2019

XXIV Congreso Sociedad Dominicana de Obstetricia y Ginecología “Mujer-Familia-Salud”

Punta Cana, RD

Sociedad Dominicana de Obstetricia y Ginecología www.sdog.org.do

CONGRESO

16 al 18 de marzo 2019

American College of Cardiology 2019 Annual Meeting

16 al 19 de marzo 2019

2019 Society of Gynecologic Oncology Anual Meeting

23 al 26 de marzo 2019

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CONVENCIÓN

Fecha

Actividad

Lugar

Coordinador o Contacto

Comentarios

15 al 18 de mayo 2019

Congreso Interamericano de Cardiología 2019

International Convention Center Hard Rock Hotel Punta Cana, RD

Sociedad Interamericana de Cardiología 809-685-0331 siac2019@bcocongresos.com

CONGRESO

18 al 22 de mayo 2019

American Psychiatric Association 2019 Annual Meeting

San Francisco, CA USA

American Psychiatric Association www. psychiatry.org

CONVENCIÓN

28 de mayo al 1 de junio 2019

American College of Sports Medicine 2019 Annual Meeting

Orange County Convention Center & Rosen Center Hotel Orlando, FL

American College of Sports Medicine mmeting@acsm.org www.acsmannualmeeting.org

CONVENCIÓN

12 al 15 de junio 2019

European Congress of Rheumatology 2019

Feria de Madrid Madrid, España

EULAR www.congress.eular.org

CONGRESO

18 al 21 de junio 2019

XVII Congreso de la Sociedad Cubana de Ginecología y Obstetricia

Palacio de Convenciones La Habana, Cuba

Sociedad Cubana de Ginecología y Obstetricia www.ginecobstcuba.com

CONGRESO

22 al 25 de junio 2019

Society for Nuclear Medicine & Molecular Imaging 2019 Annual Meeting

Annaheim Convention Center Anaheim, CA, USA

Society for Nuclear Medicine & Molecular Imaging www.snmmi.org

CONVENCIÓN

20 al 28 de julio 2019

2019 AMHE Medical Convention

Habana, Cuba

AMHE-Marie Bruno (202)-681-3506 www.amhe.org

CONVENCIÓN

1 al 3 de agosto 2019

Frei Caneca Convention Congreso Sociedad Latinoamericana Center de Cardiología Intervencionista (SOLACI) Sao Paulo, Brasil

SOLACI www.solacicongress.org

CONGRESO

7 al 10 de agosto de 2019

15 Encuentro Latinoamericano de Cirujanos de Cadera y Rodilla ELCCR

ELCCR direccion@elccr.org

CONGRESO

12 al 15 de septiembre 2019

XVIII Congreso Latinoamericano de Nefrología e Hipertensión (SLANH 2019)

Swisshotel, San Isidro Lima, Perú

SLANH www.congresoslanh.org info@congresoslanh.org

CONGRESO

15 al 18 de septiembre 2019

2019 ASTRO Annual Meeting- American Society for Radiation Oncology

Mc Cormick Place West Chicago, Il, USA

American Society for Radiation Oncology www.astro.org

CONVENCIÓN

19 al 21 de septiembre de 2019

6to Simposio Internacional de Pie y Tobillo

Cartagena, Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología secretaria@sccot.org.com

SIMPOSIO

30 de septiembre al 6 de octubre 2019

IX Congreso de la Sociedad Cubana de Medicina Física y Rehabilitación

Palacio de Convenciones La Habana, Cuba

Sociedad Cubana de Medicina Física y Rehabilitación 787-758-4800 lucia.viajescarely@gmail.com

CONGRESO

17 al 18 de octubre 2019

8va Conferencia Interamericana de Oncología

Universidad Católica de Argentina Buenos Aires, Argentina

www.oncologyconferences.co.ar

CONFERENCIA

25 al 30 de octubre 2019

American College of Gastroenterology 2019 Annual meeting

San Antonio, TX USA

American College of Gastroenterology https://gi.org

CONVENCIÓN

8 al 3 de noviembre 2019

American College of Rheumatology 2019 Annual Meeting

Atlanta, GA USA

American College of Rheumatology www.rheumatology.org

CONVENCIÓN

24 al 26 de noviembre de 2019

Congreso Internacional de Medicina Deportiva

Cartagena, Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología secretaria@sccot.org.com

CONGRESO

21 de noviembre de 2019

1er Curso Nacional de Ortopedia para Médicos Generales

Bucaramanga, Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología secretaria@sccot.org.com

CURSO

22 al 24 de noviembre de 2019

14 Encuentro Nacional de Residentes de Ortopedia y Traumatología

Bucaramanga, Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología secretaria@sccot.org.com

CONGRESO

Cento de convenciones Las Americas Cartagena, Colombia

Revista Puertorriqueña de Medicina y Salud Pública

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www.medicinaysaludpublica.com

Servicio de Noticias Científicas de Medicina y Salud Pública de Puerto Rico

Sor Nelly Marie Arroyo Vázquez, residente en el Convento de las Hermanas Dominicas de Fátima en Guánica Alberto Santiago Cornier,MD,PhD

SOR NELLY MARIE ARROYO: LA ÚNICA MONJA MÉDICA EN PUERTO RICO Sor Nelly es residente en el Convento de las Hermanas Dominicas de Fátima en Guánica, fundado por Madre Dominga Guzmán en el 1949. Es la única monja médica de la isla, estudió en el Recinto de Ciencias Médicas de la UPR y realizó su internado en los hospitales “La Concepción” y “Auxilio Mutuo”. Su principal motivación ha sido ayudar a los más desvalidos y a su comunidad religiosa.

Doctores, Luis Gerena y Christian Castillo Latorre, residentes de medicina interna del Hospital Municipal de San Juan.

SE BUSCA PROMOVER LA MOVILIDAD TEMPRANA DE PACIENTES CRÍTICAMENTE ENFERMOS Se trata de una iniciativa del Hospital Municipal de San Juan que busca dar la oportunidad de aumentar la esperanza de vida a los pacientes que sufren de enfermedades crónicas después de una hospitalización prolongada. Por lo general, estos pacientes presentan pérdida de la movilidad y entumecimiento, lo que afecta su calidad de vida y complica su cuadro clínico. Por esta razón, médicos y enfermeros buscan impulsar la terapia física para contrarrestar los síntomas de estas enfermedades.

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Revista Puertorriqueña de Medicina y Salud Pública

ALBERTO SANTIAGO CORNIER, EL MÉDICO QUE TRABAJA CON EL PENTAGRAMA DE LA CIENCIA: EL ADN El Dr. Cornier es un médico puertorriqueño que estudió medicina en República Dominicana. La investigación es una de las ramas que más lo apasionan; es por eso que ha desarrollado múltiples descubrimientos y aportes a la medicina. Entre los que se destacan la localización del gen del síndrome Bardet-Bied y el gen asociado al síndrome de Jarcho-Levin.

Alexandra Franco O’Connell

JOVEN DE 14 AÑOS HACE HISTORIA AL SER ACEPTADA EN LA ESCUELA DE MEDICINA Esta joven boricua se convirtió en la persona más joven de la historia puertorriqueña en ser admitida en la Escuela de Medicina. Desde su infancia, la ciencia y la investigación fueron sus pasiones. Su desarrollo intelectual estuvo definido desde muy temprana edad, tanto así, que pasó de séptimo a noveno grado gracias a su alto y avanzado coeficiente.

¡Dile SÍ a la donación!

Familia de Gerald, J. Otero donante de órganos.

¡Únete a LifeLink de Puerto Rico!

Habla con tus seres queridos y comparte con ellos tu deseo de ser donante de órganos y tejidos para trasplantes.

Regístrate e invita a otros a registrarse.

Ayúdanos a salvar las vidas de aquellos en espera de una segunda oportunidad.

www.donevidapuertorico.org

www.medicinaysaludpublica.com

Servicio de Noticias Científicas de Medicina y Salud Pública de Puerto Rico

Dr. Ana Judith Román, neurofisióloga

LA PRIMERA MUJER NEURÓLOGA EN PUERTO RICO: “TODO ES UN MARAVILLOSO PROCESO DE APRENDIZAJE” La doctora Ana Judith Román, nacida en Río Piedras, Puerto Rico, lleva a cuestas un amplio prontuario en la medicina. Tiene el honor y el reconocimiento de ser la primera neuróloga en su país natal. Además, es una de las pocas afortunadas en el mundo, al ser invitada por Harvard para realizar una especialización en neurofisiología. Actualmente, imparte sus conocimientos en las diferentes facultades de medicina de la isla.

Nombres de izquierda a derecha: Damaris Del Mar Nieves Torres, Úrsula Gelpi Domínguez, Dra. Marian T. Sepúlveda Orengo, Ángel Echevarría Rivera, John Alvarado Torres y Roberto Morales Silva.

DESARROLLAN ESTUDIOS PARA UN FUTURO FÁRMACO QUE CONTROLARÍA LA ADICCIÓN A LAS DROGAS El estudio, liderado por una importante institución educativa de Puerto Rico, busca comprender los mecanismos del cerebro que están involucrados en el proceso de adicción a sustancias como la cocaína y el papel que cumple el ejercicio durante los períodos de abstinencia. Los investigadores esperan poder desarrollar un nuevo tratamiento terapéutico para la adicción a las drogas.

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Revista Puertorriqueña de Medicina y Salud Pública

Luis M. Vilá, MD Jefe de la División de Reumatología, Alergia e Inmunología y Director del Programa de Reumatología en la Escuela de Medicina del Recinto de Ciencias Médicas

DESDE PUERTO RICO BUSCAN CREAR EL PERFIL GENÉTICO DEL LUPUS Algunos estudios han logrado develar la alta incidencia de lupus en Puerto Rico. Por esta razón, los investigadores de la isla intentan crear el perfil genético de la población que padece de esta enfermedad, lo cual ayudaría a establecer los problemas de salud que pueden tener estos pacientes de forma temprana, tratarlos de forma individualizada y establecer una farmacoterapia contra la enfermedad.

Juan José Bibiloni, MD, FAAOS Especialista en Cirugía Ortopédica Certificado por la Junta en Cirugía Ortopédica y miembro de la Junta Americana de Cirugía Ortopédica.

FIRME LABOR POR LOS PACIENTES CON CÁNCER DE HUESO EN PUERTO RICO El doctor Juan José Bibiloni es el único ortopedista en Puerto Rico que practica la oncología musculoesquelética, una ciencia con un elevado riesgo médico-legal que ejerce -según él- por un llamado vocacional. Actualmente, el especialista está en búsqueda de una alternativa para tratar los tumores en los huesos y lucha constantemente por los pacientes que padecen de cáncer de hueso en la isla.

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A CIENCIA CIERTA

DOCTOR ARSMTRONG, CASI UN SIGLO DE VIDA AL SERVICIO DE LA SOCIEDAD EL DOCTOR RAÚL ARMSTRONG MAYORAL NACIÓ HACE CASI UN SIGLO EN UNA ISLA MARCADA POR EL ATRASO; AUNQUE, ESTO NO LE IMPIDIÓ ROMPER PARADIGMAS Y SER ETERNAMENTE EJEMPLO A SEGUIR EN LA MEDICINA PUERTORRIQUEÑA.

S

u etapa educativa inició en tiempos adversos, cuando en Puerto Rico no existía una escuela de Medicina. Decidió cruzar el océano con anhelos de conocimiento que la isla no podía ofrecer.

Al regresar, iniciaría sus estudios en el Hospital de San Juan, mientras finalizaba la subespecialidad de cirugía.

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“Lo más que me gusta de la cirugía es que uno tiene el privilegio de atender a un paciente que tiene una necesidad quirúrgica y que uno sirve de instrumento para resolver ese problema”.

Siempre logró un balance extraordinario para no dejar de lado nada. Todos los que le conocen saben que su cepa de hombre ilustre

fue forjada día a día con empeño y perseverancia.

Con un corazón a la medida para su especialidad, se encuentra comprometido con la humanidad, marcado por la nobleza, su mayor virtud. Por ella, y su inquebrantable voluntad humana, se ha ganado el respeto de colegas, aprendices y pacientes. No sería suficiente enumerar sus labores, -desde sus prácticas en el Hospital Oncológico de Ponce hasta sus cargos como jefe de cirugía, encargado de residencias, decano o profesorpara resumir su labor.

Actualmente, mantiene la energía y la jocosidad sin que los años le arrebaten la alegría y las ganas de ayudar. Aunque su carga de trabajo ha disminuido, continúa aportando, ahora desde las aulas.

El secreto, según él, es amar su profesión.