Revista Medicina y Salud Pública (MSP)

www.medicinaysaludpublica.com

@medicinaysaludpublica

Perfil de supervivencia

con VIH/SIDA en Puerto Rico

La genética del cáncer de seno en la familia puertorriqueña Endometriosis en Puerto Rico Sobreviviendo al linfoma de Hodgkin

CONTENIDO 26

Sobreviviendo al linfoma de Hodgkin.

De intoxicación por comida a infarto agudo del miocardio en hombre de 30 años de edad

08 Perfil de supervivencia

20

con VIH/SIDA en Puerto Rico

46

Doctores Ruiz: Padre e hijo comparten la pasión por la endocrinología

22

Endometriosis en Puerto Rico

48

Infografía: Evolución de SPED

34

La genética del cáncer de seno en la familia puertorriqueña

El estrés afecta la progresión, los mecanismos centrales de percepción de dolor y los parámetros inflamatorios de la endometriosis

53

Tendencias avanzadas para el tratamiento de la diabetes en el 2018

58

Complicaciones de la piel en el paciente diabético

68

Manejo Farmacológico de las insulinas

Comité Editorial Científico

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

PRESIDENTE COMITÉ EDITORIAL CIENTÍFICO:

COMITÉ EDITORIAL

Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR Alberto Santiago Cornier, MD, PhD Ileana Santiago Álvarez, MBA VICEPRESIDENTA EDITORIAL MUNDO Y FUNDADORA Laila Paloma Lorraine CONTABILIDAD Julio Soto ADMINISTRACIÓN Marta Ivelisse Vélez Ramos, MBA PERIODISTAS Mayra Acevedo, Belinda Burgos, Jenny Marcela Moreno Wilches, Jessica Alejandra González Roncacio, REALIZADORA AUDIOVIZUAL Alejandra Montenegro Arango PROGRAMADOR WEB Diego Esteban Gutiérrez ARTISTAS GRÁFICOS Natalia Zoé Rivera Torres, Pablo Bermúdez Robayo, Marcela Castro Villamarín FOTOS : Revista Medicina y Salud Pública ASISTENTE DE PRODUCCIÓN Marta I. Vélez Ramos DIRECCIÓN GENERAL Y PRESIDENTE FUNDADOR Carlos Alexis Lugo Marrero JEFE DE OPERACIONES Y FUNDADOR Pedro Carlos Lugo Hernández III DISTRIBUCIÓN OFICINAS Y TORRES MÉDICAS Editorial Mundo ENVÍO DE REVISTAS Y DISTRIBUCIÓN A GRUPOS MÉDICOS Servicio de correo postal/Comunicación Inteligente EDITOR FUNDADOR

PRINCIPAL OFICIAL EJECUTIVA

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

Síguenos en www.medicinaysaludpublica.com, www.facebook.com/revistamsp, en Twitter @revistamsp, en LinkedIn como Revista Puertorriqueña de Medicina y Salud Pública. Las normas editoriales de la Revista Puertorriqueña de Medicina y Salud Pública para la publicación de artículos originales y cartas al editor pueden ser accesadas en la página web: www.medicinaysaludpublica.com, y solicitadas a través de msp@editorialmundo.com.

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

Revista Puertorriqueña de Medicina y Salúd Pública

5

La importancia de la investigación biomédica en Puerto Rico Existe un número importante de investigadores en nuestro país haciendo ciencia de vanguardia. Ese trabajo en las clínicas y en los laboratorios puertorriqueños lo menos que merece es un medio creíble y respetable en la sociedad científica, tanto académica como clínica e industrial, en el que sus aportes al mundo de la ciencia puedan ser valorizados, escudriñados, revisados y utilizados por sus pares.

En la Revista Puertorriqueña de Medicina y Salud Pública (MSP) hemos creado una plataforma para la difusión de la actividad científica que se genera en los laboratorios del país. Por ser tan fecundo y de alto impacto en la ciencia y la salud el trabajo que en éstos se hace, es imprescindible que la comunidad científica pueda publicar sus trabajos en una revista con una gestión profesional íntegra y notables rasgos de calidad. En nuestros doce años de existencia hemos trabajado para posicionar nuestro medio a la altura de los más exigentes lectores para así ganarnos su confianza y la de los principales médicos e investigadores.

Los alcances científicos de nuestros investigadores son, como es la norma,

parte de lo que MSP transmite a la comunidad médica y científica en esta edición. Por ejemplo, en momentos que el cáncer de mama es un enemigo común en las familias puertorriqueñas se hace pertinente destacar la investigación en la que se han sumergido varios investigadores en la Ponce Health Sciences University capitaneados por la Dra. Julie Dutil, donde se desarrolla un tratamiento especializado acorde con las características genéticas de la mujer puertorriqueña. Este hecho permitiría abordar médica y farmacológicamente la enfermedad desde una perspectiva muy particular pues los descubrimientos han revelado una realidad molecular única: el cáncer es más agresivo cuando la mujer posee más genes africanos y ésta, además, tiene mayor probabilidad de desarrollar el tumor por la baja influencia de genes taínos en su ADN. La actividad científica no se ha detenido ahí ya que el trabajo investigativo de la doctora Idhaliz Flores, de la Ponce Health Sciences University, ha logrado darle visibilidad a la endometriosis. Esta bióloga molecular nativa de Coamo, Puerto Rico, se ha aproximado a la

enfermedad y por medio de ello, hoy existen estadísticas que reflejan que afecta a 50,000 mujeres boricuas. Más aún, sus estudios en el laboratorio han sugerido que el estrés afecta la severidad de la enfermedad debido a que altera el sistema inmunológico.

Estos son solo dos de los muchos ejemplos de actividad científica de primer orden realizados en los laboratorios de las principales entidades académicas de nuestro país.

La gestión editorial de MSP facilita la labor de difundir muchas de estas investigaciones, así como el trabajo y los quehaceres en los laboratorios.

Asimismo, nuestra rev ista facilita la discusión de temas por parte de la comunidad científica y médica, mientras les da protagonismo a nuestros científicos puertorriqueños, quienes podrían quedar en el anonimato si no existiera esta publicación.

Para más información, visite nuestro portal en www.medicinaysaludpublica. com.

Revista Puertorriqueña de Medicina y Salúd Pública

7

con VIH/SIDA en Puerto Rico

MSP ARTÍCULO ORIGINAL

Al iniciar la era de la terapia antiretroviral para el VIH, se han evidenciado cambios en las tendencias de supervivencia de la enfermedad. El objetivo de este estudio fue estimar la supervivencia de las personas con VIH/SIDA en Puerto Rico para el periodo de 2003-2011. Se realizó un estudio de cohorte retrospectiva utilizando una base de datos secundarios del Sistema de Vigilancia VIH de Puerto Rico. Se registró un total de N = 9,240 sujetos diagnosticados con la enfermedad durante el periodo de estudio. La probabilidad de supervivencia a 6 años en personas en estadío de VIH fue de 0.87 (IC95%: 0.09, 0.72) en comparación con aquellos en estadío SIDA de 0.57 (IC95%: 0.55, 0.60) p<0.001. El modo de transmisión con menor probabilidad de supervivencia a 5 años fue el relacionado con el uso de drogas inyectables (UDI) con 0.69 (IC95%: 0.67, 0.71) p<0.001. Se recomienda estrategias de prevención dirigidas a personas con VIH/SIDA e historial de UDI de manera que se produzca un aumento en la supervivencia de esta población.

Revista Puertorriqueña de Medicina y Salúd Pública

9

MSP ARTÍCULO ORIGINAL

Abstract After the introduction of HAART, the HIV/AIDS epidemiological trends has shown an increasing in the survival rates. HAART has dramatically improved the life expectancy of HIV/AIDS. The objective of this study was to estimate survival in people diagnosed with HIV/AIDS in Puerto Rico (PR) from 2003-2011.

A population-based study using the PR HIV Surveillance System was implemented. A total of N = 9,290 people were diagnosed with HIV/ AIDS in PR for 2003-2011period.

Cox regression models for survival analysis were assessed. Survival at 6 years after diagnosis in HIV patients was 0.87 (CI95%: 0.09, 0.72) when compare with AIDS patients at same time of diagnosis was 0.57 (CI95%: 0.55, 0.60) p<0.001.

Intravenous drug users [IDU] have less probability of survival at 5 years after diagnosis when compare with other transmission modes 0.69 (CI95%: 0.67, 0.71) p<0.001.

Assertive prevention strategies must be developed and implemented in PR for IDU’s in order to increase their survival rates.

MSP ARTÍCULO ORIGINAL

Epidemiología Descriptiva VIH/SIDA La ONUSIDA [1] reportó que para el año 2016 habrá una prevalencia de 36.7 [IC95%: 30.8, 42.9] millones de personas a nivel mundial con VIH. La Oficina de Vigilancia del SIDA del Departamento de Salud de Puerto Rico [2] reportó N = 48,695 casos de VIH/SIDA hasta 31 de octubre de 2017.

El 74.1% (N = 36,093) eran hombres y 25.9% (N = 12,602) mujeres. Los medios de transmisión más comunes son: el uso de drogas inyectables (UDI) con el 42% de los casos (N = 20,374); contacto heterosexual (HET) son el 29% de los casos (N = 14,046); las relaciones entre hombres que tienen sexo con otros hombres (HSH) son el 20% (N = 9,571) y, los HSH con historial de UDI son el 6% de los casos (N = 2,956).

Supervivencia y VIH/SIDA Durante el periodo de 2000-16, se estima 13.1 millones de vidas salvadas por el uso de las terapias anti retrovirales altamente activa (HAART, por sus siglas en inglés) [3]. Las tendencias de supervivencia sobre VIH/SIDA alrededor del mundo, Estados Unidos y Puerto Rico señalan el aumento en la probabilidad de supervivencia y esto en parte a la introducción de HA A RT [1,4,5,6,7]. Luego de la introducción de HAART, las tendencias de supervivencia han aumentado significativamente [1].

Recientemente, en un meta-análisis que analizó 57 estudios de supervivencia

en personas con diagnósticos de VIH/ SIDA, encontró que en su mayoría las personas en estadío I (VIH) progresaron a estad ío I I I (SI DA) durante la primera década de su diagnóstico [8].

Específicamente, aquellos en HAART sobrevivieron más de 10 años luego de su diagnóstico en estadio III. Aunque HAART ha sido un evento que ha marcado un aumento en la tendencia de supervivencia de VIH/ SIDA, es necesario entender los factores alrededor de la epidemia. Ante este reto, los estudios de supervivencia en VIH/SIDA han logrado asociar algunos factores que requieren iniciativas de prevención específicas en subpoblaciones con la enfermedad [9]. Entre estos factores asociados a la supervivencia de las personas con VIH/SIDA se encuentran: sexo, edad, modo de transmisión, nivel educativo, conteo de células CD4, carga viral, acceso a tratamiento, entre otros [10,11,12,13,14,].

Las tendencias epidemiológicas muestran el éxito de HAART a través del aumento de la probabilidad de supervivencia y la disminución en la mortalidad en las personas con VIH/ SIDA [1,15]. Sin embargo, sigue siendo un asunto de salud pública identificar los factores que pueden reducir o aumentar la supervivencia en las personas con VIH/SIDA. Estimar la supervivencia de VIH/SIDA en Puerto Rico ayuda a una mejor comprensión de los factores que aumentan y/o disminuyen la expectativa de vida en esta población dentro de nuestro contexto social.

Método Se realizó un estudio de cohorte retrospectivo [16,17], utilizando una base de datos secundaria que proviene del Sistema de Vigilancia VIH de Puerto Rico, para estimar la probabilidad de supervivencia para la población de estudio.

Muestra Los sujetos a evaluar para este análisis de supervivencia son todos aquellos individuos que tuvieron una primera prueba positiva al VIH durante el periodo de 1 de enero de 2003 hasta el 31 de diciembre de 2011. Para el periodo de estudio, el Sistema de Vigilancia VIH de Puerto Rico registró N = 9,290 individuos con una primera prueba positiva al VIH. Instrumento Los datos utilizados en este estudio fueron recopilados por el Sistema de Vigilancia VIH de Puerto Rico, el cual utiliza un instrumento estandarizado por los Centros para el Control y Prevención de Enfermedades (CDC, por sus siglas en inglés) para recopilación de datos sobre los casos diagnosticados con VIH/SIDA. Además, de este instrumento, el Sistema de Vigilancia VIH de Puerto Rico en conjunto con el Registro Demográfico de Puerto Rico realizó un pareo de datos para identificar las muertes que fueron reportadas en el periodo de estudio.

Informatización de los datos La información de las variables de interés fueron obtenidas en el formato del programa estadístico de Excel, de esta manera, los datos fueron incorporados al programa de análisis de datos Statistical Package for Social Sciences (SPSS v19.0) y el programado R. Datos Perdidos Para completar los datos perdidos relacionados con los tiempos de supervivencia se utilizó un método de verosimilitud, en concreto el de imputación múltiple (Modelos de Markov Monte Carlo) [18]. Las imputaciones múltiples son una práctica para completar los valores perdidos por valores plausibles en un banco de datos. Regularmente, esta práctica suele ser llamativa para casos con altos porcentajes de valores perdidos porque permite analizar datos incompletos [17,19].

Para este estudio se tomó la determinación de generar el modelo de imputaciones múltiples utilizando 10 imputaciones. Hay varias razones para esto: primero, imputar a 10 asegura el reducir el error estándar y problemas con el valor de p (significancia estadística). Segundo, 10 imputaciones garantizan una alta eficiencia según la teoría de Robin. El modelo de eficiencia de este estudio se estimó en un 93.5% [18,20].

de Variable Año #Riesgo Probabilidad supervivencia

Mujer

Hombre

0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10

2697 2208 1979 1742 1477 1182 903 595 294 5 1 6597 5265 4595 3956 3287 2638 1949 1258 670 10 1

0.930 0.913 0.896 0.878 0.854 0.837 0.815 0.786 0.767 0.516 0.437 0.937 0.918 0.902 0.888 0.870 0.851 0.831 0.811 0.787 0.453 0.005

IC95%

Valor p

0.92, 0.94 0.90, 0.92 0.88, 0.91 0.87, 0.89 0.84, 0.87 0.82, 0.85 0.80, 0.84 0.76, 0.81 0.74, 0.80 0.35, 0.77 0.26, 0.74 0.00, 0.94 0.00, 0.93 0.00, 0.91 0.00, 0.90 0.00, 0.88 0.00, 0.86 0.00, 0.84 0.00, 0.83 0.00, 0.81 0.00, 0.73 0.00, 1.00

<0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001*

Revista Puertorriqueña de Medicina y Salúd Pública

11

En estudios que han analizado los datos de los Sistemas de Vigilancia de VIH de los CDC han utilizado hasta 20 imputaciones [21,22]. Sin embargo, se reconoce que 10 imputaciones ayudan a alcanzar la eficiencia adecuada para realizar posteriormente los análisis [23].

estimar la probabilidad de supervivencia por las variables de: estadío inmunológico sexo y modo de transmisión. El primer análisis fue realizado por la variable de estadío inmunológico. En general, los casos VIH (asintomáticos) mantienen una expectativa de supervivencia mayor con un 0.87 (IC95%: 0.09, 0.72) (p<0.001) en comparación con los casos en estadio SIDA con un 0.57 (IC95%: 0.55, 0.60) (p<0.001) al sexto año de diagnóstico ajustado por las variables de interés.

A continuación, la figura 1 presenta las curvas de supervivencia y la tabla resumen 1 de la función de probabilidad de supervivencia por estadio de la enfermedad en personas diagnosticadas con VIH/SIDA para el periodo de 200311 en años.

Análisis Estadísticos S e est i mó l a probabi l id a d de supervivencia utilizando modelos de regresión de Cox y se representó en curvas de supervivencia de Kaplan-Meier con su prueba de log rank para determinar si habían diferencias estadísticamente signif icativas. Los modelos fueron calculados con la aportación de los casos en años. Se realizaron tres modelos utilizando las variables de: sexo, estadío inmunológico y modo de transmisión, todos ajustados por las posibles variables Discusión de confusión disponibles. [2] En Puerto Rico para el periodo de 2003-11, al igual que en otros estudios Asuntos Éticos de supervivencia [24], las personas que Este protocolo de estudio fue aprobado fueron diagnosticadas en estadio SIDA por el Institutional Review Board de presentaron tener una menor probabilidad la Ponce Health Sciences University de supervivencia 0.57 (p<0.001) en (Número de protocolo: 140403-DZ). comparación con la probabilidad de supervivencia en casos diagnosticados en Resultados estadio VIH, donde fue de 0.87 (p<0.001) El acumulativo en años fue de 44,047 ambos a 6 años del diagnóstico. Respecto personas-años en personas diagnosticadas a la probabilidad de supervivencia a 5 con VIH/SIDA para el periodo de 2003- años luego del diagnóstico de VIH o 11 (p<0.001). Se realizó tres análisis para SIDA, los UDI tienen menor probabilidad

12

de supervivencia 0.69 (IC95%: 0.67, 0.71) (p<0.001) en comparación con: HSH 0.84 (IC95%: 0.82, 0.85) (p<0.001); HSH con historial de UDI 0.80 (IC95%: 0.75, 0.85) (p<0.001) y HET 0.79 (IC95%: 0.77, 0.80) (p<0.001). Igualmente, otros estudios han encontrado que personas con VIH/SIDA con historial UDI tienen una menor probabilidad de supervivencia con un 0.35 (IC95%: 0.13, 1.00) en comparación con otros modos de transmisión [24,25].

Para poder alcanzar la meta de aumento en la supervivencia, es necesaria la identificación temprana de los casos nuevos en las comunidades.

Ante este reto, se sugiere realizar esfuerzos conjuntos entre las autoridades federales y locales con organizaciones de base comunitarias que trabajen con las poblaciones vulnerables impactadas por la epidemia como lo son: las personas con historial de UDI. De manera que se puedan atender los retos que esta población se presentan como: factores asociados a la pobreza, escasas o ninguna política pública desde un modelo salubrista, estigma social y acceso a tratamiento. Trabajar estrategias de prevención específicas que incluyan las necesidades de las personas con VIH/ SIDA e historial UDI puede lograr un aumento en la supervivencia de esta población.

0

1

2

3

4

5

6

7

8

9

0,99

0,99

0,90

0,98

0,98

0.98

0,92

0,91

0,91

0,91

VIH Asintomático

0,94

0,94

0,94

0,94

0,94

0,94

0,94

0,94

0,88

0,87

VIH Sintomático

0,93

0,91

0,89

0,87

0,85

0,82

0,79

0,76

0,74

0,5

SIDA*

Revista Puertorriqueña de Medicina y Salúd Pública

Referencias

http://www.sho.int/mediacentre/factsheets/ fs360/en/ [4] Lesko, C.R., Cole, S.R., Miller, W.C., Westreich, D., Eron, J.J., Adimora, A.A., Moore, R.D., Mathews, W.C., Martin, J.N., Drozd, D.R., Kitahata, M.M, Edwards, J.K., & Mugavero, M.J. (2015). Ten-year Survival by Race/Ethnicity and Sex Among Treated, HIV-infected Adults in the United States. Clin Infect Dis., pii: civ183. [Epub ahead of print].

[5] Lima, V. D., Lepik, K. J., Zhang, W., Muldoon, K. A., Hogg, R. S., & Montaner,

Probabilidad de Supervivencia

[1] ONUSIDA (2017). Global data.

Recuperado el 13 de noviembre de 2017, de: http://www.unaids.org/sites/default/files/ media_asset/20170720_Data_book_2017_en.pdf [2] Departamento de Salud del Estado Libre de Asociado de Puerto Rico (2017).

Reporte de Estadísticas de la Oficina de Vigilancia de SIDA. San Juan, Puerto Rico: Departamento de Salud del Estado Libre Asociado de Puerto Rico.

[3] OMS (2017). VIH/SIDA. Key facts.

Recuperado el 14 de noviembre de 2017, de:

J. S. G. Regional and temporal changes in HIV-related mortality in British Columbia, 1987-2006. Can J Public Health, 101 (5): 415-419.

[6] de Aguiar-Perreira, C., Jorge-Machado, C., & do Nascimento-Rodrigues, R. (2007). Perfis de causas múltiples de morte relacionadas ao HIV/AIDS nos municipios de Sao Paulo e Santos, Brasil, 2001. Cad Saúde Pública, Rio de Janeiro, 23 (3): 645-655.

[7] Quinn, T. C. (2008). HIV epidemiology and the effects of antiviral therapy on longterm consequences. AIDS, 22 (3): s7-s12.

Figura 2 Probabilidad de supervivencia por sexo en personas diagnosticadas con VIH/SIDA en Puerto Rico para el periodo de 2003 - 2011 Años.

0

1

2

3

4

5

6

7

8

9

0,93

0,91

0,9

0,88

0,85

0.84

0,82

0,79

0,77

0,52

0,94

0,92

0,9

0,89

0,87

0,85

0,83

0,81

0,79

0,4 5

Hombre* Mujer*

Los casos transmitidos por UDI tienen una expectativa menor de supervivencia 0.64 en comparación con los casos por HET 0.75 ; los casos por HSH 0.80 y los casos HSH con historial de UDI 0.73 al séptimo año de diagnóstico ajustado por las

variables de interés.

Tabla 3 Probabilidad de supervivencia por modo de transmisión en personas diagnosticadas con VIH/SIDA para el periodo de 2003-2011-Años

Ajustado por variables de confusión: estado civil, sexo, edad, conteo de células CD4, nivel educativo y modo de transmisión. *Estadísticamente Significativo

Revista Puertorriqueña de Medicina y Salúd Pública

13

Probabilidad de Supervivencia

14

Figura 3 Probabilidad de supervivencia por modo de transmisión en personas diagnosticadas con VIH/SIDA en Puerto Rico para el periodo de 2003- 2011 - Años.

0

1

2

3

4

5

6

7

8

9

Heterosexual*

0,95

0,93

0,92

0,91

0,89

0,87

0,86

0,84

0,82

0,44

UDI*

0,91

0,88

0,86

0,84

0,82

0,79

0,76

0,7

0,48

0,38

HSH*

0,94

0,92

0,91

0,9

0,88

0,87

0,85

0,84

0,81

0,6

HSH/UDI*

0,96

0,95

0,92

0,9

0,89

0,87

0,85

0,81

0,8

0,8

Revista Puertorriqueña de Medicina y Salúd Pública

S:15”

BRIEF SUMMARY

JULUCA (dolutegravir and rilpivirine) tablets The following is a brief summary only; see full prescribing information for complete product information.

CONTRAINDICATIONS JULUCA is contraindicated in patients: with previous hypersensitivity reaction to dolutegravir or rilpivirine; receiving the following coadministered drugs for which elevated plasma concentrations are associated with serious and/or life-threatening events or that significantly decrease rilpivirine plasma concentrations: Drug Class

Clinical Comment

Antiarrhythmic: Dofetilide

Potential for serious and/or life-threatening events due to the potential for increased dofetilide plasma concentrations.

Anticonvulsants: Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin

Potential for significant decreases in rilpivirine plasma concentrations due to CYP3A enzyme induction, which may result in loss of virologic response.

Antimycobacterials: Rifampin, Rifapentine Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) Herbal Products: St John’s wort (Hypericum perforatum) Proton Pump Inhibitors: e.g., Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole

Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response.

WARNINGS AND PRECAUTIONS Skin and Hypersensitivity Reactions: Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in less than 1% of subjects receiving dolutegravir in Phase 3 clinical trials. Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials of rilpivirine, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects.

No Grade 4 rash was reported. Discontinue JULUCA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing).

Clinical status, including laboratory parameters with liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with JULUCA after the onset of hypersensitivity may result in a life-threatening reaction. Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Additionally, in some patients receiving dolutegravir-containing regimens, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity including elevated serum liver biochemistries and hepatitis have also been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to acute liver failure has been reported with dolutegravir-containing products, including liver transplant with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended. Depressive Disorders: Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation) have been reported with rilpivirine. For information regarding depressive disorders reported in patients taking dolutegravir, see Adverse Reactions. Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to JULUCA and to determine whether the risks of continued therapy outweigh the benefits. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of JULUCA and other drugs may result in known or potentially significant drug interactions, some of which may lead to: Loss of therapeutic effect of JULUCA and possible development of resistance; Possible clinically significant adverse reactions from greater exposures of concomitant drugs. In healthy subjects, 75 mg once daily rilpivirine (3 times the dose in JULUCA) and 300 mg once daily (12 times the dose in JULUCA) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes. See the Drug

Interactions section for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with JULUCA; review concomitant medications during therapy with JULUCA; and monitor for the adverse reactions associated with the concomitant drugs.

ADVERSE REACTIONS The safety assessment of JULUCA in HIV-1–infected, virologically suppressed subjects switching from their current antiretroviral regimen to dolutegravir plus rilpivirine is based on the pooled primary Week 48 analyses of data from 2 identical, international, multicenter, open-label trials, SWORD-1 and SWORD-2. A total of 1,024 adult HIV-1–infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 nucleoside reverse transcriptase inhibitors [NRTIs] plus either an integrase strand transfer inhibitor [INSTI], a non-nucleoside reverse transcriptase inhibitor [NNRTI], or a protease inhibitor [PI]) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine, were randomized and received treatment. Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to dolutegravir plus rilpivirine administered once daily. In the pooled analyses, the proportion of subjects who discontinued treatment due to an adverse event was 4% in subjects receiving dolutegravir plus rilpivirine once daily and was <1% in subjects who remained on their current antiretroviral regimen. The most common adverse events leading to discontinuation were psychiatric disorders: 2% of subjects receiving dolutegravir plus rilpivirine and <1% on their current antiretroviral regimen. The most common adverse reactions (grades 1 to 4) reported in at least 2% of virologically suppressed subjects with HIV-1 infection in SWORD-1 and SWORD-2 trials (week 48 pooled analyses) in either treatment arm – JULUCA (n=513) vs current antiretroviral regimen (n=511), respectively: diarrhea (2%, <1%), headache (2%, 0). Less Common Adverse Reactions occurred in less than 2% of subjects receiving dolutegravir plus rilpivirine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EDURANT (rilpivirine). Some events have been included because of their seriousness and assessment of potential causal relationship. General Disorders: Fatigue. Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, nausea, upper abdominal pain, vomiting. Hepatobiliary Disorders: Cholecystitis, cholelithiasis, hepatitis. Immune System Disorders: Immune reconstitution syndrome.

Metabolism and Nutrition Disorders: Decreased appetite. Musculoskeletal Disorders: Myositis. Nervous System Disorders: Dizziness, somnolence. Psychiatric Disorders: Depressive disorders including depressed mood; depression; suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Other reported psychiatric adverse reactions include anxiety, insomnia, sleep disorders, and abnormal dreams.

Renal and Urinary Disorders: Glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis, renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus, rash. Laboratory Abnormalities: Selected laboratory abnormalities with a worsening grade from baseline (grades 2 and 3 to 4; week 48 pooled analyses) and representing the worst-grade toxicity in at least 2% of subjects in SWORD-1 and SWORD-2 trials were – JULUCA (n=513) vs current antiretroviral regimen (n=511), respectively: ALT Grade 2 (>2.5-5.0 x Upper Limit of Normal [ULN]) 2%, <1%; Grade 3 to 4 (>5.0 x ULN) <1%, <1%; AST Grade 2 (>2.5-5.0 x ULN) <1%, 2%; Grade 3 to 4 (>5.0 x ULN) <1%, <1%; Total Bilirubin Grade 2 (1.6-2.5 x ULN) 2%, 4%; Grade 3 to 4 (>2.5 x ULN) 0, 3%; Creatine kinase Grade 2 (6.0-9.9 x ULN) <1%, <1%; Grade 3 to 4 (≥10.0 x ULN) 1%, 2%; Hyperglycemia Grade 2 (126-250 mg/dL) 4%, 5%; Grade 3 to 4 (>250 mg/dL) <1%, <1%; Lipase Grade 2 (>1.5-3.0 x ULN) 5%, 5%; Grade 3 to 4 (>3.0 x ULN) 2%, 2%. Changes in Serum Creatinine: Dolutegravir and rilpivirine have been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment with dolutegravir plus rilpivirine and remained stable through 48 weeks. A mean change from baseline of 0.093 mg per dL (range: -0.30 to 0.58 mg per dL) was observed after 48 weeks of treatment with dolutegravir plus rilpivirine.

These changes are not considered to be clinically relevant. Serum Lipids: At 48 weeks, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol to HDL ratio were similar between the treatment arms. Bone Mineral Density Effects: Mean bone mineral density (BMD) increased from baseline to Week 48 in subjects who switched from an antiretroviral treatment (ART) regimen containing tenofovir disoproxil fumarate (TDF) to dolutegravir plus rilpivirine (1.34% total hip and 1.46% lumbar spine) compared with those who continued on treatment with a TDF-containing antiretroviral regimen (0.05% total hip and 0.15% lumbar spine) in a dual-energy X-ray absorptiometry (DXA) substudy. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of subjects receiving JULUCA and 5% of subjects who continued their TDFcontaining regimen. The long-term clinical significance of these BMD changes is not known. Fractures (excluding fingers and toes) were reported in 3 (0.6%) subjects who switched to dolutegravir plus rilpivirine and 9 (1.8%) subjects who continued their current antiretroviral regimen through 48 weeks. Adrenal Function: In the pooled Phase 3 trials results analysis of rilpivirine, at Week 96, there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the rilpivirine group and of -0.02 (-0.48, 0.44) micrograms/dL in the efavirenz group. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation (cont’d on next page)

BRIEF S

tests in adverse receivin reporte reliably Muscul failure, Skin an includin

DRUG Concom regime HIV-1 interact JULUC renal o (MATE) or MAT Compo (UDP)P450 ( resistan enzyme reduce drugs Coadm to decr

by CYP Coadm plasma resistan drugs t Coadm plasma resistan subject daily (1 electroc with a k Drug In and rilp interact magnit Alterati predict • Anta JULU • Antia • Antic - co conc • Antid metf or st bloo reco • Antim JULU • Antim with • Gluc - co conc • H2-R shou H2-re • Herb cont • Macr poss • Med prod 4 ho

nificant or drug cations with the

pressed pivirine ational, 4 adult egimen her an riptase story of egravir zed 1:1 ir plus ubjects ceiving ned on ding to vir plus adverse ubjects ses) in n=511), actions re from IVICAY ause of orders: ulence, cystitis, drome. orders: orders: ttempt, with a chiatric reams. ephritis Tissue malities alyses) D-1 and n=511), Grade 3 4 (>5.0 4 (>2.5 (≥10.0 4 (>250 x ULN) shown without hin the hrough .58 mg pivirine. weeks, esterol Effects: ts who oproxil spine) troviral ometry rienced ir TDFis not ts who d their pooled l mean in the up. The ulation

xt page)

S:15”

BRIEF SUMMARY for JULUCA (dolutegravir and rilpivirine) tablets (cont’d) tests in the rilpivirine group is not known. Postmarketing Experience: The following adverse reactions have been identified during postmarketing experience in patients receiving a dolutegravir- or rilpivirine-containing regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal Disorders: Arthralgia, myalgia. Hepatobiliary Disorders: Acute liver failure, hepatotoxicity. Renal and Genitourinary Disorders: Nephrotic syndrome.

Skin and Subcutaneous Tissue Disorders: Severe skin and hypersensitivity reactions including DRESS. DRUG INTERACTIONS Concomitant Use with Other Antiretroviral Medicines: Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided. Potential for JULUCA to Affect Other Drugs: Dolutegravir, a component of JULUCA, inhibits the renal organic cation transporters (OCT)2 and multidrug and toxin extrusion transporter (MATE)1, thus it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide and metformin. Potential for Other Drugs to Affect the Components of JULUCA: Dolutegravir: Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 with some contribution from cytochrome P450 (CYP)3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.

Coadministration of dolutegravir with polyvalent cation-containing products may lead to decreased absorption of dolutegravir. Rilpivirine: Rilpivirine is primarily metabolized

by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of rilpivirine.

Coadministration of JULUCA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of JULUCA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.

Coadministration of JULUCA with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. QT-Prolonging Drugs: In healthy subjects, 75 mg once daily rilpivirine (3 times the dose in JULUCA) and 300 mg once daily (12 times the dose in JULUCA) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes. Established and Other Potentially Significant Drug Interactions: Information regarding potential drug interactions with dolutegravir and rilpivirine are provided below. These recommendations are based on either drug interaction trials of individual components or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.

Alterations in dose or regimen may be recommended based on drug interaction trials or predicted interactions with JULUCA: • Antacids: e.g., aluminum or magnesium hydroxide, calcium carbonate - administer JULUCA 4 hours before or 6 hours after taking antacids.

• Antiarrhythmic: dofetilide - coadministration is contraindicated with JULUCA. • Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin - coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations.

• Antidiabetics: metformin - with concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or JULUCA. When starting or stopping JULUCA, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of JULUCA is recommended.

• Antimycobacterials: rifampin, rifapentine - coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations.

• Antimycobacterials: rifabutin - an additional rilpivirine 25-mg tablet should be taken with JULUCA once daily with a meal when rifabutin is coadministered.

• Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) - coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations.

• H2-Receptor Antagonists: Famotidine, cimetidine, nizatidine, ranitidine - JULUCA should only be administered at least 4 hours before or 12 hours after taking H2-receptor antagonists.

• Herbal Products: St John’s wort (Hypericum perforatum) - coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations.

• Macrolide or ketolide antibiotics: clarithromycin, erythromycin, telithromycin - Where possible, consider alternatives, such as azithromycin.

• Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing products or laxatives, sucralfate, or buffered medications - Administer JULUCA 4 hours before or 6 hours after taking products containing polyvalent cations.

• Narcotic analgesics: methadone - No dose adjustments are required when starting coadministration of methadone with JULUCA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

• Oral calcium and iron supplements, including multivitamins containing calcium or iron (non-antacid) - administer JULUCA and supplements containing calcium or iron together with a meal or take these supplements 4 hours before or 6 hours after taking JULUCA. • Proton Pump Inhibitors: e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole - coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations.

Consult the full Prescribing Information for potential drug interactions; this list is not all inclusive.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to JULUCA during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. There is insufficient prospective pregnancy data from the APR to adequately assess the risk of birth defects and miscarriage. Given the limited number of pregnancies exposed to dolutegravircontaining regimens reported to the APR, no definitive conclusions can be drawn on the safety of dolutegravir in pregnancy, and continued monitoring is ongoing through the APR. Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population.

Lactation: The Centers for Disease Control and Prevention recommend that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known whether JULUCA or components of JULUCA are present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, dolutegravir and rilpivirine were present in milk. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving JULUCA. Pediatric Use: The safety and efficacy of JULUCA have not been established in pediatric patients. Geriatric Use: Clinical trials of JULUCA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of JULUCA in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment: No dosage adjustment is necessary for patients with mild or moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min).

In patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease, increased monitoring for adverse effects is recommended.

Hepatic Impairment: No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir or rilpivirine is unknown.

OVERDOSAGE There is no known specific treatment for overdose with JULUCA. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. Administration of activated charcoal may be used to aid in removal of unabsorbed active substance. As both dolutegravir and rilpivirine are highly bound to plasma proteins, it is unlikely that either would be significantly removed by dialysis. by:

ViiV Healthcare GlaxoSmithKline Research Triangle Park, NC 27709 Research Triangle Park, NC 27709 ©2017 ViiV Healthcare group of companies or its licensor.

Revised 11/2017 JLC:1BRS Trademarks are owned by or licensed to the ViiV Healthcare group of companies.

The other brand listed is a trademark of its respective owner and is not a trademark of the ViiV Healthcare group of companies. The maker of this brand is not affiliated with and does not endorse the ViiV Healthcare group of companies or its products. ©2017 ViiV Healthcare group of companies or its licensor.

Printed in USA. 822414R0 December 2017

MSP PERIODISMO CIENTÍFICO

Endometriosis en Puerto Rico

EN CIFRAS:

55,000

Por: Dra. Idhaliz Flores Caldera Department of Microbiology, Department of Ob-Gyn, Co-Leader Puerto Rico Biobank, U54 PSM-MCC Cancer Center Partnership, Ponce Health Sciences University School of Medicine, & Research Institute, Ponce Puerto Rico

mujeres en Puerto Rico padecen de Endometriosis

de

de

mujeres en edad reproductiva padecen de Endometriosis en Puerto Rico

1 de 4 1 de4 22 BILLONES

mujeres en edad reproductiva padecen de Endometriosis en el mundo

CASOS CON SÍNTOMAS comenzaron en la adolescencia MUJERES CON ENDOMETRIOSIS padecen de infertilidad

COSTO ESTIMADO DEL MANEJO CLÍNICO DE LA ENDOMETRIOSIS. Más que los costos de migraña y de enfermedad de Crohn's

En Puerto Rico 55 mil mujeres, de acuerdo a la Dra. Flores, incluyendo adolescentes luchan contra el dolor y la esterilidad causados por la endometriosis. Esta infografía explica el ciclo de la actividad de la enfermedad.

La endometriosis y el trabajo

13% 60% se ausenta al trabajo por los síntomas

65%

ve limitado el poder llevar a cabo actividades de la vida diaria

están presentes en sus trabajos con limitaciones

7.41

64%

horas

promedio de horas que las pacientes reportaron que pierden a la semana cuando los síntomas son más severos

está por debajo de los niveles de eficiencia y productividad en el trabajo

Infografía: Concepto Gráfico: Natalia Z. Rivera Torres Dirección General: Carlos Alexis Lugo Marrero

20

Revista Puertorriqueña de Medicina y Salúd Pública

MSP PERIODISMO CIENTÍFICO

SÍNTOMAS PRINCIPALES

DIAGNÓSTICO DE LA ENDOMETRIOSIS

Dolor menstrual: El tejido afectado libera prostaglandinas, sustancias que producen fuertes contracciones del útero

Hay distintas formas de diagnosticar la enfermedad Dolor en las relaciones sexuales: La penetración genera presiones molestas en las zonas afectadas. Es el segundo síntoma más reportado por mujeres con Endometriosis Dolor al orinar o al evacuar Dolor pélvico crónico: se define como dolor pé​​lvico de más de seis meses de duració​​n

Implantes (pequeños) o nódulos (mayores): Zonas de desarrollo más habituales Examen Pélvico: Se pueden observar diferencias en el tamaño de los ovarios, adherencias, etc. Además durante el examen pélvico se puede detectar dolor o sensibilidad al palpar esa área Sonografía Endovaginal: Importante prueba que muestra quistes ováricos y lesiones de endometriosis pélvica profunda

ENDOMETRIOSIS Y EMBARAZO Problemas de infertilidad

Las adherencias impiden el movimiento de las trompas o las obstruyen

CT-Scan y MRI: Se recurre a esta técnica cuando las anteriores técnicas no son concluyentes Laparoscopia: Valiosa cirugía minimo-invasiva que permite observar la endometriosis, realizar una biopsia y un diagnóstico definitivo

GRADOS DE LA ENDOMETRIOSIS

Gracias al examen laparoscópico podemos clasificar la enfermedad en cuatro fases mediante un sistema que va sumando puntos según las lesiones y adherencias encontradas al final.

GRADO 1 (MÍNIMO): 1-5 puntos

GRADO 2 (LEVE): 6-15 puntos

GRADO 3 (MODERADO): 16-30 puntos

GRADO 4 (GRAVE): 31-54 puntos

Mayor riesgo de aborto seguramente por alteraciones por causas aun desconocidas Baja receptividad del endometrio debido a resistencia a la progesterona, dominancia de estrógeno o expresión de aromatasa Pobre calidad del óvulo y/o embrión debido a la liberación de substancias inflamatorias tóxicas Referencia : Endometriosis Science and Practice, Giuduce, Evers and Healy. Wiley Blackwell, 2012

Tratamiento farmacológico

Para tratar la paciente con tratamientos farmacológicos o quirúrgicos según el grado de la endometriosis, el ginecólogo debe valorar además la edad, los síntomas y los deseos de fertilidad de la paciente.

TRATAMIENTOS FARMACOLÓGICOS: Antiprostaglandínicos:

CICLO DE LA ACTIVIDAD El endometrio responde a los cambios hormonales del ciclo menstrual

Reducen las contracciones del útero Anticonceptivos orales:

El reposo de los ovarios reduce la progresión Progestágenos:

incisiones se extraen las lesiones activas visibles Laparotomía: Cirugía más extensa para casos más avanzados Histerectomía: Extirpación del

útero y, a veces, de los ovarios

Danazol:

Producir efecto androgrénico Análogos de la Gn-RH:

5cm

Cámara

Solo en estudio

10cm

Antagonistas de la Gn-RH:

5cm

Tratamiento más comunmente utilizado.

Induce una menopausia reversible

Útero

Provoca inflamación, hinchazón y cicatrices

Laparoscopia: Mediante varias

Ovario

Si el endometrio esta fuera del útero (endometriosis) el fluido se acumula

Reducen el dolor menstrual

MEDIANTE VARIAS INCISIONES

Incisiones

El endometrio crece para alojar el embrión

Al final del ciclo menstrual, el endometrio se desintegra

Tratamiento combinado

Pinzas o Electrodos

10cm

MSP ARTÍCULO ORIGINAL

Caroline B. Appleyard1, Siomara Hernandez1, Marielly Cuevas1, Kenira J. Thompson1, Idhaliz Flores2, and Annelyn Torres-Reverón1 1) Department of Physiology, Ponce Health Sciences University - School of Medicine & Research Institute, Ponce Puerto Rico 2) Department of Microbiology, Department of Ob-Gyn, Co-Leader Puerto Rico Biobank, U54 PSM-MCC Cancer Center Partnership, Ponce Health Sciences University - School of Medicine, & Research Institute, Ponce Puerto Rico

Resumen El estrés afecta la severidad de la endometriosis. Creemos que es probable que haya una conexión con el sistema inmunológico debido a los niveles observados de mastocitos en el colon y el aumento de los niveles de células inflamatorias en el peritoneo de ratas con endometriosis inducida, similar a lo observado en pacientes con endometriosis.

Estos resultados sugieren que las técnicas de manejo estrés pueden ayudar a mujeres que se ven afectadas por la enfermedad a enfrentar y lidiar mejor con sus síntomas además del beneficio directo en la progresión de las lesiones.

22

Revista Puertorriqueña de Medicina y Salúd Pública

Abstract Stress affects the severity of endometriosis.

We believe that there is probably a connection to the immune system due to mast cell levels observed in the colon and increased levels of inflammatory cells into the peritoneum of rats, as this was also observed in patients with endometriosis. The results provide a basis to help identify stress management actions that will help women who are affected by the disease.

MSP ARTÍCULO ORIGINAL

"La endometriosis afecta aproximadamente 176 millones de mujeres, niñas y adolescentes en el mundo. Todavía hoy, la endometriosis sigue sin ser completamente entendida y continua incapacitando, afectando la productividad y el estilo de vida de millones de mujeres de todo el mundo"

L

a endometriosis es un trastorno ginecológico definido por la presencia de glándulas endometriales y estroma fuera de la cavidad endometrial, principalmente en los ovarios, las trompas de Falopio, cul-de-sac y los ligamentos uterinos (Bulun 2009).

Esta condición se caracteriza por la inf lamación peritoneal, fibrosis, adherencias y quistes ováricos, que resultan en dolor pélvico crónico, dolor durante el coito (dispareunia), períodos dolorosos (dismenorrea) y la infertilidad. Se estima que la prevalencia de endometriosis en mujeres pre-menopaúsicas es de 10%, o sea una de cada 10 (Nnoham 2010).

La endometriosis afecta aproximadamente 176 millones de mujeres, niñas y adolescentes en el mundo.

Todavía hoy, la endometriosis sigue sin ser completamente entendida y continua incapacitando, afectando la productividad y el estilo de vida de millones de mujeres de todo el mundo (Nnoham 2010, Fourquet 2011).

El estrés es un componente importante de muchas condiciones crónicas, inflamatorias y recurrentes de la salud. En el plano fisiológico, el estrés puede causar trastornos en la producción de cortisona de las

glándulas suprarrenales, afectando la función inmune, aumentando la presión arterial y la frecuencia cardíaca, y afectando el equilibrio hormonal. Entre las células inmunes que se ven afectadas durante este proceso se encuentran los mastocitos que ya han sido previamente identificados infiltrando lesiones de endometriosis peritoneal (Matsuzaki, 1998). En vista de que el estrés puede afectar el sistema inmunológico y, por tanto, el reclutamiento de células inf lamatorias como los mastocitos, es posible que estas células puedan contribuir a la patogénesis del dolor crónico y la inf lamación que se observan en la endometriosis. Las mujeres con endometriosis sufren de altos niveles de estrés debido a los síntomas de la condición, y además por la preocupación por su salud y el posible impacto de la endometriosis en la fertilidad. El dolor durante el coito, que es común en mujeres con endometriosis, interrumpe una relación sexual saludable, causando angustia y discordia, lo que lleva a más estrés. Aunque hay pruebas circunstanciales que sugieren que una variedad de técnicas para manejo de estrés y cambios en los cambios de estilo de vida pueden ayudar a las

Revista Puertorriqueña de Medicina y Salúd Pública

23

MSP ARTÍCULO ORIGINAL

mujeres que sufren de endometriosis (Lark, 1993), hasta recientemente ningún estudio había sido diseñado para determinar si el estrés afecta la progresión o los síntomas de la endometriosis en las pacientes. En la Ponce Health Sciences University, hace aproximadamente 8 años, un grupo interdisciplinario de científicas se dieron a la tarea de demostrar que el estrés puede afectar la progresión de la endometriosis a través de diferentes mecanismos, entre ellos el sistema inmunológico, utilizando un modelo animal de endometriosis.

En este estudio se indujo endometriosis intestinal en ratas hembras maduras, mediante un procedimiento quirúrgico, basado en el método de Vernon y Wilson (1985). Después de un corto período de recuperación y de comprobar que su ciclo reproductivo no fue alterado por la cirugía, se expuso a los animales a un protocolo de estrés por 10 días.

Este protocolo consiste en nadar en una piscina de plástico llena de agua

20-

(37 ± 1 ° C) durante 60 segundos, diez veces consecutivas cada día. Durante el periodo de estrés, se tomaron varias medidas para determinar si de hecho las ratas habían sentido estrés (por ejemplo, contar el número de “pellets” fecales y los niveles de corticosterone.

Todos los animales fueron sacrificados 60 días después mediante una laparotomía, donde se abrió la cavidad peritoneal y se examinó sistemáticamente la presencia de los implantes. La clasificación de los implantes en términos de grados de crecimiento se realizó según un sistema de clasificación ya establecido por Ingelmo et al., (1999). Básicamente, el sitio de los implantes fue examinados para detectar la presencia y el desarrollo de vesículas o quistes y su diámetro y peso fue medido. Además los animales fueron examinados para detectar signos de inflamación (números de células blancas en fluido peritoneal, niveles de myeloperoxidasa), se tomaron muestras de colon para

TOTAL VESICLE LENGTH/ANIMAL (MM)

15-

10-

5-

24

sham endo

endo

normal

0-

uncontrollable stress

Fig. 1. Efectos del estrés en el tamaño del implante.

Ninguno de los animales en el grupo sham-estrés desarrollaron vesículas. Todos los animales en el grupo endo desarrollaron vesículas en al menos una de las áreas implantadas. El grupo endo (sin estrés) tuvo un promedio de largo de vesículas de 6.57 ± 0.96mm por cada animal. Esto aumentó significativamente a 11.26 ± 5.27mm en el grupo de endo y estrés incontrolable (n=3-4 ± sem;*p<0.05 vs. normal).

Revista Puertorriqueña de Medicina y Salúd Pública

evaluar los daños macroscópicos y microscópicos, y se examinaron el tejido del cerebro y del cordón espinal para evaluar la expresión de receptores y neurotransmisores de dolor.

Entre nuestros resultados se encuentran varios hallazgos noveles en este campo de la investigación. Estos estudios demostraron por primera vez que el estrés aumenta el tamaño de las lesiones en las ratas. En el grupo de ratas con endometriosis sin estrés, los animales tenían un promedio total de longitud de la vesícula de 6.57 ± 0.96mm por animal. Esto se vio aumentado a 11,26 ± 5.27mm en el grupo de las ratas con endometriosis que recibieron estrés (Fig. 1 y 2). En adición, observamos que el estrés aumentó la inf lamación y el daño macroscópico y microscópico en el tejido del colon. El grupo de ratas con endometriosis y estrés también tuvo los más altos niveles de MPO al igual que un aumento en la infiltración de células blancas en el líquido peritoneal y mastocitos en el colon (Fig. 3 y

Fig. 2. Modelo animal de endometriosis peritoneal. Area de sutura (flecha ennegrecida) y presencia de vesículas (flechas entrecortadas) en animals implantados con tejido endometrial.

MSP ARTÍCULO ORIGINAL

4). También el número de pellets fecales observado en las ratas con endometriosis y estrés fue mayor en comparación con las ratas sin estrés, lo que indica un aumento de los niveles de ansiedad. En adición, el tejido del colon y del útero de las ratas con endometriosis y estrés demostraron tener niveles más altos de Nerve Growth Factor (NGF) y de su receptor especifico (TRK), y niveles abe-rrantes del receptor de dolor conocido como Mu Opiod Receptor (MOR), en un área del cerebro que se conoce juega un rol importante en la regulación del dolor, el “periaqueductal gray” o PAG. Independiente de estrés, las ratas con endometriosis mostraron tener niveles bajos de “Corticotropin Releasing Factor (CRF, un neurotransmisor que regula la respuesta a estrés) en el hipocampo, lo cual sugiere una desregulación en el eje HPA (hipotálamo-pituitaria-adrenal) causado por la endometriosis. Estos estudios en animales confirman datos que demuestran que el eje HPA está comprometido en pacientes con enfermedades dolorosas crónicas, incluyendo la endometriosis y la dismenorrea. De hecho, hay ya tres estudios independientes, incluyendo el nuestro, que muestran que las mujeres con endometriosis tienen

niveles más bajos de cortisol que mujeres sin la condición. Sin embargo los mecanismos subyacentes y las consecuencias fisiológicas de las disfunciones en el eje HPA en estos pacientes todavía son desconocidos.

Es importante llevar a cabo estas investigaciones para saber si niveles bajos de cortisol son causa o consecuencia de la endometriosis, y si aberraciones en el eje HPA pueden aumentar el riesgo a enfermedades inflamatorias, lo que explicaría la alta comorbilidad entre la endometriosis y el asma, las alergias y otras afecciones inflamatorias.

manejo del estrés ofrece alternativas terapéuticas útiles para aminorar los síntomas y progresión de esta condición.

Referencias •Anaf V, Chapron C, Nakadi IE, De Moor, V, Simonart T, Noel, J-C (2006) Fertility and Sterility 86:1336-1343.

•Appleyard CB and Wallace JL. (1995) American Journal of PhysiologyGastrointestinal and Liver Physiology.

269(1 pt 1):G119-125.

•Boughton-Smith NK, Wallace JL and Whittle BJ (1998) Agents Actions 25: 115-123.

•Child TJ, Lin Tan S (2001) Drugs, 71: 1735-1750.

•Corson SL: Endometriosis: the enigmatic disease. 1st Edition, Essential Medical Information Systems, Inc, USA. 1992.

•Fibroid Tumor and Endometriosis Self Help Book by Susan M. Lark, M.D. •Ingelmo JMR Quereda F, Acién P. (1999) Fertility and Sterility May (Vol. 71, Issue 5, Pages 907-911) •Smith JW and Castro GA. (1978) Am J Physiol 234(1): 72-79.

•Vernon MW, Wilson EA. (1985) Fertil Steril 44 : 684-94.

Conclusión Este estudio presenta pruebas por primera vez de los efectos negativos del estrés en la progresión, la inflamación, y la percepción del dolor en un modelo animal de endometriosis.

En este modelo la exposición a estrés aumentó la severidad de la enfermedad y también parámetros inflamatorios, y aberraciones en la expresión de moléculas asociadas a la regulación y percepción del dolor. Estos datos sugieren que el estrés modula al sistema inmunológico y al eje HPA, contribuyendo a la fisiopatología de la endometriosis. Nuestros resultados sugieren que el uso de técnicas para el

NUMBER OF MAST CELLS/FIELD OF VIEW 12.5107.55.0-

Fig. 3. Mastocitos en el colon de las ratas. Colon de una rata en condiciones normales mostrando arquitectura normal con pocos mastocitos. (A); colon de una rata con endometriosis que no recibió estrés demuestra pocos mastocitos (B); colon de una rata con endometriosis que fue expuesta a estrés incontrolable por 10 días, demuestra aumento significativo de mastocitos. (C). Mastocitos fueron teñidos con alcian blue/safranine O. Magnificación, x40.

2.5-

0-

normal

endo sham

endo

Fig. 4. Efectos del estrés en la expresión de mastocitos en el colon. El grupo expuesto a endometriosis y estrés incontrolable tuvo el mayor número de mastocitos (n=3-4 ± sem; *p<0.01 vs. normal unless otherwise noted).

uncontrollable stress

Revista Puertorriqueña de Medicina y Salúd Pública

25

MSP CASO CLÍNICO

Sobreviviendo

al linfoma de Hodgkin De intoxicación por comida a infarto agudo del miocardio en hombre de 30 años de edad.

Autores: 1Kathy Caraballo Rivera, MD; 2Vielka Cintrón, MD; 3José Martínez Barroso, MD. Manatí Medical Center: 1Programa de Residencia de Medicina de Familia, PGY-1; 2Departamento de Medicina de Familia; 3 Departamento de Medicina Interna/Cardiología. Manatí Medical Center, PO BOX 1142, Manatí, Puerto Rico, 00641

26

Revista Puertorriqueña de Medicina y Salúd Pública

MSP CASO CLÍNICO

Resumen El tratamiento del linfoma de Hodgkin incluye, frecuentemente, la radioterapia supradiafragmática.

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

De igual modo, el paciente tiene un historial médico pasado de linfoma de Hodgkin a los 22 años por lo cual había recibido radioterapia supradiafragmática.

Considerando la poca respuesta del paciente al tratamiento inicial y el historial de linfoma de Hodgkin se solicitó una evaluación cardiológica, la cual evidenció enzimas cardíacas elevadas y disquinesia en el ecocardiograma. La cateterización del lado izquierdo del corazón reveló una lesión de la arteria descendente anterior izquierda corregida con la implantación de un estent. Posteriormente, el paciente fue dado de alta para seguimiento externo con el médico primario y el cardiólogo. Aunque la enfermedad coronaria aguda es una complicación conocida de la radioterapia, la presentación clínica de este caso fue inusual. Todos los pacientes con historial de radioterapia tienen que ser evaluados completamente para enfermedad coronaria comenzando a los 5-10 años después de terminado el tratamiento. El médico primario juega una papel fundamental en el monitoreo para complicaciones tardías en pacientes en remisión de linfoma de Hodgkin después de radioterapia.

Revista Puertorriqueña de Medicina y Salúd Pública

27

MSP CASO CLÍNICO

Introdución Los pacientes con linfoma de Hodgkin (LH) tienen una alta tasa de curación. El tratamiento de LH incluye, regularmente, radioterapia supradiafragmática (RT) en portales que incluyen parte del corazón.

Numerosos estudios han demostrado que los sobrevivientes de LH tienen una alta incidencia de enfermedad cardiovascular, siendo la causa más común de muerte no-maligna1.

Las complicaciones incluyen enfermedad del pericardio, isquemia al miocardio o infarto, cardiomiopatía, fallo cardíaco, anormalidad valvular o defectos de conducción. Estas complicaciones se piensa que son el producto de la radiación la cual induce inflamación y fibrosis en las estructuras cardíacas1.

Caso clínico Un hombre de 30 años de edad se presenta a nuestra sala de emergencia con síntomas gastrointestinales y malestar de pecho de tres días de evolución. El indica que su novia tenía los mismos síntomas para el mismo periodo de tiempo aunque ella mejoró. El refiere náuseas, vómitos, malestar general, diarrea, fiebre, dolor abdominal y de espalda además del malestar del pecho.

En el examen f ísico solamente un dolor abdominal difuso fue encontrado.

Los laboratorios realizados en la sala de emergencia se encontraban dentro de los límites normales. Debido a los síntomas y presentación del paciente fue sospechado primeramente una intoxicación alimentaria.

El historial médico pasado del paciente incluye LH a los 22 años por el cual completó 20 ciclos de radioterapia y fue acompañado por su oncólogo dándole de alta de su servicio 2 años después de finalizado el tratamiento.

Durante la admisión el paciente manifesto falta de aire y dolor de pecho. Como parte de su evaluación fueron realizados gases arteriales los cuales mostraron hipoxemia y un electrocardiograma mostró cambios isquémicos no específicos. Dado el historial 28

Revista Puertorriqueña de Medicina y Salúd Pública

A

B

C

D

de LH una evaluación cardiológica fue realizada para descartar cardiomiopatía. La ventriculografía nuclear mostró evidencia de hipocinesia focal apical del ventrículo izquierdo.

Un set de enzimas cardíacas elevadas (troponin 13.84ng/mL) confirmó la sospecha de infarto al miocardio sin elevación de ST, síndrome agudo coronario ( NSTEM I-ACS) ( ICD10, I21.4). La cateterización del lado izquierdo del corazón reveló

una lesión excéntrica severa de 95% de la arteria descendente izquierda. La intervención cardíaca percutánea de la arteria anterior descendente media con un ESTENT (3.5mm x 2.4 mm) fue realizada exitosamente dilatando la arteria a 4mm (Figura 1).

Después de dos días el paciente fue dado de alta para continuar con el cuidado externo con su médico primario y cardiólogo.

La ventriculografía nuclear mostró evidencia de hipocinesia focal apical del ventrículo izquierdo.

MSP CASO CLÍNICO

"La proporción de incidencia estandarizada para todas las enfermedades cardiovasculares combinadas se mantiene elevada al menos por 25 años. Estudios recientes muestran una incidencia cumulativa de 40 años de 50% de riesgo de enfermedades cardiovasculares"

Discusión Aunque la enfermedad coronaria aguda es una complicación de la radioterapia conocida, la presentación clínica de este caso fue inusual. Según la población envejece y los tratamientos para el linfoma de Hodgkin mejoran, más pacientes son clasificados como sobrevivientes de linfoma. Después del tratamiento de LH y una vez alcanzada la remisión los sobrevivientes de LH pasan al cuidado de su médico primero, quien es la persona más indicada para atender todos los problemas después de la remisión.

El paso más importante como médico primario es el monitoreo apropiado para las complicaciones tardías del paciente en remisión de LH después de RT. Los sobrevivientes están a mayor riesgo de recurrencia de cáncer, cáncer secundario, complicaciones cardiovasculares y problemas psicosociales, entre otras complicaciones. Se ha encontrado que los sobrevivientes de LH tienen un mayor riesgo de infarto al miocardio y fallo cardíaco congestivo cuando se comparan a la población en general (proporción de incidencia estandarizada 3.6 y 4.9, respectivamente)2. La proporción de incidencia estandarizada para todas las enfermedades cardiovasculares

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

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

combinadas se mantiene elevada al menos por 25 años2. Estudios recientes muestran una incidencia cumulativa de 40 años de 50% de riesgo de enfermedades cardiovasculares3.

Con estas estadísticas presentes es importante como médico primario estar consciente de las posibles complicaciones.

Con una población de sobrevivientes de LH creciendo, todos los pacientes con malestar o dolor de pecho con historial médico de RT supradiafragmática debería tener una evaluación completa para enfermedad coronaria empezando 5-10 años después de completada la terapia.

Como médico primario la primera evaluación de pacientes sobrevivientes de LH debería incluir un electrocardiograma y ecocardiograma base1.

El monitoreo de estos pacientes es desaf iante porque no hay una guía completa aceptada para el manejo y cernimiento de las complicaciones4.

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

Referencias 1. Ng AK. Review of the cardiac long-term effects of therapy for Hodgkin lymphoma. Br J Haematol 2011; 154:23.

2. Aleman BM, van den BeltDusebout AW, De Bruin ML, et al.

Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood 2007; 109:1878.

3. Van Nimwegen, Schaapveld,

Junus, et al. Cardiovascular disease after Hodgkin lymphoma treatment 40 year disease risk.

JAMA Internal Medicine 2015; 175:6.

4. Thompson, C. A., Mauck, K., Havyer, R., Bhagra, A., Kalsi, H., & Hayes, S. N. (2011). Care of the Adult Hodgkin Lymphoma Survivor. The American Journal of Medicine, 124(12), 1106–1112.

Revista Puertorriqueña de Medicina y Salúd Pública

29

La

genética del cáncer de seno

en la familia puertorriqueña Los estudios sobre la ascendencia genética han demostrado que ​ los ​ puertorriqueños poseen más genes africanos y europeos, pero significativamente menos influencia del genoma taíno que las​ poblaciones de México. Las mujeres ​hispánica​s​tienen menos riesgo de desarrollar un cáncer de seno, pero el pronóstico es peor que el de las mujeres europea​s​o estadounidenses​.

34

Revista Puertorriqueña de Medicina y Salúd Pública

Revista Puertorriqueña de Medicina y Salúd Pública

35

MSP ARTÍCULO ORIGINAL

El rol de la genética en el desarrollo y manejo clínico del cáncer de seno Por: Julie Dutil, PhD, Profesora Asociada Ponce Health Sciences University Department of Biochemistry Member, Advisory Board of the Tampa Bay Community Cancer Network's (TBCCN) initiative on bioethics and biobanking Member, American Society for Human Genetics Reviewer, American Journal of Medical Genetics Part A Reviewer, US Pakistan Scientific Exchange Program of the National Academies of Science Collaborator, US-Latin America Cancer Research Network Member, American Association for Cancer Research Reviewer, Molecular Carcinogenesis

Los genomas ancestrales dibujan el rostro del cáncer de seno en la isla y dan indicadores de menos sobreprotección de las mujeres puertorriqueñas sobre el tumor de la mortal afección Resumen En Puerto Rico, aproximadamente 1,540 mujeres son diagnosticadas con cáncer de seno invasivo cada año, representando el 32% de todos los cánceres y el 16% de las muertes por cáncer. Entre 5 a 10% de todos los cánceres de mama se producen debido a la herencia de raras mutaciones deletéreas en genes de predisposición muy penetrantes como BRCA1 y BRCA2. Las mujeres portadoras de una mutación deletérea en los genes de BRCA están en un riesgo substancialmente más alto de desarrollar cáncer de mama (hasta 87% en la vida) e, inclusive, otros tipos de cáncer.

Abstract About 1,540 women are diagnosed with invasive breast cancer each year in Puerto Rico, representing 32% of all cancers and 16% of cancer deaths.

Approximately 5–10% of all breast cancers occur due to the inheritance of rare deleterious mutations in highly penetrating predisposition genes, such as BRCA1 and BRCA2. Women carrying a deleterious mutation in BRCA genes are at a substantially higher risk for developing breast cancer (up to 87% in their lifetime) and even other cancers.

Palabras claves: cáncer hereditario, cáncer de mama, mutaciones deletéreas, genes BRCA, genética, prueba de genética

Keywords: inherited cancer, breast cancer, deleterious mutations, BRCA genes, genetics, genetic testing

Para obtener alguna información sobre nuestra investigación o sobre los cánceres hereditarios en general, se puede comunicar a través del correo electrónico: jdutil@psm.edu con la Profesora Asociada Julie Dutil, en la Ponce Health Sciences University.

36

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Introducción En Puerto Rico, aproximadamente 1,540 mujeres son diagnosticadas con cáncer de seno invasivo cada año, representando el 32% de todos los cánceres y el 16% de las muertes por cáncer. Los factores de riesgo para el cáncer de mama incluyen edad, ubicación geográfica, estatus socioeconómico, eventos reproductivos, hormonas exógenas, factores de estilo de vida, densidad de la mama y antecedentes familiares de mama y otros cánceres. Entre 5 a 10% de todos los cánceres de mama se producen debido a la herencia de raras mutaciones deletéreas en genes de predisposición muy penetrante como BRCA1/2. Se ha demostrado que mutaciones hereditarias en genes como PTEN, p53, CHEK2, ATM, NBS1, RAD50, BRIP1 y PALB2 también confieren un riesgo moderado a alto de cáncer de mama.

Proporción del cáncer de mama con causas genéticas o ambientales Las mujeres portadoras de una mutación deletérea en los genes de BRCA están en un riesgo substancialmente más alto de desarrollar cáncer de mama (hasta 87% en la vida) u ovario (hasta 44%) en comparación con la población en general. También, han demostrado estar en mayor riesgo de otros cánceres, entre ellos el melanoma, cáncer de la

próstata y del páncreas. Además, las mutaciones de BRCA dominante se asocian al diagnóstico a temprana edad y a una probabilidad más alta que el tumor sea de tipo triple negativo. El único método para el diagnóstico de un cáncer hereditario es hacer una prueba de genética, donde se hace la secuenciación de los genes de BRCA u otros.

Manejo clínico de las familias con una predisposición genética al cáncer de seno Las pruebas genéticas para los cánceres hereditarios sirven para educar a las personas con predisposición sobre los riesgos de desarrollar cáncer de mamas y otros tipos de cáncer. La asesoría genética y pruebas típicamente se ofrecen a pacientes con cáncer de mama o sus familiares basados en el riesgo de portar una mutación de cáncer hereditario estimada por antecedentes personales y familiares de cáncer. Esto se considera el estándar de atención, según lineamientos nacionales de múltiples médicos profesionales organizaciones de Estados Unidos, incluyendo la Sociedad Americana de Oncología Clínica (ASCO) y la Red Nacional Integral de Cáncer (NCCN). Las personas con un alto riesgo de tener mutaciones de cáncer de seno hereditario son reconocidas por una historia personal de cáncer de ovario o seno, inicio temprano (< 50 años de edad)

del cáncer de mama o antecedentes familiares de cáncer de mama, cáncer de mama bilateral, el cáncer de mama masculino o el cáncer de ovario.

La mayor vigilancia, la cirugía profiláctica e intervenciones de quimiopreventivo son, entre las opciones disponibles, para los portadores de mutaciones de BRCA para gestionar el riesgo de mama y otros cánceres. Investigaciones han demostrado que quienes son educados acerca de su riesgo de cáncer de mama son más propensos a participar en riesgo, reducir comportamientos y estrategias de detección temprana -como examen mensual automática de mama-, visitas a médicos, mamografía y proyección de imagen por resonancia magnética (MRI) de mama. Además, el uso de la quimioterapia y/o quirúrgica preventiva tienen un impacto positivo en la supervivencia en portadoras de mutaciones de cáncer hereditario. En pacientes con cáncer recién diagnosticado, los resultados de prueba genética de BRCA afecta también las decisiones quirúrgicas.

Los beneficios de la evaluación del riesgo de cáncer y pruebas de BRCA también se extienden a otros miembros de la familia, como portador de detección se puede distinguir entre los de alto riesgo y aquellos con riesgo promedio, escasamente algunos individuos de opciones de reducción de riesgos innecesarias.

Revista Puertorriqueña de Medicina y Salúd Pública

37

MSP ARTÍCULO ORIGINAL

Investigaciones sobre la genética de los cánceres de mama en Puerto Rico Desde 2007, nuestro grupo en la Ponce Health Sciences University se dedica a identificar los factores genéticos involucrados en el riesgo de cáncer en la población puertorriqueña. Esta investigación es financiada por el Instituto Nacional de Cáncer (NCI, por siglas en inglés), del Instituto Nacional de Salud de Estados Unidos (NIH).

Los proyectos y cursos incluyen la identificación de las mutaciones frecuentes en la población de Puerto Rico en los genes de BRCA y otros genes de susceptibilidad, usando la secuenciación de próxima generación. Además, tenemos proyectos dedicados a determinar el rol de la ancestría genética en el desarrollo de los tumores de cáncer de seno agresivo de tipo triple negativo.

Mientras que la mayo-ría de las poblaciones hispanas son una mezcla de 3 razas ancestrales (africana, europea y taína), la proporción relativa de cada una dentro y a través de las poblaciones del Caribe y América del Sur. Por ejemplo, estudios utilizando marcadores genéticos informativos sobre la ascendencia genética han demostrado que los puertorriqueños llevan más ascendencia

38

Revista Puertorriqueña de Medicina y Salúd Pública

europea y africana, pero significativamente menos ascendencia taína que las poblaciones de México. Las mujeres hispanas tienen menos riesgo de desarrollar cáncer de seno, pero el pronóstico es peor que para las mujeres europeas o de Estados Unidos.

Nuestros estudios muestran que las mujeres puertorriqueñas con más ascendencia genética africana tienen más probabilidad de desarrollar un cáncer de seno de tipo triple negativo, conocido como más agresivo y con menos opciones de tratamiento.

En el espectro de la mutación subyacente a los cánceres de seno hereditarios en Puerto Rico, tres mutaciones recurrentes cuentan para más del 70% de todas las mutaciones BRCA observado en este estudio poblacional.

Las mutaciones frecuentes en Puerto Rico son diferentes de las que se encuentran en otros países de American Latina y del Caribe. Estos resultados indican la importancia de seguir la investigación dirigida a la población de Puerto Rico para entender bien las causas genéticas de los cánceres de seno en la Isla.

"Nuestros estudios muestran que las mujeres puertorriqueñas con más ascendencia genética africana tienen más probabilidad de desarrollar un cáncer de seno de tipo triple negativo, conocido como el más agresivo y con menos opciones de tratamiento" Conclusión Una historia familiar de cáncer de seno desempeña un rol muy importante en el riesgo de padecerlo, por lo que las pruebas genéticas para los cánceres hereditarios pueden educar a las personas con predisposición a desarrollar cáncer de mamas y otros tipos de cáncer. A través de la historia médica y fami-liar, se puede identificar a pacientes y familiares para recibir educación sobre los riesgos de cáncer.

Indication for Humulin® R U-500

Select Safety Information for Humulin R U-500

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.

•

•

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

• 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.

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

Please see Instructions for Use included with the pen.

U-500 helps provide high-dose patients with the power to get back on track.* When you have a patient who injects more than 200 units of insulin a day and glycemic levels continue to rise, it may be time to consider Humulin® R U-500— the only insulin studied in a randomized, controlled clinical trial of these high-dose patients.† Used as insulin monotherapy, U-500 was shown to lower A1C by an average of 1.1%, whether it was injected two or three times a day.1 *Back on track refers to improving glycemic control. † 24-week, open-label, randomized trial to compare the efficacy and safety of 2 dosing regimens (TID, n=162 vs BID, n=163) for U-500 insulin replacing high-dose U-100 insulin (>200 units per day) with or without oral antihyperglycemic drugs in adult patients with uncontrolled type 2 diabetes. These regimens were found to be equivalent for A1C reduction over 24 weeks, and both were efficacious.1 Study conducted with U-100 insulin syringes and Humulin R U-500 vials.

Questions? Talk to a healthcare professional at The Lilly Answers Center at 1-800-545-5979.

Watch your colleagues discuss how high-dose patients may benefit from U-500 at Humulin.com/5x

Select Safety Information for Humulin R U-500, continued 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 a syringe for administration. Overdose and severe hypoglycemia can occur.

•

Reference: 1. Hood RC, Arakaki RF, Wysham C, et al. Two treatment approaches for human regular U-500 insulin in patients with type 2 diabetes not achieving adequate glycemic control on high-dose U-100 insulin therapy with or without oral agents: a randomized, titration-to-target clinical trial. Endocr Pract. 2015;21(7):782-793.

Erratum, 2016;22(7):905.

® ® ® Indication forforHumulin R RU-500 Indication Humulin U-500 Indication for Humulin R U-500 • Humulin • Humulin is aisconcentrated human insulin indicated to improve glycemic control in adults andand children with diabetes mellitus requiring R U-500 a concentrated human insulin indicated to improve glycemic control in adults children with diabetes mellitus requiring • R U-500 •

Humulin R U-500 is a concentrated human insulin indicated to improve glycemic control in adults and children with diabetes mellitus requiring more than 200200 units of insulin per day.day.per day. more than units ofunits insulin per more than 200 of insulin • Limitation of Use: The safety andand efficacy Humulin U-500 used in combination with other insulins notnot been determined.

TheThe safety Limitation of Use: The safety efficacy of Humulin R U-500 used inused combination with other insulins has been safety • Limitation of Use: The safety andofefficacy ofRHumulin R U-500 in combination with otherhas insulins has notdetermined. been determined.

The safety andand efficacy of Humulin R U-500 delivered by continuous subcutaneous infusion has not been determined. efficacy of Humulin R U-500 delivered by continuous subcutaneous infusion has not been determined. and efficacy of Humulin R U-500 delivered by continuous subcutaneous infusion has not been determined.

Important Safety Information forforHumulin R RU-500 Important Safety Information Humulin U-500 Important Safety Information for Humulin R U-500 Contraindications Contraindications Contraindications • Humulin • Humulin U-500 isRcontraindicated during episodes hypoglycemia andand in patients to Humulin U-500 orR any of its excipients.

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

Warnings and Precautions Warnings and Precautions Warnings and Precautions • Dosing • Dosing Errors: Extreme caution must be be observed in measuring thethe dose of U-500 because inadvertent overdose may result in serious Errors: Extreme caution must observed in measuring dose ofdose Humulin R U-500 because inadvertent overdose may result in serious • Dosing Errors: Extreme caution must be observed in measuring theHumulin ofRHumulin R U-500 because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia. adverse reaction or life-threatening hypoglycemia. adverse reaction or life-threatening hypoglycemia.

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

Dispensing Dispensing Dispensing - Instruct patients topatients always inspect insulin vials to confirm thethe correct insulin is dispensed including the correct brand andand concentration.

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

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

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

Prescribing Prescribing Prescribing - Dosing errors have occurred Humulin U-500 was administered with syringes than a U-500 syringe.

Patients should beshould prescribed - Dosing errors have occurred when Humulin R U-500 was administered with syringes other than a U-500 insulin syringe.

Patients should be prescribed - Dosing errors have when occurred whenRHumulin R U-500 was administered withother syringes other thaninsulin a U-500 insulin syringe.

Patients 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.

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.

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 Administration Administration - Instruct patients topatients always check thethe insulin label before each injection.

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

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

- Use onlyonly a U-500 insulin syringe with Humulin R U-500 to avoid administration errors.

Doerrors. notnot useDo any other type of syringe tosyringe administer Humulin RHumulin U-500.

- Use a U-500 insulin syringe with Humulin R U-500 to avoid errors.

Do use any other type of type syringe to administer Humulin R U-500.

- Use only a U-500 insulin syringe with Humulin R U-500 toadministration avoid administration not use any other of to administer R U-500.

Adhere toAdhere administration instructions.

Adhere to administration instructions. to administration instructions.

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

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

- Instruct the to inform or emergency department ofoftheHumulin ofRHumulin R U-500 prescribed. ® ® ® ® • If• using the Humulin R U-500 KwikPen , patients should be counseled to dial and dose the prescribed number units ofofinsulin (NO dose conversion ® ® If using the Humulin R U-500 KwikPen , patients should be counseled to dial and dose the prescribed number of units ofunits insulin (NO dose • If using the Humulin R U-500 KwikPen , patients should be counseled to dial and dose the prescribedofnumber of insulin (NOconversion dose conversion is required). is required). is required).

• DO • DO NOT RHumulin U-500 from thethe Humulin U-500 KwikPen into anyany syringe forsyringe administration.

Overdose andand severe hypoglycemia cancan occur.

NOT transfer Humulin R U-500 from Humulin R U-500 KwikPen into syringe for administration.

Overdose severe hypoglycemia occur.

•transfer DO NOTHumulin transfer R U-500 from theRHumulin R U-500 KwikPen into any for administration.

Overdose and severe hypoglycemia can occur.

• Never • 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.

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.

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

• Hypoglycemia: • Hypoglycemia: Hypoglycemia is the most reaction associated with insulin, including Humulin RHumulin U-500.

Severe hypoglycemia cancan cause Hypoglycemia is the most adverse reaction associated with insulin, including Humulin R U-500.

Severe hypoglycemia cause • Hypoglycemia: Hypoglycemia is common thecommon mostadverse common adverse reaction associated with insulin, including 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. 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. 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 cancan impair concentration ability andand reaction thisthis maymay place an an individual andand others at risk in situations where these abilities Hypoglycemia impair concentration ability reaction time; place individual others at risk in where these abilities are are Hypoglycemia can impair concentration ability andtime; reaction time; this may place an individual and others at situations risk in situations where theseare abilities important, such as driving or operating other machinery. important, such as driving or operating other machinery. important, such as driving or operating other machinery.

- Hypoglycemia cancan happen and symptoms maymay differ in each individual andand change time in the same - Hypoglycemia happen suddenly and symptoms differ indiffer each change over time in time the same - Hypoglycemia cansuddenly happen suddenly and symptoms may inindividual each individual andover change over in individual. theindividual. same individual.

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

- The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation.

As As with allAs insulin preparations, thethe glucose - The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. with all insulin preparations, glucose - The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. 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 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 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. many conditions. many conditions.

- Patients and caregivers must be be educated to recognize andand manage Self-monitoring of blood glucose an an essential in the - Patients and caregivers must educated to recognize manage hypoglycemia.

Self-monitoring of blood plays essential role in the - Patients and caregivers must be educated to recognize andhypoglycemia. manage hypoglycemia.

Self-monitoring ofglucose bloodplays glucose plays an role essential role in the prevention and management of hypoglycemia.

In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of of prevention and management of hypoglycemia.

In patients at higher forrisk hypoglycemia and patients who have symptomatic awareness prevention and management of hypoglycemia.

In patients at risk higher for hypoglycemia and patients whoreduced have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. hypoglycemia, increased frequency of bloodofglucose monitoring is recommended. hypoglycemia, increased frequency blood glucose monitoring is recommended.

• Hypersensitivity • Hypersensitivity andand Allergic Severe, life-threatening, generalized allergy, including anaphylaxis, cancan occur with insulin products, including Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, occur with insulin products, including • Hypersensitivity andReactions: Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Humulin RHumulin U-500.

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

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

• Hypokalemia: • Hypokalemia: Insulin useInsulin cancan lead tocan hypokalemia thatthat leftleft untreated maymay cause respiratory paralysis, ventricular arrhythmia, andand death.

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

PP-HM-US-0518 05/2017 USA, LLCLLC 2017.

All rights reserved.

PP-HM-US-0518 05/2017©Lilly ©Lilly USA, 2017.

All rights reserved.

PP-HM-US-0518 05/2017 ©Lilly USA, LLC 2017. All rights reserved.

Important Safety Information Humulin U-500, continued Important Safety Information forforHumulin R RU-500, continued Important Safety Information for Humulin R U-500, continued Warnings Precautions, continued Warnings andand Precautions, continued Warnings and Precautions, continued • Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Thiazolidinediones (TZDs), which PPAR-gamma agonists, • Fluid Retention andFailure Heart Failure with Concomitant of PPAR-gamma Agonists: Thiazolidinediones which areare PPAR-gamma agonists, cancan • Fluid Retention and Heart with Concomitant Use of Use PPAR-gamma Agonists: Thiazolidinediones (TZDs),(TZDs), which are PPAR-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin.

Fluid retention may lead to or exacerbate heart failure.

Observe cause dose-related fluid retention, particularly wheninused in combination with insulin.

Fluid retention may to or exacerbate heart failure. cause dose-related fluid retention, particularly when used combination with insulin.

Fluid retention may lead tolead or exacerbate heart failure.

ObserveObserve patients for signs symptoms of heart failure.

If heart failure develops, it should managed according tostandards current standards of care, discontinuation forand signs andand symptoms heart failure.

Iffailure heart failure develops, it should be be managed according to current standards care, andand discontinuation patientspatients for signs symptoms of heartoffailure.

If heart develops, it should be managed according to current of care,ofand discontinuation or dose reduction of the PPAR-gamma agonist must be considered. dose reduction of the PPAR-gamma be considered. or doseorreduction of the PPAR-gamma agonistagonist must bemust considered.

Adverse Reactions Adverse Reactions Adverse Reactions • Adverse reactions include hypoglycemia, allergic reactions, lipodystrophy, injection-site reactions, weight gain, peripheral edema, immunogenicity.

• Adverse reactions hypoglycemia, reactions, lipodystrophy, injection-site reactions, gain, peripheral andand immunogenicity.

• Adverse reactions includeinclude hypoglycemia, allergicallergic reactions, lipodystrophy, injection-site reactions, weight weight gain, peripheral edema,edema, and immunogenicity.

Drug Interactions Drug Interactions Drug Interactions • Some medications may alter glucose metabolism and may necessitate insulin dose adjustment.

Signs of hypoglycemia may or in patients Some medications may alter glucose metabolism and may necessitate dose adjustment. of hypoglycemia be be reduced or absent in patients • Some• medications may alter glucose metabolism and may necessitate insulin insulin dose adjustment.

Signs ofSigns hypoglycemia may bemay reduced orreduced absent in absent patients taking antiadrenergic drugs.

Particularly close monitoring may be required. taking antiadrenergic drugs.

Particularly close monitoring may be required. taking antiadrenergic drugs. Particularly close monitoring may be required.

Use inPopulations Specific Populations in Specific Populations Use in Use Specific • Pregnancy Category B: While there adequate well-controlled in women, pregnant women, evidence from published literature suggests good • Pregnancy Category While there areare no no adequate andand well-controlled in pregnant women, evidence from published literature suggests thatthat good • Pregnancy Category B: WhileB:there are no adequate and well-controlled studiesstudies instudies pregnant evidence from published literature suggests that good glycemic control in patients with diabetes during pregnancy provides significant maternal and fetal benefits. glycemic in patients with diabetes pregnancy provides significant maternal andbenefits. fetal benefits. glycemic controlcontrol in patients with diabetes during during pregnancy provides significant maternal and fetal • Pediatric Use: There are no well-controlled studies of use of Humulin R U-500 in children.

Standard precautions to use ofRHumulin • Pediatric Use: There are no well-controlled studies of use of Humulin R U-500 in children.

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

• Geriatric Use: There well-controlled of use ofRHumulin U-500 inpatients. geriatric patients.

In elderly patients with diabetes, initial dosing, dose • Geriatric Use: There areare no no well-controlled of Humulin use of Humulin R U-500 in geriatric patients.

In elderly patients with diabetes, thethe initial dosing, dose • Geriatric Use: There are no well-controlled studiesstudies ofstudies use of U-500 inR geriatric In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. increments, and maintenance dosage should be conservative to avoid hypoglycemia. increments, and maintenance dosage should be conservative to avoid hypoglycemia.

• Renal orImpairment: Hepatic Impairment: Frequent glucose monitoring insulin dose reduction may inwith patients with renal orimpairment. hepatic impairment.

Renal or Hepatic Impairment: Frequent monitoring andand insulin dose reduction be be required in patients with or hepatic impairment.

• Renal• or Hepatic Frequent glucoseglucose monitoring and insulin dose reduction may bemay required inrequired patients renal orrenal hepatic Dosage Administration andand Administration DosageDosage and Administration • Prescribe Humulin R U-500 ONLY towho patients require more than units of insulin day.

• Prescribe Humulin R U-500 to patients whowho require more than 200200 of insulin day.

• Prescribe Humulin R U-500 ONLY toONLY patients require more than 200 units ofunits insulin per day.perper • Humulin R U-500 is available as a KwikPen or a multiple dose vial.

Patients using the vial must prescribed U-500 insulin to avoid medication errors.

• Humulin R U-500 is available as a KwikPen or a multiple dose vial. Patients using vialbemust be be prescribed thethe U-500 insulin syringe avoid medication • Humulin R U-500 is available as a KwikPen or a multiple dose vial.

Patients using the vialthe must prescribed the U-500 insulin syringe tosyringe avoidtomedication errors. errors.

• NOT perform dose conversion when using R U-500 KwikPen. The dose of the KwikPen shows ofHumulin units ofRHumulin R U-500 • DODO NOT perform dose conversion when using thethe Humulin R U-500 KwikPen. Thewindow dose window of the KwikPen shows thethe number of Humulin R U-500 • DO NOT perform dose conversion when using the Humulin RHumulin U-500 KwikPen. The dose ofwindow the KwikPen shows the number ofnumber unitsofofunits U-500 to be injected and NO dose conversion is required. to be injected and NO dose conversion is required. to be injected and NO dose conversion is required.

• DO NOT perform dose conversion when using a U-500 insulin syringe. markings syringe show ofHumulin units ofRHumulin R be U-500 to be injected.

• DO NOT perform dose conversion when a U-500 insulin syringe.

TheThe markings on on thethe syringe show thethe number of Humulin R U-500 to be injected.

• DO NOT perform dose conversion when using ausing U-500 insulin syringe.

The markings on the syringe show the number ofnumber unitsofofunits U-500 to injected.

Each marking represents 5 units of insulin.

Each marking represents 5 units of insulin.

Each marking represents 5 units of insulin.

• Instruct patients using toause only a U-500 insulin syringe and how to draw correctly draw prescribed dose into syringe.

Confirm that patient • Instruct using vialvial to use only a U-500 insulin syringe on how to correctly draw thethe prescribed dose thethe syringe.

Confirm thethe patient • Instruct patientspatients using the vialthe tothe use only U-500 insulin syringe and on and how toon correctly the prescribed dose into theinto syringe.

Confirm that thethat patient has understood these instructions and can correctly draw the prescribed dose with their syringe. has understood these instructions can correctly draw the prescribed dose withsyringe. their syringe. has understood these instructions and canand correctly draw the prescribed dose with their • Advise the patient to read the Patient Information and Instructions for Use. • Advise the patient to read the Patient Information and Instructions for Use. • Advise the patient to read the Patient Information and Instructions for Use. • Instruct to always check insulin label before administration tothe confirm correct insulin is being used.

• Instruct to always check thethe insulin label before administration to confirm thethe correct insulin product being used.

• Instruct patientspatients topatients always check the insulin label before administration to confirm correct insulin product isproduct beingisused.

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

• Humulin R U-500 and usesolution if the solution clear and colorless.

• InspectInspect Humulin R U-500 visuallyvisually and only useonly if the appearsappears clear and colorless.

• Administer Humulin R U-500 subcutaneously two or three times daily approximately minutes before a meal.

Rotate injection sites to • Administer Humulin R U-500 subcutaneously two or three times daily approximately 3030 minutes before aRotate meal.

Rotate injection to reduce riskrisk • Administer Humulin R U-500 subcutaneously two or three times daily approximately 30 minutes before a meal. injection sites tosites reduce thereduce riskthethe of lipodystrophy. of lipodystrophy. of lipodystrophy.

• Individualize the dose ofRHumulin R U-500 based metabolic needs , blood glucose monitoring results, glycemic control goal.

• Individualize theof dose of Humulin R U-500 based on on metabolic ,glucose blood glucose monitoring andand glycemic control goal.

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

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

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

• Do NOTDo administer Humulin R U-500 intravenously or intramuscularly.

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

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

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

Storage StorageStorage • Protect from heat light.

Do not R U-500 after expiration date stamped label.

• Protect from heat andand Do notnot freeze. not useuse Humulin R U-500 after thethe expiration date stamped on on thethe label.

• Protect from heat and light.

Dolight. not freeze.

Dofreeze. not Do useDo Humulin RHumulin U-500 after the expiration date stamped on the label.

• Humulin R U-500 Vials: Unopened vials of Humulin R U-500 should be kept in a refrigerator.

Opened (in-use) vials ofRHumulin R U-500 in the • Humulin R U-500 Vials: Unopened of Humulin R U-500 in a refrigerator. of Humulin R U-500 should kept in the • Humulin R U-500 Vials: Unopened vials ofvials Humulin R U-500 should should be keptbeinkept a refrigerator.

OpenedOpened (in-use)(in-use) vials ofvials Humulin U-500 should beshould keptbeinbe thekept refrigerator ortemperature at room temperature used within days ofThrow opening.

Throw away opened vial after days of use, even ifinsulin there is insulin in the refrigerator or at room temperature andand used within days of opening.

Throw away anyany opened vial40 after 40of40 days of use, ifisthere is insulin leftleft in the vial.vial. refrigerator or at room and used within 40 days40of40 opening. away any opened vial after days use, even if even there left in the vial.

• Humulin R U-500 KwikPen: Unopened Humulin R U-500 KwikPens should be kept in a refrigerator.

Opened (in-use) Humulin R U-500 KwikPens should be • Humulin R U-500 KwikPen: Unopened Humulin R U-500 KwikPens should be kept in a refrigerator.

Opened (in-use) Humulin R U-500 KwikPens should be • Humulin R U-500 KwikPen: Unopened Humulin R U-500 KwikPens should be kept in a refrigerator. Opened (in-use) Humulin R U-500 KwikPens should be kept at room temperature and used within 28 days of opening.

Do not refrigerate opened KwikPens.

Throw away any opened KwikPen after 28 days of use, kept at room temperature and used within 28 days of opening.

Do not refrigerate opened KwikPens.

Throw away any opened KwikPen after 28 days of use, kept at room temperature and used within 28 days of opening. Do not refrigerate opened KwikPens. Throw away any opened KwikPen after 28 days of use, even ifinsulin there is insulin in the pen. ifisthere is insulin leftleft in the pen. even if even there left in the pen.

Please see Brief Summary of Prescribing Information adjacent pages.

Instructions for included with pen. seeSummary Brief Summary of Prescribing Information on on adjacent pages.

SeeSee Instructions UseUse included with thethe pen.

PleasePlease see Brief of Prescribing Information on adjacent pages.

See Instructions for Usefor included with the pen.

HM U500 ISI 27SEP2016 HMHCP U500 HCPHCP ISI 27SEP2016 HM U500 ISI 27SEP2016

Humulin® KwikPen® registered trademarks owned or Humulin® andand KwikPen® areare registered trademarks Humulin® and KwikPen® are registered trademarks owned orowned or licensed

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

by Eli Lilly Company, its subsidiaries, or affiliates.

Humulin® R U-500 is available by prescription only.

Humulin® is available by prescription Humulin® R U-500RisU-500 available by prescription only. only.

Revista Puertorriqueña de Medicina y Salúd Pública

43

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

HI U500 HCP BS 27SEP2016

Revista Puertorriqueña de Medicina y Salúd Pública

45

MSP SUPLEMENTO SPED

H

ace unos años, los unían los deportes, particular mente el baloncesto, ya que el doctor Luis Ruiz era entrenador del equipo al que pertenecían sus hijos cuando eran niños. Hoy día, aunque aún es un tema que los vincula, la endocrinología es la pasión que comparte con su segundo hijo, el doctor Oscar Luis Ruiz. Son el primer equipo padre-hijo en Puerto Rico dedicado a esa subespecialidad.

El doctor Luis Ruiz, natural de Cayey, residente en Ponce desde hace 37 años, 33 de ellos en su profesión.

Se formó en la Escuela de Medicina

46

Revista Puertorriqueña de Medicina y Salúd Pública

en España, en el Centro Médico de Mayagüez, y en el Recinto de Ciencias Médicas.

Su padre era cartero y su madre maestra, “desde pequeño dije que iba a ser médico y que iba a ser endocrinólogo”, recordó, durante la entrevista con la Revista de Medicina y Salud Pública (MSP).

Aunque en un momento consideró otras especialidades, “la realidad es que la endocrinología es de las subespecialidades, la que más abarca, porque entrena en casi todas las condiciones del ser humano, como diabetes, hipertensión, fallo cardíaco, problemas del riñón. Tiene que

estar entrenado en todas las demás subespecialidades para tener un conocimiento general y completo del ser humano, incluyendo las emociones, condiciones siquiátricas, sicológicas y las reacciones ante la enfermedad”, mencionó.

El presidente entrante de la Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED) es padre de dos varones y abuelo de tres niñas: Gabriela de 19, quien estudia en los Estados Unidos para ser nutricionista.

Carla Mia de 10, y Camila Sofía de 11, las niñas de su hijo mayor, quien es corredor de bienes raíces.

Mientras tanto, a su segundo

MSP SUPLEMENTO SPED

vástago, el interés por la Medicina le surgió en la adolescencia. Narró que a los 17 años ya sabía que quería estudiar ciencias. En la universidad determinó que iba a ser médico.

Optar por la endocrinología “en parte, fue algo objetivo y práctico, ya que tenía al lado a mi maestro, mi mentor. Nosotros siempre hablábamos del tema, compartíamos muchos temas de endocrinología y en la medida que seguí estudiando en la Escuela de Medicina, vi que era un tema que me apasionaba. Y en la relación hijopadre, también me ayuda a tener un

tema para conversar con mi padre”, recordó el papá de Gabriela, con quien comparte la afición por el surfing, deporte que le enseñó de pequeña.

Sin embargo, su padre nunca pensó que seguiría sus huellas y que en un momento determinado, caminaría a su lado y se convertiría en su mano derecha, tanto en el área de estudios clínicos que realizan en el consultorio de Ponce, como en la consulta de pacientes en Ponce y Cayey, donde trabajan hombro a hombro.

“Nunca traté de inculcarle, porque cada cual tiene sus gustos. Y hay que

gustarle y tener vocación, porque es para toda la vida. Y mucha gente cree que es bien fácil y bien glamuroso y económicamente recompensado, pues no es así. Hay muchas dificultades en el camino, pero a la larga hay que poner la vocación por encima de lo que no nos gusta”, enfatizó Ruiz padre, quien también es profesor y conferencista.

El doctor Oscar, como le llama su padre en la oficina, es egresado del Programa Binario de la Pontificia Universidad Católica en Ponce, donde se graduó con honores, y de la Pontificia Universidad Católica Madre

y Maestra, de República Dominicana, donde hizo el internado en Medicina Interna en el Hospital San Lucas, en Ponce, y estudió endocrinología en el Recinto de Ciencias Médicas de la Universidad de Puerto Rico.

Ambos se emocionaron hasta las lágrimas al recordar que ya siendo médico trabajaba en la oficina del padre como subinvestigador del área clínica.

Oscar Luis enfermó de gravedad, y luego de ese proceso, se afianzó aún más en estudiar esa subespecialidad.

“Se nos saltan las lágrimas de la emoción porque me enfermé del páncreas y desarrollé diabetes también. Vivo en carne propia lo que es un paciente diabético”, dijo quien día a día recibe pacientes con esta condición en el consultorio.

Con voz entrecortada, Ruiz hijo, añadió que pues se nos saltan las lágrimas porque “realmente fueron

momentos difíciles en los que estuve con mi papá y tuve su apoyo completo. Y entonces, ver que uno pudo sobrepasar esa etapa y lograr alcanzar las metas que uno quiere”.

La enfermedad lo aquejó justo al terminar estudios en la Escuela de Medicina, a los 36 años.

Ya entre risas, mencionaron que el deporte sigue uniéndolos y que han jugado tenis y juegos de mesa, como ajedrez, Chinese Checkers y Monopolio, dijeron.

En cuanto a la dinámica laboral, se alternan la atención a los pacientes.

Y la ventaja, además de compartir la carga del día, es que pueden consultar.

“Me quedo sorprendido porque no lo puedo alcanzar, porque él es súper rápido. Lo ayudo aquí (en Ponce) y en Cayey, y compartimos mucho.

Cuando hay dudas sobre el manejo de un paciente, siempre me gusta tenerlo a él cerca y preguntarle, y

sentirme en la confianza de que lo que estamos haciendo está bien. Es bien satisfactorio”, indicó Ruiz hijo, quien participó como conferencista en la reciente Convención de la SPED. Cuando el padre acude a seminarios y convenciones fuera del País, es el hijo quien se queda a cargo de las oficinas médicas, la tecnología facilita la comunicación. En cambio, si es el hijo quien no se encuentra, “lo llamo y le pregunto qué es lo último en tal cosa. Y si atendió a un paciente, que me dé detalles. La comunicación es directa, sobre todo con la tecnología, que lo permite.

Y ya muchos pacientes prefieren atenderse con él que conmigo, porque los ‘regaño’ mucho y el ‘nene’, como le dicen, es más ‘suavecito’ y llevadero.

Entretanto, yo me dedico a otras labores administrativas y a preparar conferencias”, reveló en tono jovial Ruiz padre.

Revista Puertorriqueña de Medicina y Salúd Pública

47

MSP SUPLEMENTO SPED

Por más de 40 años ha contribuido al progreso continuo de la Endocrinología y Diabetología en Puerto Rico Dra. Myriam Allende

Dr. José García Mateo

Los fundadores se encargaron de mantener vivo el espíritu de colaboración y armonía con otros profesionales de la Medicina.

Dr. Ángel Comulada

48

Revista Puertorriqueña de Medicina y Salúd Pública

MSP SUPLEMENTO SPED

A nivel local, SPED apoya las actividades de entidades de valores afines, tales como: • Fundación Pediátrica de Diabetes.

• Campamentos de verano para jóvenes con diabetes del Comité de Educación y Bienestar para Niños y Adolescentes con Diabetes.

• Actividades de la Asociación Puertorriqueña de Diabetes y el “CardiDay”.

Sus convenciones siempre son El “SPED/AACE Joint International foro para la presentación de Clinical Endocrinology Update”. Es un evento, avalado por la American trabajos de investigación.

Association of Clinical También SPED ha apoyado Endocrinologists (AACE), y reúne los económicamente mediante máximos expositores a nivel nacional becas para el adiestramiento e internacional en Diabetes, de endocrinólogos.

Osteoporosis, Pituitaria y Tiroides.

Los espacios “Endo’s to Endos” son actividades educativas para los miembros de SPED con la intención de intercambiar conocimientos y prácticas y con el fin de actualizarse en cuidado clínico de condiciones endocrinológicas.

Texto: Marcela Moreno Diseño: Natalia Rivera, Pablo Bermúdez Fuente: Medicina y Salud Pública

Cada dos años se celebra:

Conferencia Magistral dedicada al Dr. Agustín Martínez de Andino

Curso de osteoporosis en honor a la Dra. Lillian Haddock

Actividades de investigación en homenaje al Dr. Francisco Aguiló

En la conferencia de cáncer de tiroides en memoria del Dr. Rómulo Ayuso

Revista Puertorriqueña de Medicina y Salúd Pública

49

MSP SUPLEMENTO SPED

Tendencias avanzadas para el tratamiento de la diabetes en el 2018 Por: Dr. Luis Ruiz

Endocrinólogo Presidente de la Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED)

La diabetes es una enfermedad crónica que afectaba en 2014 a 422 millones de adultos en todo el mundo. Cada año acaba con la vida de 1.6 millones de personas y puede conducir a una muerte lenta, con propensión a ataque cardiacos, 2 a 4 veces más que la población general, insuficiencia renal, ceguera, 25 veces más que la población general y amputación de extremidades, 28 veces más que la población general. En Estados Unidos la prevalencia es de 30.2 millones, de los cuales hay 23 millones diagnosticados y 7.2 millones no diagnosticados.

La depresión tiene un papel importante en la incidencia y prevalencia de diabetes tipo 2.

Para ello, analizaron a 2,861 pacientes con edades comprendidas entre los 40 y los 75 años, que tuvieron que responder a un cuestionario sobre el tamaño de la red de amigos, la frecuencia de contacto y la distancia que vivían.

Los resultados, que se publicaron en BMC Public Health, muestran que tener una red más pequeña se relacionaba directamente con un diagnóstico nuevo o previo de diabetes tipo 2 entre hombres y mujeres. Aunque las razones subyacentes detrás del enlace no se conocen.

En Puerto Rico

550,000

Aproximadamente pacientes con diagnóstico de diabetes.

1 de cada 3 adultos de

DIABETES EN PUERTO RICO

65 años+ padece de diabetes en P.R.

de los casos y su inicio es característico en niños, jóvenes y/o adultos jóvenes.

AMPUTACIONES

Puerto Rico es el país con MAYOR PREVALENCIA de diabetes en adultos entre las edades de

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

2,500 Amputaciones anuales de la extremidad inferior se hacen en Puerto Rico de las cuales el 70% son en pacientes diabéticos

20 a 79 años,

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

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

Revista Puertorriqueña de Medicina y Salúd Pública

53

MSP SUPLEMENTO SPED

La edad, el sobre peso y tener familiares afectados son factores de riesgo para la enfermedad, además de, el sedentarismo, colesterol alto e hipertensión. La dolencia actualmente no tiene cura y los pacientes se ven obligados a recibir un tratamiento Diabetes tipo 1 Una vacuna que se probará en humanos el año que viene Este tipo se suministra a menudo durante de los primeros años de vida, y tras más de 20 años de investigación, un prototipo de la vacuna que podría prevenir esta enfermedad en niños comenzará los ensayos clínicos en 2018. De acuerdo con un artículo publicado en julio en Vaccine, los científicos han proporcionado evidencia sólida del vínculo entre el enterovirus coxsackievirus B1 y la reacción autoinmune que hace que el cuerpo destruya las células en su propio páncreas. No es una cura, y no eliminará la enfermedad por completo, pero se espera que la vacuna, creada por investigadores de la Universidad de Tampere (Finlandia), proporcione inmunidad contra el virus y consiga reducir potencialmente el número de nuevos casos de diabetes cada año.

Existe más riesgo en bebés prematuros Los bebés que nacen antes de las 37 semanas de gestación y bajo peso, se relacionan con un mayor riesgo de diabetes y enfermedades relacionadas con la obesidad en la adultez, así como una vida más corta, según un estudio de

de por vida. Sin embargo, son muchos los equipos dedicados a encontrar un tratamiento o una mejora de la calidad de vida de estas personas. Esto es lo que han dado de sí, las investigaciones para cada unos de los tipos de diabetes en 2017:

la Universidad Ben-Gurion de Israel. El estudio, publicado en agosto por el American Journal of Obstetrics and Gynecology, analizó informaciones sobre hospitalización de niños hasta los 18 años, comparando la salud de los bebés prematuros con la de los que nacieron a término (54,073 partos tempranos y 171,000 partos a término): las hospitalizaciones hasta los 18 años estuvieron relacionadas a la morbilidad endocrina y metabólica, más frecuentemente en el grupo de bebés prematuros que en los nacidos a término, especialmente desde que cumplen cinco años.

Inmunoterapia efectiva con proinsulina El avance de la diabetes tipo 1 exige gradualmente dosis más altas de insulina. Hasta ahora, todas las inmunoterapias para regular la actividad de las células T y así resguardar el correcto funcionamiento del páncreas, han resultado infructuosas. Ahora, un equipo del King’s College de Londres, parece que ha logrado dar con una inmunoterapia segura para los pacientes, que frena el avance de la enfermedad.

Los resultados preliminares del ensayo, publicados en la revista

El paso del huracán María por Puerto Rico

Science Translational Medicine en agosto, fueron alcanzados gracias a la inyección de segmentos cortos de proinsulina, una molécula producida por las células beta del páncreas que luego se convierte en insulina. En el torrente sanguíneo de los pacientes, los segmentos entrenan a las células T para que reconozcan a las células pancreáticas como inofensivas y dejen de atacar a las células beta que producen proinsulina. A los 12 meses del inicio del estudio, los pacientes que recibieron el placebo, habían necesitado aumentar sus dosis de insulina en 50%. Los que recibieron proinsulina mantuvieron sus dosis estables, sin reacciones adversas.

Novedosa terapia con células madre implantadas En agosto, ViaCyte, una firma especializada en medicina regenerativa, informó de un ensayo exitoso en dos pacientes con diabetes tipo 1, los primeros en recibir una nueva terapia de reemplazo de células de islote que consiste en la implantación de células generadas a partir de células madre embrionarias.

Como se trata de una enfermedad autoinmune, la cura definitiva de este tipo de desorden consistiría en

Se evidenció que la gente no está preparada, educada, ni llevan la dieta y ejercicios adecuados para su bienestar.

Igualmente, quedó demostrado que los abastecimientos de insulina en nuestro país no fueron suficientes.

54

Revista Puertorriqueña de Medicina y Salúd Pública

MSP SUPLEMENTO SPED

"La metformina, medicamento que se prescribe para reducir la cantidad de glucosa producida por el hígado, parece ser eficaz, pese a que solo pequeñas cantidades de ella lleguen al hígado, incluso en personas con variantes genéticas que le impiden llegar al hígado. Esto levantó las sospechas ..." que el sistema inmune del paciente dejará de afectar el desempeño de las células pancreáticas. Por ello, los desarrolladores de la terapia consideran que esta cura es “funcional”: no ataca el problema de fondo, sino que soluciona la consecuencia grave en la salud.

Cuando los niveles de azúcar en la sangre suban, los implantes liberarán insulina para restaurarlos a la normalidad. Dicho sea de paso, un puertorriqueño, el doctor Rodolfo Alejandro, es un pionero en el implante de células beta en el páncreas que ulteriomente producen insulina y mejoran la diabetes.

Un tumor de páncreas benigno podría esconder la clave para acabar con ella Además de la insulina, otro factor crítico son las células beta, que la producen. La diabetes tipo 1, tiene al sistema inmune atacando y destruye por error a las células beta. Mientras que la deficiencia de funcionamiento de las células beta también contribuye de manera importante a la diabetes tipo 2. El desarrollo de fármacos que pueden aumentar el número de células beta sanas, por tanto, es una prioridad en la lucha contra la diabetes. Los insulinomas, inusuales tumores pancreáticos benignos, derivados de las células beta productoras de insulina, encierran la clave para el desarrollo de mejores fármacos contra la diabetes, de acuerdo con una investigación de la Icahn School of Medicine en Mount Sinai (EE.UU.) publicada en Nature Communications.

Diabetes tipo 2 Se cree que el secreto para mantenerla a raya puede estar vinculado a hormonas segregadas en el estómago y el intestino, además de lo que se llama la microbiota intestinal Una investigación conjunta de las Universidades de Gotemburg (Suecia) y Girona (España) explicaba en mayo el mecanismo de acción de la más efectiva terapia contra la diabetes tipo 2, a través del maquillaje de bacterias intestinales. La metformina, medicamento que se prescribe para reducir la cantidad de glucosa producida por el hígado, parece ser eficaz, pese a que solo pequeñas cantidades de ella lleguen al hígado, incluso en personas con variantes genéticas que le impiden llegar al hígado. Esto levantó las sospechas sobre que las miles de millones de bacterias intestinales serían los agentes de la acción del fármaco, lo que podría ser el paso para el establecimiento de dietas y terapias que propicien el crecimiento de bacterias, a fin de mejorar la calidad de vida de los diabéticos.

Tiene un origen bacteriano, lo que abre la posibilidad a nueva terapia Aunque las terapias actuales para mantener a raya el mal se enfocan en administrar fármacos que regulen los niveles de glucosa en la sangre, pocos han enfocado su trabajo en dilucidar de las bacterias en esta enfermedad inflamatoria. Un equipo de investigadores de las universidades de Stellenbosch (Sudáfrica) y Manchester (Reino Unido), afirmaba en un

artículo publicado en agosto: “Ahora tenemos una cantidad considerable de pruebas, muchas de ellas nuevas, que a diferencia de las actuales estrategias para atacar la diabetes tipo 2, involucran el reconocimiento de microbios latentes, procesos inflamatorios crónicos y coagulopatías, ofreciendo nuevas oportunidades para el tratamiento”.

Los SMS ayudan a controlarla Según el estudio publicado en junio en Diabetes Care por Investigadores de Scripps Whittier Diabetes Institute, de la Universidad de San Diego (EE. UU.), hispanos de bajos ingresos con diabetes tipo 2 que recibieron mensajes de texto sobre su salud, a diario y por seis meses, vieron mejoras en sus niveles de azúcar en la sangre similares a las que causan algunos medicamentos reductores de glucosa.

Los SMS ayudan a controlar esta condición con el apoyo adecuado de un especialista en diabetes.

Se trata del primer estudio controlado aleatorio para examinar el uso de mensajes de texto para asistir a pacientes hispanos, sin acceso óptimo a servicios de salud, a controlar

su diabetes. El estudio del proyecto Dulce Digital se llevó a cabo entre octubre de 2012 y agosto de 2014 con 126 participantes reclutados en clínicas médicas operadas por Neighborhood Healthcare, una organización de salud comunitaria sin fines de lucro, en los condados del sur de California de San Diego y Riverside. Los participantes

estaban sin seguro o recibieron cobertura a través de MediCal. Revista Puertorriqueña de Medicina y Salúd Pública

55

MSP SUPLEMENTO SPED

El sobre peso, la obesidad y la diabetes están relacionados con el cáncer El alto índice de masa corporal (IMC) está relacionado con el riesgo de padecer cáncer y casi el 6% de todos los casos de cáncer en el mundo están relacionados con la combinación de este factor y la diabetes. Los cálculos fueron realizados por científicos franceses y publicados en The Lancet el pasado noviembre.

Los investigadores estudiaron todas las publicaciones en las que los autores establecieron un vínculo entre el IMC, la diabetes y el cáncer para evaluar los riesgos de cada factor. Después, analizaron los datos sobre el IMC de la población y la prevalencia de la diabetes, tanto del primero como del segundo tipo entre 1980 y 2002. También analizaron los datos GLOBOCAN sobre el cáncer en 2012. De este modo recogieron todos los datos de 175 países del mundo. Los datos sobre el IMC, diabetes y cáncer se compararon con los principales indicadores demográficos. Aunque es imposible establecer exactamente las relaciones causa-efecto, estos resultados enfatizan la importancia de combatir la diabetes y el alto índice de masa corporal.

más propensos a dejar de tomar las dosis requeridas, concretamente el 30%, en comparación con otros medicamentos para la diabetes: 23% de tasa de abandono de las sulfonilureas (como la gliclazida) y 20% de la pioglitazona.

Los SMS ayudan a controlarla Según el estudio publicado en junio en Diabetes Care por Investigadores de Scripps Whittier Diabetes Institute, de la Universidad de San Diego (EE.UU.), hispanos de bajos ingresos con diabetes tipo 2 que recibieron mensajes de texto sobre su salud, a diario y por seis meses, vieron mejoras en sus niveles de azúcar en la sangre similares a las que causan algunos medicamentos reductores de glucosa. Los SMS ayudan a controlar esta condición con el apoyo adecuado de un especialista en diabetes.

Se trata del primer estudio controlado aleatorio para examinar el uso de mensajes de texto para asistir a pacientes hispanos, sin acceso óptimo a servicios de salud, a controlar su diabetes. El estudio del proyecto Dulce Digital se llevó a cabo entre octubre de 2012 y agosto de 2014 con 126 participantes reclutados en clínicas médicas operadas por Neighborhood Healthcare, una Un tercio de los pacientes organización de salud comunitaria sin abandona el tratamiento por fines de lucro, en los condados del sur efectos secundarios de California de San Diego y Riverside.

Un metaanálisis publicado hace unos Los participantes estaban sin seguro días en la revista Diabetes, Obesity and o recibieron cobertura a través de Metabolism afirma que uno de cada MediCal. tres afectados por diabetes de tipo 2, abandona el tratamiento debido a sus El sobre peso, la obesidad efectos secundarios. Los investigadores y la diabetes están de la Universidad de Surrey (Reino relacionados con el cáncer Unido), examinaron en detalle la El alto índice de masa corporal adherencia al tratamiento de 1.6 (IMC) está relacionado con el riesgo millones de personas y descubrieron de padecer cáncer y casi el 6% de todos que los que tomaron metformina, el los casos de cáncer en el mundo están medicamento más común, fueron los relacionados con la combinación de este 56

Revista Puertorriqueña de Medicina y Salúd Pública

factor y la diabetes. Los cálculos fueron realizados por científicos franceses y publicados en The Lancet el pasado noviembre.

Los investigadores estudiaron todas las publicaciones en las que los autores establecieron un vínculo entre el IMC, la diabetes y el cáncer para evaluar los riesgos de cada factor.

Después, analizaron los datos sobre el IMC de la población y la prevalencia de la diabetes, tanto del primero como del segundo tipo entre 1980 y 2002. También analizaron los datos GLOBOCAN sobre el cáncer en 2012.

De este modo recogieron todos los datos de 175 países del mundo. Los datos sobre el IMC, diabetes y cáncer se compararon con los principales indicadores demográficos. Aunque es imposible establecer exactamente las relaciones causa-efecto, estos resultados enfatizan la importancia de combatir la diabetes y el alto índice de masa corporal.

Un tercio de los pacientes abandona el tratamiento por efectos secundarios Un metaanálisis publicado hace unos días en la revista Diabetes, Obesity and Metabolism afirma que uno de cada tres afectados por diabetes de tipo 2, abandona el tratamiento debido a sus efectos secundarios. Los investigadores de la Universidad de Surrey (Reino Unido), examinaron en detalle la adherencia al tratamiento de 1.6 millones de personas y descubrieron que los que tomaron metformina, el medicamento más común, fueron los más propensos a dejar de tomar las dosis requeridas, concretamente el 30%, en comparación con otros medicamentos para la diabetes: 23% de tasa de abandono de las sulfonilureas (como la gliclazida) y 20% de la pioglitazona.

MSP SUPLEMENTO SPED

Tiene un origen bacteriano, lo que abre la posibilidad a nueva terapia

Aunque las terapias actuales para mantener a raya el mal se enfocan en administrar fármacos que regulen los niveles de glucosa en la sangre, pocos han enfocado su trabajo en dilucidar de las bacterias en esta enfermedad inflamatoria. Un equipo de investigadores de las universidades de Stellenbosch (Sudáfrica) y Manchester (Reino Unido), afirmaba en un artículo publicado en agosto: “Ahora tenemos una cantidad considerable de pruebas, muchas de ellas nuevas, que a diferencia de las actuales estrategias para atacar la diabetes tipo 2, involucran el reconocimiento de microbios latentes, procesos inflamatorios crónicos y coagulopatías, ofreciendo nuevas oportunidades para el tratamiento”.

Revista Puertorriqueña de Medicina y Salúd Pública

57

MSP SUPLEMENTO SPED

Complicaciones de la piel en el paciente diabético

58

Revista Puertorriqueña de Medicina y Salúd Pública

MSP SUPLEMENTO SPED

Resumen La piel en el paciente diabético también puede mostrar los efectos de la enfermedad. Los pacientes diabéticos están expuestos a problemas en la piel de diferentes tipos. Hasta un 33% de las personas con diabetes presentan manifestaciones cutáneas. Hay un gran número de alteraciones en la piel que se asocian en mayor o menor grado con la presencia de la diabetes. De hecho, estas manifestaciones cutáneas pueden ser expresión de la enfermedad o, simplemente, predecirla. Algunas manifestaciones en la piel podrían no parecer importantes, sin embargo, deben recibir atención médica inmediata. Mantener la diabetes bajo control es lo más importante para prevenir complicaciones en la piel asociadas a la enfermedad.

L

a diabetes puede afectar cualquier parte del cuerpo, incluida la piel. Hasta 33% de las personas con diabetes tienen en algún momento de la vida una afección en la piel causada por la diabetes. De hecho, a veces tales problemas son el primer indicio de que la persona tiene diabetes. Afortunadamente, es posible prevenir o tratar fácilmente la mayoría de las afecciones de la piel si se detectan a tiempo. Algunos de estos problemas son trastornos de la piel que cualquier persona puede tener, pero son más comunes en las personas con diabetes.

Incluyen infecciones con bacterias y con hongos, y picazón. Otros problemas de piel se presentan particular o solamente en personas con diabetes. Incluyen dermopatía diabética, necrobiosis lipoídica diabética, ampollas diabéticas y xantomatosis eruptiva.

Abstract The skin in diabetic patients may also indicate the effects of the disease. Many people with diabetes are exposed to skin problems of different types. Sometimes skin problems can be the first sign that a person has diabetes. In fact, up to 33% of people with diabetes have cutaneous manifestations.

Keeping your diabetes under control is the most important factor in preventing the skin-related complications of diabetes.

It is important to be able to recognize these signs in order to treat them appropriately. Some skin manifestations may not seem important, however, they should receive immediate medical attention.

las glándulas del párpado) • Forúnculos foliculitis (infección de los folículos del pelo) • Carbuncos (infecciones más profundas de la piel y el tejido debajo de ésta) • Infecciones alrededor de las uñas Por lo general, los tejidos inflamados están calientes, hinchados, rojizos y duelen. Las bacterias más comunes son los estafilococos. Anteriormente, las infecciones bacterianas eran potencialmente mortales, especialmente para las personas con diabetes. Hoy en día, este tipo de muerte es poco común gracias a los antibióticos y mejores métodos de control de la glucosa en la sangre. Pero incluso ahora, las personas con diabetes tienen más infecciones bacterianas que otras personas. Los médicos consideran que las personas con diabetes pueden reducir la posibilidad de estas infecciones mediante un buen cuidado de la piel.

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

Afecciones de la piel relacionadas con la diabetes Acantosis nigricans Es una afección en la que se presentan parches elevados de apariencia bronceada o marrón en los lados del cuello, las axilas y la ingle. A veces, también salen en las Enfermedades de la manos, codos y rodillas. La acantosis piel en general nigricans generalmente afecta a las Infecciones con bacterias personas que tienen mucho sobrepeso.

Se presentan varios tipos de El mejor tratamiento es perder peso. infecciones con bacterias en las personas Infecciones con hongos con diabetes: Las infecciones micóticas o con hongos Algunas cremas pueden ayudar a que • Orzuelos (infecciones de en personas con diabetes a menudo se las manchas mejoren.

Revista Puertorriqueña de Medicina y Salúd Pública

59

MSP SUPLEMENTO SPED

Dermopatía diabética La diabetes puede causar cambios en los vasos sanguíneos más pequeños. Estos cambios pueden causar problemas de la piel llamados dermopatía diabética.

A menudo, la dermopatía se presenta como manchas escamosas marrones.

Estas manchas pueden ser ovaladas o circulares. Algunas personas piensan que son manchas por la edad. Este trastorno ocurre más a menudo en la parte frontal de las piernas. Pero es posible que las piernas no se vean afectadas al mismo grado. Las manchas no duelen, ni se abren ni pican. La dermopatía es inofensiva y no requiere tratamiento.

medicamentos como las pastillas de insulina o para la diabetes. Si piensa que está teniendo una reacción a un medicamento, debe consultar con su médico. Esté atento a erupciones, depresiones o protuberancias en los puntos donde se inyecta insulina.

Ampollas diabéticas En ocasiones poco frecuentes, a las personas con diabetes les salen ampollas.

Las ampollas diabéticas pueden salir en el dorso de las manos, dedos, pies y a veces en las piernas o antebrazos.

Estas llagas parecen ampollas debidas a quemaduras y a menudo les salen a personas con neuropatía diabética. A veces son grandes, pero no duelen ni Necrobiosis lipoídica diabética Esta produce manchas similares a la causan enrojecimiento a su alrededor. dermopatía diabética, pero en menor Se curan solas, generalmente sin causar cantidad, más grandes y más profundas. cicatrices, en aproximadamente tres La necrobiosis a menudo surge como una semanas. El único tratamiento es zona opaca, rojiza y elevada. Después de controlar el nivel de glucosa en la sangre. un tiempo, parece una cicatriz brillante con borde violeta. Es posible ver los Xantomatosis eruptiva vasos sanguíneos debajo de la piel más Es otra afección causada por la fácilmente. A veces, causa picazón y diabetes no controlada. Consiste en dolor y en otras ocasiones las manchas dilataciones de la piel que se ven firmes, se abren. La necrobiosis es poco común. amarillentas y parecen guisantes o Las mujeres adultas son más propensas arvejas. Cada bulto tiene un halo rojo a ella. Mientras las llagas no se abran, y quizá pique. Esta afección ocurre con no necesita tratamiento. Pero si tiene mayor frecuencia en el dorso de las llagas abiertas, vaya al médico para que manos, pies, brazos, piernas y glúteos. le haga un tratamiento.

El trastorno generalmente ocurre en hombres jóvenes con diabetes de tipo 1.

A menudo, la persona tiene un alto nivel Reacciones alérgicas Pueden ocurrir como reacción a de triglicéridos y grasa en la sangre. Al

60

Revista Puertorriqueña de Medicina y Salúd Pública

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

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

Todas estas afecciones deben ser evaluadas y tratadas adecuadamente para prevenir complicaciones, unas son más comunes que otras. Su médico evaluará y decidirá si necesita la intervención de un especialista en condiciones de la piel (dermatólogo).

Referencias ADA Practice Guidelines 2015 AACE / ACE Comprehensive Diabetes Management Algorithm 2015.

Endocrine Practice Vol. 21 No 4. April 2015 ADA Standards of Medical Care in Diabetes 2015. Supp Diabetes Care.

January 2015 Clinical Diabetes. V Fonseca.

Textbook. Saunders. 2006

No-see, No-see, no-handle no-handle needle needle NoNo reconstitution reconstitution required required NoNo need need to to dialdial a dose a dose 1,2

1,2

ÂŽ ÂŽ TrulicityTrulicity (dulaglutide) (dulaglutide) is a glucagon-like is a glucagon-like SelectSelect Important Important SafetySafety Information Information peptide-1 peptide-1 receptor receptor agonistagonist (GLP-1 RA) (GLP-1 thatRA) that is indicated is indicated as an adjunct as an adjunct to diet and to diet exercise and exercise WARNING: WARNING: RISK OF RISK THYROID OF THYROID C-CELLC-CELL TUMORS TUMORS to improve to improve glycemic glycemic control control in adults inwith adults with In male In and male female and female rats, dulaglutide rats, dulaglutide causes causes a dose-related a dose-related and and type 2 diabetes. type 2 diabetes. treatment-duration-dependent treatment-duration-dependent increase increase in the incidence in the incidence of thyroid of thyroid Limitations Limitations of Use: of Not Use: recommended Not recommended as as C-cell tumors C-cell tumors (adenomas (adenomas and carcinomas) and carcinomas) after lifetime after lifetime exposure. exposure. first-linefirst-line therapytherapy for patients for patients inadequately inadequately It is unknown It is unknown whether whether TrulicityTrulicity causes causes thyroidthyroid C-cell tumors, C-cell tumors, controlled controlled on diet on anddiet exercise and exercise because because of the of the including including medullary medullary thyroidthyroid carcinoma carcinoma (MTC), (MTC), in humans in humans as human as human uncertain uncertain relevance relevance of rodent of rodent C-cell tumor C-cell tumor relevance relevance of dulaglutide-induced of dulaglutide-induced rodent rodent thyroidthyroid C-cell tumors C-cell tumors has has findingsfindings to humans. to humans.

Prescribe Prescribe only if potential only if potential not been notdetermined. been determined. benefitsbenefits outweigh outweigh potential potential risks. Has risks. notHas been not been is contraindicated is contraindicated in patients in patients with a personal with a personal or family or family studiedstudied in patients in patients with a history with a history of pancreatitis; of pancreatitis; TrulicityTrulicity of MTCof and MTC in patients and in patients with Multiple with Multiple Endocrine Endocrine Neoplasia Neoplasia consider consider anotheranother antidiabetic antidiabetic therapy.therapy.

Not for Not for history history syndrome syndrome type 2 (MEN type 22).

(MEN Counsel 2). Counsel patientspatients regarding regarding the potential the potential the treatment the treatment of type of 1 diabetes type 1 diabetes mellitusmellitus or or risk of MTC risk of with MTC thewith usethe of Trulicity use of Trulicity and inform and them informofthem symptoms of symptoms diabeticdiabetic ketoacidosis. ketoacidosis.

Not a substitute Not a substitute for for of thyroid tumorstumors (eg, mass (eg,inmass the neck, in thedysphagia, neck, dysphagia, dyspnea, dyspnea, insulin. insulin.

Has notHas been notstudied been studied in patients in patients with with of thyroid persistent hoarseness). hoarseness).

RoutineRoutine monitoring monitoring of serum of calcitonin serum calcitonin or or severe gastrointestinal severe gastrointestinal disease,disease, including including severe severepersistent using thyroid ultrasound ultrasound is of uncertain is of uncertain value for value early for detection early detection of of gastroparesis. gastroparesis.

Not for Not patients for patients with pre-existing with pre-existing using thyroid MTC in MTC patients in patients treatedtreated with Trulicity. with Trulicity. severe gastrointestinal severe gastrointestinal disease.disease.

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

Information.

Please see Please Instructions see Instructions for Use for included Use included with thewith pen.the pen.

2 2 Preparation Preparation

•

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

•

• Choose Choose an area an for area for injection injection (abdomen (abdomen or thigh), or thigh), beingbeing sure sure to choose to choose a different a different site (even site (even withinwithin area)area) each each weekweek

TheThe keykey administration administration steps steps 2

2 2 Disposal Disposal

2

•

1

1

Uncap Uncap the pen the pen

2

2

PlacePlace and unlock and unlock

3

• Dispose Dispose of theofpen the in pen in a closable a closable puncturepunctureresistant resistant container container and and not innot household in household trashtrash

3

PressPress and hold and hold

Please Please review review thethe fullfull Instructions Instructions for for UseUse with with your your patients patients to ensure to ensure they they understand understand how how to properly to properly administer administer Trulicity.

Trulicity.

Select Select Important Important Safety Safety Information Information • Trulicity • Trulicity is contraindicated is contraindicated in patients in patients with awith personal a personal or family or family historyhistory of medullary of medullary thyroidthyroid carcinoma carcinoma or in patients or in patients with Multiple with Multiple Endocrine Endocrine Neoplasia Neoplasia

syndrome syndrome type 2,type and2,inand patients in patients with awith prioraserious prior serious hypersensitivity hypersensitivity reaction reaction to dulaglutide to dulaglutide or to any or to ofany the of product the product components. components.

• Cases • Cases of medullary of medullary thyroidthyroid carcinoma carcinoma (MTC) (MTC) in patients in patients treatedtreated with liraglutide, with liraglutide, another another GLP-1 GLP-1 RA, have RA,been have reported been reported in the in postmarketing the postmarketing period;period; the data the data

in these in these reportsreports are insufficient are insufficient to establish to establish or exclude or exclude a causal a causal relationship relationship between between MTC and MTCGLP-1 and GLP-1 RA useRA inuse humans. in humans.

If serum If serum calcitonin calcitonin is measured is measured and and foundfound to be elevated to be elevated or thyroid or thyroid nodules nodules are noted are noted on physical on physical examination examination or neckorimaging, neck imaging, the patient the patient shouldshould be further be further evaluated. evaluated.

Yes, Yes, Yes, I think I think I think I can I can I can dodo do this this this *

* *

•

• Patients • with Patients Patients type withwith type 2 diabetes type 2 diabetes 2 diabetes who were whowho were naïve were naïve to self-injection naïve to self-injection to self-injection and injecting andand injecting injecting others others others (n=214) (n=214) participated (n=214) participated participated in a phase in a in phase 3b, a phase multicenter, 3b, 3b, multicenter, multicenter, open-label, open-label, open-label, single-arm, single-arm, single-arm, outpatient outpatient outpatient studystudy onstudy the onsafe the on and the safesafe effective andand effective effective use of use the use ofTrulicity the of the Trulicity single-dose Trulicity single-dose single-dose pen penpen

•

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

•

• Patients • were Patients Patients were trained were trained attrained baseline at baseline at baseline on proper on proper onself-injection proper self-injection self-injection technique technique technique with the withpen with the the penpen

• Final injection injection injection (4th weekly (4th(4th weekly injection) weekly injection) injection) success success was success observed waswas observed observed in 99.1% in 99.1% in [95% 99.1% [95% CI: [95% 96.6% CI: 96.6% CI: 96.6% In a In study, aInstudy, a 99% study, 99% of99% patients of patients of patients • Final• Final to 99.7%] to 99.7%] to(n=209) 99.7%] (n=209) of (n=209) patients of patients of patients (primary (primary (primary objective objective objective met).met).

Success met).

Success determined Success determined determined by by by reported reported reported thatthat overall, that overall, overall, the thethe evaluation evaluation evaluation of patients’ of patients’ of patients’ ability ability toability accurately to accurately to accurately complete complete complete each each step each in step the step insequence the in the sequence sequence Trulicity Trulicity Trulicity PenPen was Pen was easy was easy oreasy or or of drug of drug administration of drug administration administration 3 3 veryvery easy very easy toeasy use to 3use to use • After • After • After the final the self-injection, the finalfinal self-injection, self-injection, patients patients patients completed completed completed a 12-item a 12-item aease 12-item ease of use ease ofmodule use of use module module

(secondary (secondary (secondary endpoint). endpoint). endpoint).

209 (99%) 209209 (99%) out(99%) ofout 210 out ofpatients 210 of 210 patients patients reported reported reported that overall, thatthat overall, the overall, single the the single single dosedose pendose was penpen “easy” waswas “easy” or“easy” “very or “very easy” or “very easy” to use easy” to use to use

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

*Patient *Patient will *Patient need will will need additional need additional additional assistance assistance assistance from from their from their healthcare their healthcare healthcare professional professional professional as well as as well astowell as review toasreview to review the full theInstructions the full Instructions full Instructions for Use forincluded Use for Use included included with the withTrulicity with the the Trulicity Pen. Trulicity Pen.Pen. PleasePlease seePlease Important see Important see Important SafetySafety Information Safety Information Information for Trulicity, for Trulicity, forincluding Trulicity, including Boxed including Boxed Warning Boxed Warning about Warning about possible about possible thyroid possible thyroid tumors thyroid tumors tumors including including thyroid including thyroid cancer, thyroid cancer, on cancer, following on following on pages following pages andpages accompanying and accompanying and accompanying Brief Summary BriefBrief Summary of Summary Prescribing of Prescribing of Prescribing Information.

Information.

Information.

PleasePlease seePlease Instructions see Instructions see Instructions for Useforincluded Use for included Usewith included the with pen. with the pen. the pen.

Important Safety Information WARNING: 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. It is unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutideinduced 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. 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 (eg, 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.

Renal Impairment: 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.

PP-DG-US-1091

09/2017

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, on following pages.

Please see Instructions for Use included with the pen.

DG HCP ISI 06FEB2017 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.

©Lilly USA, LLC 2017. All rights reserved.

Trulicity® (dulaglutide) Brief Summary: Consult the package insert for complete prescribing 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 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. Renal Impairment: In patients treated with GLP-1 receptor agonists, 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.

ADVERSE REACTIONS

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. 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. 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

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 Placebo-controlled 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 Placebo-Controlled 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 (%) of Documented Symptomatic (≤70 mg/dL Glucose Threshold) and Severe Hypoglycemia in Placebo-Controlled Trials: Add-on to Metformin at 26 weeks, Placebo (N=177), Trulicity 0.75 mg (N=302), Trulicity 1.5 mg (N=304), Documented symptomatic: Placebo: 1.1%, 0.75 mg: 2.6%, 1.5 mg: 5.6%; Severe: 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), Documented symptomatic: Placebo: 1.4%, 0.75 mg: 4.6%, 1.5 mg: 5.0%; Severe: all 0. Add-on to Glimepiride at 24 weeks, Placebo (N=60), Trulicity 1.5 mg (N=239), Documented symptomatic: Placebo: 1.7%, 1.5 mg: 11.3%; Severe: all 0. Add-on to Insulin Glargine with or without Metformin at 28 weeks, Placebo (N=150), Trulicity 1.5 mg (N=150), Documented symptomatic: Placebo: 30.0% 1.5 mg: 35.3%; Severe: Placebo: 0% 1.5 mg: 0.7%. Hypoglycemia was more frequent when Trulicity was used in combination with a sulfonylurea or insulin. In a 78-week clinical trial documented symptomatic hypoglycemia occurred in 39% and 40% of patients when Trulicity 0.75 mg and 1.5 mg, respectively, was 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, was co-administered with a sulfonylurea. Documented

Trulicity® (dulaglutide)

Trulicity® (dulaglutide)

INDICATIONS AND USAGE 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.

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

DG HCP BS 10FEB2017 7 x 9.5

Trulicity, DG HCP BS 10FEB2017 7 x 9.75

DG HCP BS 10FEB2017 7 x 9.5

PRINTER VERSION 1 OF 2

symptomatic hypoglycemia occurred in 85% and 80% of patients when Trulicity 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin. Severe hypoglycemia occurred in 2.4% and 3.4% of patients when Trulicity 0.75 mg, and 1.5 mg, respectively, was 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.

Immunogenicity: Across four Phase 2 and five Phase 3 clinical studies, 64 (1.6%) Trulicitytreated 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. 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 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 placebotreated patients had mean increases of up to 3%. Postmarketing Experience: Anaphylactic 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.

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.

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. 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 ®

Trulicity (dulaglutide)

DG HCP BS 10FEB2017 7 x 9.5

Trulicity, DG HCP BS 10FEB2017 7 x 9.75

varying degrees of hepatic impairment, no clinically relevant change in dulaglutide pharmacokinetics (PK) was observed. Renal Impairment: In the 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).

No overall differences in safety or effectiveness were observed relative to patients with normal renal function, though conclusions are limited due to small numbers. 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. There is limited clinical experience in patients with severe renal impairment or ESRD. Trulicity should be used with caution, and if these patients experience adverse gastrointestinal side effects, renal function should be closely monitored. 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 long-term glycemic control.

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

Additional information can be found at www.trulicity.com DG HCP BS 10FEB2017 Trulicity® (dulaglutide)

DG HCP BS 10FEB2017 7 x 9.5

PRINTER VERSION 2 OF 2

MSP SUPLEMENTO SPED

ESTADÍSTICAS Prevalencia de diabetes Prevalencia de diabetes

30.2 Millones

23 millones diagnosticados 7.2 millones sin diagnosticar

Diabetes por edad

18-44 45-64 ≥ 65 (4.6 millones)

Costos Relacionados a Diabetes Total de costos

$245

Billones al año Gastos médicos promedio para diabéticos

$13,700

Directos

$176 billones al año Indirectos

(reducidos en productividad)

$69 billones al año Gastos Médicos

2.3 veces mayor que los no diabéticos

Hospitalizaciones & ED

al año

7.2 millones

($7,900 de estos se atribuyen directamente a la diabetes)

de hospitalizaciones asociadas a la diabetes

14.2 millones

Visitas ED asociadas a la diabetes

(14.3 millones) (12 millones)

Otras estadísticas Factores de riesgo para la diabetes

Ajuste por edad Prevalencia de diagnóstico de Diabetes en adultos estadounidences

1994

Data desconocida Menos de 4.5% 4.5%-5.9% 6.0%-7.4% 7.5%-8.9%

Data Desconocida Menor de 4.5% 4.5%-5.9% 6.0%-7.4%

2015

9.0%

Fumar • Sobre peso y Obesidad • Inactividad Física • Presión Arterial Alta • Colesterol Alto

En Puerto Rico

550,000

Aproximadamente pacientes con diagnóstico de diabetes.

7ma

causa líder de muerte

Las personas con diabetes

están en mayor riesgo de desarrollar serias complicaciones (en comparación con pacientes no diabéticos)

Ataque fulminante (2-4 veces más que la población general)

Enfermedad del Riñón

Ceguera

(2-4 veces más que la población general)

Amputaciones

(2-4 veces más que la población general)

(25 veces más que la población general)

(28 veces más que la población general)

Ataque al Corazón

7.5%-8.9% 9.0%

Revista Puertorriqueña de Medicina y Salúd Pública

67

MSP SUPLEMENTO SPED

68

Revista Puertorriqueña de Medicina y Salúd Pública

MSP SUPLEMENTO SPED

Revista Puertorriqueña de Medicina y Salúd Pública

69

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

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

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

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

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

IMPORTANT SAFETY INFORMATION BOXED WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

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

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

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

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

FOR ADULTS WITH

ACTIVE PsA1 Visit XELJANZPsAHCP.com.

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

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

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

WARNINGS AND PRECAUTIONS SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ/XELJANZ XR in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.

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

Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection.

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

XELJANZ XELJANZ DELIVERED DELIVERED RAPID RAPID RELIEF RELIEF AS EARLY AS EARLY AS WEEK AS WEEK 2 AND 2 AND POWERFUL POWERFUL EFFICACY EFFICACY 1-4 1-4 AT MONTH AT MONTH 3. RESPONSES 3. RESPONSES WERE WERE SUSTAINED SUSTAINED AT MONTH AT MONTH 6 AND 6 AND OUTOUT TO YEAR TO YEAR 1 1 1-4 1-4 OPAL OPAL Clinical Clinical Program Program Description Description

All patients All patients in the Oral in the Psoriatic Oral Psoriatic Arthritis Arthritis TriaL (OPAL) TriaL (OPAL) ClinicalClinical Program Program had active had active PsA forPsA ≥6 for months ≥6 months based based on theon CASPAR, the CASPAR, ≥3 tender/painful ≥3 tender/painful joints and joints ≥3and swollen ≥3 swollen joints,joints, and active and active plaqueplaque psoriasis. psoriasis.

AcrossAcross all treatment all treatment arms, patients arms, patients were required were required to receive to receive a stable a stable dose ofdose oneof csDMARD one csDMARD throughout throughout the studies. the studies.

In bothInclinical both clinical trials, trials, the primary the primary endpoints endpoints were ACR20 were ACR20 response response rate and rate change and change from baseline from baseline in HAQ-DI in HAQ-DI score at score month at month 3. To control 3. To control for type forI error type Iaterror the at 5%the level 5%for level primary for primary and certain and certain secondary secondary endpoints, endpoints, statistical statistical testingtesting was performed was performed for XELJANZ for XELJANZ 10 mg 10 BIDmg arm, BIDthen arm,XELJANZ then XELJANZ 5 mg BID 5 mg arm BID vsarm placebo vs placebo arm, inarm, a hierarchical in a hierarchical sequence. sequence.

TestingTesting stopped stopped at any at point anyin point a fixed in asequence fixed sequence wherever wherever statistical statistical significance signifiwas cance not was reached. not reached.

The testing The testing hierarchy hierarchy was ACR20 was ACR20 response response rate, change rate, change from baseline from baseline in in HAQ-DI HAQ-DI score, score, PASI75PASI75 response response rate, change rate, change from baseline from baseline in LEI score, in LEI score, changechange from baseline from baseline in DSS,inchange DSS, change from baseline from baseline in SF-36 in SF-36 score, score, and change and change from baseline from baseline in in FACIT-F FACIT-F total score totalat score month at month 3. For the 3. For family the family of ACRofresponse ACR response rates at rates month at month 3, the separate 3, the separate hierarchy hierarchy was ACR20, was ACR20, ACR50, ACR50, and ACR70. and ACR70.

For theFor ACR20 the ACR20 response response rates rates at eachattrial each visit, trialthe visit, separate the separate hierarchy hierarchy was month was month 3, 2, 1, 3, and 2, week 1, and2. week Nonresponder 2. Nonresponder imputation imputation was applied was applied to missing to missing data for data ACR forresponse ACR response rates. rates.

Mixed Mixed modelmodel for for repeated repeated measures measures was used waswithout used without imputation imputation for missing for missing valuesvalues for change for change from baseline from baseline in HAQ-DI in HAQ-DI score, score, LEI score, LEI score, DSS, SF-36 DSS, SF-36 score, score, or FACIT-F or FACIT-F total score. total score.

1-3,a 1-3,a OPAL OPAL Beyond Beyond (Study(Study PsA-II)PsA-II) in TNFi-IR in TNFi-IR Patients Patients

*P≤0.05 *P≤0.05 vs placebovs placebo

100 Placebo-controlled Placebo-controlled period period

ACR20 response rate (% of patients)†

ACR20 response rate (% of patients)†

100

80

60

80

60% 60%

50%* 50%*

60

(n=65)

(n=78)

50% 50%

40 27%* 27%*

40

(n=35)

20

(n=33)

(n=35)

(n=17)

0

(n=33)

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

1-3 1-3 OPAL OPAL Beyond Beyond (Study (Study PsA-II) PsA-II)

A 6-month, A 6-month, randomized, randomized, double-blind, double-blind, placebo-controlled, placebo-controlled, multicenter, multicenter, phase 3phase trial 3 trial in whichin394 which adult 394patients adult patients with active withPsA active who PsA hadwho inadequate had inadequate response response to at least to at least one TNFi one received TNFi received either XELJANZ either XELJANZ 5 mg BID, 5 mg 10 mg BID,BID, 10 mg or placebo.

BID, or placebo.

At month At month 3, all 3, all patients patients randomized randomized to placebo to placebo were advanced were advanced to XELJANZ to XELJANZ 5 mg BID 5 mg or 10 BID mgorBID 10 mg in BID in a blinded a blinded mannermanner based on based theiron initial theirrandomization initial randomization sequence. sequence.

Across all Across treatment all treatment arms, all arms, patients all patients were required were required to receive to receive a stableadose stable ofdose one conventional of one conventional synthetic synthetic disease-modifying disease-modifying antirheumatic antirheumatic drug (csDMARD, drug (csDMARD, also known also as known a nonbiologic as a nonbiologic DMARD, DMARD, which included which included methotrexate, methotrexate, sulfasalazine, sulfasalazine, and lefland unomide). leflunomide).

Stable low-dose Stable low-dose oral oral glucocorticoids glucocorticoids allowed.allowed.

24% 24%

20

13% 13%

0

(n=78)

(n=65)

XELJANZ XELJANZ 5 mg BID 5 mg + BID + csDMARD csDMARD (N=131) (N=131)

(n=31)

(n=31)

2

4

All patients All patients on placebo on placebo advanced advanced to to 1 XELJANZ XELJANZ at month at3. month 3.1

(n=17)

Week 2 1 Week 2 12

4

Month 3Month 3 PrimaryPrimary endpoint endpoint

6

6

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

ACR20 response.

†

1,3,4,a 1,3,4,a OPAL OPAL Broaden Broaden (Study(Study PsA-I)PsA-I) in csDMARD-IR in csDMARD-IR (Nonbiologic (Nonbiologic DMARD-IR), DMARD-IR), TNFi-Naïve TNFi-Naïve Patients Patients 1 1 Study Study PsA-I was PsA-Inot was designed not designed to demonstrate to demonstrate noninferiority noninferiority or superiority or superiority of XELJANZ of XELJANZ to Humira® to Humira® (adalimumab). (adalimumab).

*P≤0.05 *P≤0.05 vs placebovs placebo **P≤0.05**P≤0.05 vs placebo, vs nominal placebo,b nominalb

100 Placebo-controlled Placebo-controlled period period

80

60

40

20

ACR20 response rate (% of patients)†

ACR20 response rate (% of patients)†

100

(n=55)

22%40* 22%* 22%** 22%** (n=24)

(n=24)

(n=23)

(n=23)

20

6%

6%

(n=55)

50%* 50%* (n=54)

(n=54)

All patients on placebo on placebo advanced advanced to to 33% 33%All patients XELJANZ XELJANZ at month at3. month 3. (n=35)

(n=35)

2

4

1

1

(n=6)

0 Week 2

1 Week 2 12

4

Month 3Month 3 PrimaryPrimary endpoint endpoint

6

6

9

1,3,4 1,3,4 OPALOPAL Broaden Broaden (Study (Study PsA-I) PsA-I)

A 12-month, A 12-month, randomized, randomized, double-blind, double-blind, double-dummy, double-dummy, active-controlled, active-controlled, placeboplacebocontrolled, controlled, multicenter, multicenter, phase 3phase trial in3 trial in which 422 which adult 422patients adult patients with active withPsA active PsA who hadwho inadequate had inadequate response response to at least to at least one csDMARD one csDMARD and were and TNFi-naïve were TNFi-naïve receivedreceived either XELJANZ either XELJANZ 5 mg BID, 5 mg 10 mg BID,BID, 10 mg BID, Humira® Humira® 40 mg s.c.

40 mg q 2 wk, s.c. qor2placebo. wk, or placebo.

At At month 3, month all patients 3, all patients randomized randomized to placebo to placebo were advanced were advanced to XELJANZ to XELJANZ 5 mg BID 5 mg or BID or Humira®Humira® 40 mg s.c.

40 mg q 2 wk s.c.+q 2 wk 10 + mg BID 10 mg in aBID blinded in a blinded mannermanner based on based theiron their csDMARD csDMARD initial randomization initial randomization sequence. sequence.

Across all Across all (N=106) (N=106) treatment treatment arms, all arms, patients all patients were required were required to receive to receive a stableadose stable ofdose one csDMARD of one csDMARD (also known (also as known nonbiologic as nonbiologic DMARD, DMARD, which which included included methotrexate, methotrexate, sulfasalazine, sulfasalazine, and lefland unomide). leflunomide).

Stable low-dose Stable low-dose oral oral glucocorticoids glucocorticoids allowed.allowed.

Study PsA-I Studywas PsA-I was not designed not designed to demonstrate to demonstrate noninferiority noninferiority or superiority or superiority of XELJANZ of XELJANZ to Humira®. to Humira®.

PlaceboPlacebo + + (n=73) (n=73) csDMARD csDMARD (N=105) (N=105) (n=35) (n=35) to % 60% to 60 (n=64) (n=64) XELJANZ XELJANZ 5 mg BID 5 mg + BID + csDMARD csDMARD (N=52) (N=52)

52%** 52%**

60

(n=6)

0

68% 68% 67% 67%

80

XELJANZ XELJANZ 5 mg BID 5 mg + BID + csDMARD csDMARD (N=107) (N=107)

9

All other Alltime other points time measured points measured were secondary were secondary endpoints. endpoints.

12

12

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

ACR20 response.

†

a b

a Nonresponder Nonresponder imputation imputation was applied wastoapplied missingtosign/symptom missing sign/symptom data.1,2,4 data.1,2,4 3 3 NominalbP Nominal values P notvalues adjusted not adjusted for multiplicity. for multiplicity.

ACR20 response ACR20 response is definedisasdefi anned improvement as an improvement of 20% orofmore 20%from or more baseline from in baseline the number in theofnumber tender/painful of tender/painful and swollen andjoints swollen andjoints in at and leastin3atofleast the following 3 of the following domains:domains: Patient’sPatient’s Global Assessment Global Assessment of arthritis, of arthritis, Physician’s Physician’s Global Global 2,4 Assessment Assessment of arthritis, of arthritis, Patient’sPatient’s Assessment Assessment of Arthritis of Pain, Arthritis disability Pain, disability as measured as measured by the HAQ-DI, by the or HAQ-DI, hsCRP or level. hsCRP level.2,4 ACR=American ACR=American College ofCollege Rheumatology; of Rheumatology; BID=twiceBID=twice daily; CASPAR=Classifi daily; CASPAR=Classifi cation Criteria cationfor Criteria Psoriatic for Psoriatic Arthritis;Arthritis; csDMARD=conventional csDMARD=conventional syntheticsynthetic disease-modifying disease-modifying antirheumatic antirheumatic drug; DMARD=disease-modifying drug; DMARD=disease-modifying antirheumatic antirheumatic drug; DSS=Dactylitis drug; DSS=Dactylitis Severity Score; Severity FACIT-F=Functional Score; FACIT-F=Functional Assessment Assessment of ChronicofIllness Chronic Therapy-Fatigue; Illness Therapy-Fatigue; HAQ-DI=Health HAQ-DI=Health Assessment Assessment Questionnaire-Disability Questionnaire-Disability Index; hsCRP=high-sensitivity Index; hsCRP=high-sensitivity C-reactiveC-reactive protein; IR=inadequate protein; IR=inadequate responder; responder; LEI=LeedsLEI=Leeds EnthesitisEnthesitis Index; PASI=psoriasis Index; PASI=psoriasis area and area severity andindex; severity PsA=psoriatic index; PsA=psoriatic arthritis; arthritis; q 2 wk=every q 2 wk=every 2 weeks; 2RA=rheumatoid weeks; RA=rheumatoid arthritis; arthritis; s.c.=subcutaneously; s.c.=subcutaneously; SF-36=Medical SF-36=Medical OutcomesOutcomes Study 36-Item Study Short-Form 36-Item Short-Form Health Survey; HealthTNFi=tumor Survey; TNFi=tumor necrosis factor necrosis inhibitor. factor inhibitor.

The recommended The recommended dose of XELJANZ dose of XELJANZ is 5 mg twice is 5 mg daily twice or XELJANZ daily or XELJANZ XR 11mg once XR 11mg dailyonce useddaily in combination used in combination with nonbiologic with nonbiologic DMARDs.DMARDs. The efficacy TheofeffiXELJANZ/XELJANZ cacy of XELJANZ/XELJANZ XR as a monotherapy XR as a monotherapy has not been has not studied beeninstudied psoriatic in psoriatic arthritis.1arthritis.1 XELJANZ XELJANZ XR 11 mg XR administered 11 mg administered once dailyonce is pharmacokinetically daily is pharmacokinetically equivalent equivalent to XELJANZ to XELJANZ 5 mg administered 5 mg administered twice daily. twice Thedaily. recommended The recommended dose in patients dose in with patients moderate with moderate to severetorenal severe impairment renal impairment and moderate and moderate hepatic impairment hepatic impairment 1 is XELJANZ is XELJANZ 5 mg once5 daily. mg once daily.1 Humira isHumira a registered is a registered trademarktrademark of AbbVieofInc. AbbVie Inc.

IMPORTANT SAFETY INFORMATION (cont’d) Tuberculosis Evaluate and test patients for latent or active infection prior to and per applicable guidelines during administration of XELJANZ/XELJANZ XR. Consider anti-TB therapy prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Treat patients with latent TB with standard therapy before administering XELJANZ/XELJANZ XR. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was observed in clinical studies with XELJANZ. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan and Korea.

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

In the 7 controlled rheumatoid arthritis clinical studies, 11 solid cancers and 1 lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure.

Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In the 2 controlled Phase 3 clinical trials in patients with active psoriatic arthritis, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ. In Phase 2B controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus–associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

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

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

GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis).

LABORATORY ABNORMALITIES Lymphocyte Abnormalities Treatment with XELJANZ was associated with initial lymphocytosis at 1 month of exposure followed by a gradual decrease in mean lymphocyte counts of approximately 10% during 12 months of therapy. Counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended.

Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ/ XELJANZ XR treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ/ XELJANZ XR dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

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

Liver Enzyme Elevations Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ/ XELJANZ XR should be interrupted until this diagnosis has been excluded.

Lipid Elevations Treatment with XELJANZ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks.

Assess lipid parameters approximately 4-8 weeks following initiation of XELJANZ/ XELJANZ XR therapy, and manage patients according to clinical guidelines for the management of hyperlipidemia.

VACCINATIONS Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. A varicella virus naïve patient experienced dissemination of the vaccine strain of varicella zoster virus 16 days after vaccination with live attenuated virus vaccine which was 2 days after 5 mg twice daily treatment with tofacitinib. The patient recovered after discontinuation of tofacitinib and treatment with antiviral medication. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy.

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

HEPATIC and RENAL IMPAIRMENT Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. The recommended dose in patients with moderate hepatic impairment or with moderate or severe renal impairment is XELJANZ 5 mg once daily.

ADVERSE REACTIONS The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infections (4.5%, 3.3%), headache (4.3%, 2.1%), diarrhea (4.0%, 2.3%), and nasopharyngitis (3.8%, 2.8%).

USE IN PREGNANCY There are no adequate and well-controlled studies in pregnant women and the estimated background risks of major birth defects and miscarriage for the indicated population is unknown. Based on animal studies, tofacitinib has the potential to affect a developing fetus. Women of reproductive potential should be advised to use effective contraception.

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

References: 1. XELJANZ/XELJANZ XR [prescribing information]. New York, NY: Pfizer Inc; December 2017. 2. Gladman D, Rigby W, Azevedo VF, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors.

N Engl J Med. 2017;377(16):1525-1536. 3. Data on file. Pfizer Inc, New York, NY. 4. Mease P, Hall S, FitzGerald O, et al.

Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med. 2017;377(16):1537-1550.

PP-XEL-USA-2979-01 All rights reserved. © 2018 Pfizer Inc. Printed in USA/January 2018 Humira is a registered trademark of AbbVie Inc.

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

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

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

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

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

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

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

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

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

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

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

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

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.

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

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

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

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

Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection.

Tuberculosis Patients should be evaluated and tested for latent or active

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

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

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

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

Malignancies were observed in clinical studies of XELJANZ. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In the 2 controlled Phase 3 clinical trials in patients with active psoriatic arthritis, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic DMARD group (12 months exposure). No lymphomas were reported.

Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

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

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

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

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

Laboratory Abnormalities Lymphocyte Abnormalities Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.

Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended.

Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.

Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ/ XELJANZ XR dosing until ANC is greater than or equal to 1000 cells/ mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended.

Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.

Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded.

Lipid Elevations Treatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks.

The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

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

Manage patients according to clinical guidelines [e.g., National

Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

Vaccinations Avoid use of live vaccines concurrently with XELJANZ/ XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medication.

Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy.

General Specific to XELJANZ XR As with any other non-deformable material, caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation.

ADVERSE REACTIONS Clinical Trial Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

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

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

The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies.

The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.

The most common serious adverse reactions were serious infections.

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

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

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

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

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

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

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

Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients

who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

• Mean LDL/HDL ratios were essentially unchanged in XELJANZtreated patients.

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

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

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

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

Clinical Experience in Methotrexate-Naïve Patients Study VI was an active-controlled clinical trial in methotrexate-naïve patients. The safety experience in these patients was consistent with Studies I-V. Psoriatic Arthritis XELJANZ 5 mg twice daily and 10 mg twice daily were studied in 2 double-blind Phase 3 clinical trials in patients with active psoriatic arthritis (PsA).

Study PsA-I (NCT01877668) had a duration of 12 months and enrolled patients who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF-inhibitor (TNFi). Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.

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

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

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

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

XELJANZ 10 mg Twice Daily*

Placebo

N = 1336 (%)

N = 1349 (%)

N = 809 (%)

Diarrhea

4.0

2.9

2.3

Nasopharyngitis

3.8

2.8

2.8

Upper respiratory tract infection

4.5

3.8

3.3

Headache

4.3

3.4

2.1

Hypertension

1.6

2.3

1.1

Preferred Term

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

DRUG INTERACTIONS All information provided in this section is applicable to XELJANZ and XELJANZ XR as they contain the same active ingredient (tofacitinib).

Potent CYP3A4 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole).

Moderate CYP3A4 and Potent CYP2C19 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).

Potent CYP3A4 Inducers Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin).

Immunosuppressive Drugs There is a risk of added immunosuppression when XELJANZ/XELJANZ XR is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ/XELJANZ XR with potent immunosuppressants has not been studied in rheumatoid arthritis and psoriatic arthritis. Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

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

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

Risk Summary There are no adequate and well-controlled studies of XELJANZ/XELJANZ XR use in pregnant women.

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

Based on animal studies, XELJANZ/XELJANZ XR has the potential to affect a developing fetus. Fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 146 times and 13 times the human dose of 5 mg once daily, respectively. Further, in a peri and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73 times the human dose of 5 mg twice daily.

Data Human Data In the tofacitinib clinical development programs, birth defects and miscarriages were reported.

Animal Data In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/ day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/ day in pregnant rats).

In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).

In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).

Lactation Risk Summary It is not known whether tofacitinib is excreted in human milk. Additionally, there are no data to assess the effects of the drug on the breastfed child. However, tofacitinib is excreted in rat milk at concentrations higher than in maternal serum. Women should not breastfeed while treated with XELJANZ/XELJANZ XR. A decision should be made whether to discontinue breastfeeding or to discontinue XELJANZ/XELJANZ XR. Data Human Data There are no adequate and well-controlled studies of XELJANZ/XELJANZ XR use during breastfeeding.

Animal Data Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.

Females and Males of Reproductive Potential Contraception Females Embryofetal toxicity including malformations occurred in embryofetal development studies in rats and rabbits.

Females of reproductive potential should be advised to use effective contraception during treatment with XELJANZ/XELJANZ XR and for at least 4 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with XELJANZ/XELJANZ XR. Infertility Females Based on findings in rats, treatment with XELJANZ/XELJANZ XR may result in reduced fertility in females of reproductive potential.

Pediatric Use The safety and effectiveness of XELJANZ/XELJANZ XR in pediatric patients have not been established.

Geriatric Use Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Use in Diabetics As there is higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.

Hepatic Impairment XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib levels than XELJANZ-treated patients with normal hepatic function. Higher blood levels may increase the risk of some adverse reactions, therefore, the recommended dose is XELJANZ 5 mg once daily in patients with moderate hepatic impairment. XELJANZ/ XELJANZ XR has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. No dose adjustment is required in patients with mild hepatic impairment. The safety and efficacy of XELJANZ/XELJANZ XR have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

Renal Impairment XELJANZ-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than XELJANZ-treated patients with normal renal function; therefore, the recommended dose is XELJANZ 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, XELJANZ/XELJANZ XR was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockcroft-Gault equation) less than 40 mL/ min (or in patients with active psoriatic arthritis with creatinine clearance values less than 50 mL/min). No dose adjustment is required in patients with mild renal impairment.

OVERDOSAGE Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans There is no experience with overdose of XELJANZ/XELJANZ XR. Treatment or Management of Overdose Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.

There is no specific antidote for overdose with XELJANZ/XELJANZ XR. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.

This brief summary is based on XELJANZ®/XELJANZ® XR (tofacitinib) Prescribing Information LAB-0445-12.0 Issued: December 2017

© 2017 Pfizer Inc.

All rights reserved.

December 2017

2018

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

Fecha

Lugar

Coordinador o Contacto

Comentarios

7 de abril 2018

Congreso Academia de Neurología de PR

Puerto Rico Sheraton Hotel Convention Center. San Juan, PR

AMEC

14 al 15 de abril 2018

2018 AnnualMeeting- Academia de Patología y Medicina de Laboratorio de Puerto Rico

Puerto Rico Sheraton Hotel Convention Center. San Juan, PR

Serra & Serra Group

26 al 29 de abril 2018

61th Puerto Rico Academy of Family Physicians Annual Convention / Academia de Médicos de Familia de PR

Puerto Rico Sheraton Convention Center Hotel. San Juan, PR

SDMS Group

4 al 5 de Mayo 2018

6th Immunization (IMCO) Congress: “Prevention is Action"

Centro de Convenciones de PR San Juan, PR

VOCES- Coalición de vacunación de PR

4 al 6 de Mayo 2018

Cursos Obligatorios para Médicos- Área Oeste

Club de Leones de Mayagüez Mayagüez, PR

High Educational Health-Feliciano Communications

787-964-6394 787-777-1425 (Fax) heh@hehpr.com

CURSO

5 de mayo de 2018

Simposio Ortopédico de Medicina Deportiva (SPOT)

Intercontinental Hotel San Juan Isla Verde, Puerto Rico

Asis Spot

787-723-6751 asis.spot@gmail.com

SIMPOSIO

5 de mayo de 2018

Centro de Cáncer Hospital Auxilio Mutuo- AnnualLungCancerConference

Hotel la Concha San Juan, PR

AMEC

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

CONFERENCIAS

18 al 19 de Mayo 2018

American College of Surgeon PR Chapter (68th Annual Meeting)

Embassy Suites Hotel Isla Verde San Juan, PR

ACS Puerto Rico Chapter

acspuertoricochapter @gmail.com

ANNUAL MEETING

18 al 19 de mayo 2018

Caribbean Congress on Emergency Medicine

Sheraton Convention Center Hotel San Juan, PR

RiVS MarketingRina Vega

787-548-0047 info@rivsmarketing.com

18 al 20 de mayo de 2018

Convención Anual Asociación de Reumatólogos de Puerto Rico

Ponce Hilton Hotel. Ponce, PR

787-406-4571 Serra & Serra Group 787-640-5776 787-748-6022 info@serrayserra.com

CONVENCIÓN

18 al 20 de mayo 2018

Convención Anual Asociación Médica Occidental

Casa del Médico del Oeste Mayagüez, PR

Asociación Médica 787-834-1800 Occidental

CONVENCIÓN

19 de mayo de 2018

Paim Management Academy Annual Convention

Sheraton Convention Center Hotel San Juan, PR

AMEC

San Juan, PR

Educational Partners 787-646-0780 & Coaching, Inc. vperez@epcpr.com Vilma Pérez

25 al 28 de mayo 2018

76

Título

Puerto Rico

Convención SPED Sociedad Puertorriqueña de Endocrinología y Diabetología

787-289-8989 amec@amec-pr.com 787-731-3325 info@sdmsgroup.com 787-289-8989 amec@amec-pr.com 787-731-3325

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

CONGRESO

CONVENCIÓN

CONVENCIÓN

CONVENCIÓN

CURSO

CONVENCIÓN

CONVENCIÓN

2 de junio de 2018

Convención Anual Asociación de Psiquiatras de Bayamón

La Concha Hotel San Juan, PR

AMEC

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

CONVENCIÓN

21 de junio de 2018

Post ASCO AnnualConference- Centro de Cáncer Hospital Auxilio Mutuo

Vanderbilt Hotel San Juan, Pr

AMEC

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

CONFERENCIAS

21 de junio de 2018

Post ASCO AnnualConference- Centro Tde Cáncer Hospital Auxilio Mutuo

Vanderbilt Hotel San Juan, Pr

AMEC

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

COFERENCIAS

22 al 24 de junio 2018

Convención Anual Asociación Puertorriqueña de Medicina Física y Rehabilitación

Condado Plaza Hotel San Juan, PR

Serra y Serra

787-640-5776 info@serrayserra.com

CONVENCIÓN

Revista Puertorriqueña de Medicina y Salúd Pública

22 al 24 de junio 2018

Cursos Obligatorios para Médicos

Casa Club Sigma Hato Rey, PR

High Educational Health- Feliciano Communications

787-964-6394 787-777-1425 (Fax) heh@hehpr.com

CURSO

22 al 25 de junio 2018

8th Convención Anual Academia de Medicina General de Puerto Rico

Sheraton Convention Center Hotel San Juan, PR

SR Consultants and events Santiago Rivera

939-292-4115 srconsultantsandevents @gmail.com

CONVENCIÓN

28 de Junio al 1 de Julio 2018

CConvención Sociedad Dermatológica de Puerto Rico

Wyndham Rio Mar Río Grande, PR

RN Pro Events

787-368-7939 rafinieto@rnproevents.com

CONVENCIÓN

29 de Junio al 1 de Julio 2018

Bestof DDW- Asociación Puertorriqueña de Gastrienterología

Wyndham Rio Mar Río Grande, PR

RiVS Marketing Rina Vega

787-548-0047 info@rivsmarketing.com

CONVENCIÓN

13 al 15 de Julio 2018

Convención Anual Sociedad Puertorriqueña de Cardiología

Sheraton Convention Center Hotel San Juan, PR

Sociedad Puertorriqueña de Cardiología

787-620-2228 socprcardio@gmail.com

CONVENCIÓN

3 al 5 de agosto 2018

SunshineSeminar 2018- PROGYN

Sheraton Convention Center Hotel San Juan, PR

PROGYN

787-763-0832 787-405-0520 info@progyn.org

CONVENCIÓN

10 al 12 de agosto 2018

Sociedad de Cirujanos Vasculares y Endovasculares de PR Annual Meeting

La Concha Hotel San Juan, PR

AMEC

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

CONVENCIÓN

11 al 12 de agosto 2018

11thAnnual Meeting of Interventional Cardiology- Sociedad Puertorriqueña de Cardiología Intervencional

Sheraton Convention Center Hotel San Juan, PR

Healthcare Alliance for (844) 426-3674 Medical Education Planners- Enid Rivera

18 al 19 de Agosto

7th RespiratoryCongress de la Coalición de Asma y Otras Condiciones Crónicas de Puerto Rico

Intercontinental Hotel San Juan, PR

IC Planners Ivette Colón

18 al 19 de Agosto 2018

13th Annual Meeting of Infectious Diseases- Sociedad de Enfermedades Infecciosas de Puerto Rico

Ponce Hilton Hotel Ponce, PR

Healthcare Alliance for (844) 426-3674 Medical Education Planners- Enid Rivera

24 de agosto de 2018

2do Simposio de Trauma

Centro Criollo de Ciencia y Tecnología Caguas, PR

25 de agosto 2018

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

Hotel La Concha San Juan, PR

25 de agosto 2018

Mayagüez Medical Center Cardiovascular InnovationForum 2018 59 thAnnualConvention Sociedad de Médicos Graduados de la Escuela de Medicina UPR

31 de agosto al 2 de septiembre 1 de septiembre 2018

Convención Anual Academia de Neurología de PR

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

CONVENCIÓN

CONGRESO

SIMPOSIO

787-777-3760 prfact2012@gmail.com

SIMPOSIO

IC Planners Ivette Colón

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

CONVENCIÓN

Mayagüez Resort & Casino Mayagüez, PR

AMEC

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

CONFERENCIAS

San Juan Marriot Resort San Juan, PR

Sociedad de Médicos Graduados de la Escuela de Medicina UPR

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

CONVENCIÓN

La Concha Hotel San Juan, PR

AMEC

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

CONVENCIÓN

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

CONVENCIÓN

1 al 3 de septiembre 2018

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

Mayagüez Resort & Casino Mayagüez, PR

Mignaliz Vega

13 al 16 de Septiembre 2018

Convención Anual Sociedad Radiológica de PR

Condado Plaza Hotel San Juan, PR

Serra & Serra Group

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

CONVENCIÓN

15 de septiembre 2018

Convención Anual Sociedad de Nefrología de PR

Hotel Marriot San Juan, PR

AMEC

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

CONVENCIÓN

10 de octubre 2018

American Psychiatric Academy Annual Convention

*Por Confirmar lugar

AMEC

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

CONVENCIÓN

26 al 28 de octubre de 2018

Annual Convention Puerto Rico HIV Treaters Medical Association

Annual Convention Puerto Rico HIV Treaters Medical Association

Educational Partners & Coaching, Inc. Vilma Pérez

787-646-0780

2 al 4 de Noviembre 2018

Convención Anual Asociación de Médicos Pediatras Región Este (AMPRE)

Intercontinental Hotel San Juan, PR

BPlanner Merna Morales

787-706-0442 bplanner21@gmail.com

CONVENCIÓN

CONVENCIÓN

Revista Puertorriqueña de Medicina y Salúd Pública

77

2018

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

Fecha

Título

Lugar

Coordinador o Contacto

Comentarios

05-06 de abril de 2018

IV Simposio Nacional de Nutrición

Barranquilla, Colombia

Sociedad 6495352 – 7464706/07 Colombiana de http://plandeactividades Pediatría .com/eventos/

07-10 de abril de 2018

XX Congreso Panamericano de Reumatología (20° PANLAR 2018)

Buenos Aires. Hotel Hilton, Argentina

PANLAR 2018

+34 91 361 2600 panlar2018@kenes.com http://www.congreso -panlar.com/

11 al 14 de abril de 2018

16th World Congress of Endoscopic Surgery

Washington State Convention Center Seatle, WA, USA

Sages

Webmaster@sayes.org www.sages2018.org

CONGRESO

12 al 14 de abril de 2018

26th Annual Spring Congress of American Academy of Anti-Aging Medicine

The Diplomat Beach Resort Hollywood, FL, USA

A4M

info@a4m.com www.a4m.com

CONGRESO

18-21 de abril de 2018

XII Congreso Internacional de la ISHD

Hilton Cartagena Hotel Cartagena, Colombia

Kenes Group

17 al 21 de abril de 2018

American College of Physicians (ACP) Internal Medicine Meeting 2018)

Ernest N. Morial Convention Center New Orleans, LA, USA

18-21 de abril de 2018

Congreso Mundial de Hemodiálisis

Cartagena, Colombia

Asociación Colombiana Tel. 6215193 de Nefrología e asocolnef.com Hipertensión Arterial

19 al 21 de abril de 2018

2018 World Congress on Regional Anesthesia & Pain Medicine

New York Marriott Marquis, New York City, USA

Asra

20-21 de abril de 2018

XVIII Simposio Internacional de Neumología y Alergia Pediátrica

Hotel Caribe Cartagena, Colombia

Clínica Respiratoria Tel: 6436747- 6745182 www.simposio.clinialergias y de Alergiasa .com

16-29 de abril de 2018

Congreso Latinoamericano de Endocrinología

Centro de Convenciones Cartagena, Colombia

Asociación Colombiana 6420243 – 6420245 http://congreso.endo de Endocrinología, Diabetes y Metabolismo crino.org.co/

5 al 9 de mayo de 2018

2018 American Psychiatric Association Annual Meeting

Jacob K. Javits Convention Center, New York, NY, USA

09-12 de mayo de 2018

XXXI Congreso Nacional Obstetricia y Ginecología

Centro Internacional de Convenciones y Exposiciones Las Américas Cartagena, Colombia

29 de mayo American College of Sports Medicine 2018 al 2 de junio Annual Meeting de 2018

78

Internacional

Convention Center & Hyatt Regency Minneapolis, MN, USA

9 al 13 de junio de 2018

9th World Congress World Federation of Pediatric Intensive and Critical Care

Suntec Singapore Convention & Exhibition Centre, Singapur

13 al 16 de junio de 2018

EULAR 2018 Annual European Congress of Rheumatology

RAI Convention Center Amsterdam, Holanda

Revista Puertorriqueña de Medicina y Salúd Pública

Tel. +34-91-3612600 +34-91-3559208 ishd2018@kenes.com Im2018.acponline.org

asraassistant@asra.com www.asra.com

apa@psych.org www.psychiatry.org Federación Colombiana de Obstetricia y fecolsog@fecolsog.co Ginecología ACSM

meeting@acsm.org www.acsmaanualmeeting.org www.wfpiccs.kenes.com/2018/

Eular

www.congress.eular.org

MEETING

CONGRESO

ANNUAL MEETING

CONVENCIÓN

ANNUAL MEETING

CONGRESO

CONGRESO

2018

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

Internacional

14 al 17 de junio de 2018

2nd International Conference on Zika Virus and Aedes Related Infections

Hilton Tallinn Park Tallin, Estonia

16 al 19 de junio de 2018

Society for Nuclear Medicine & Molecular Imaging (2018 Annual Meeting)

Fira Gran Via Centro de Convenciones Barcelona, España

23 al 26 junio de 2018

Society for Nuclear Medicine & Molecular Imaging

Pennsylvania Convention Center Philadelphia, PN, USA

28 al 30 junio de 2018

Cardiosur 2018XXVIII Congreso Sudamericano de Cardiología

Lima, Perú

03 al 06 julio de 2018

Feria Internacional de la SaludMEDITECH 2018

04 al 05 julio de 2018

http://go.evvnt.com/127094-0

www.lcoph.org www.snmmi.org

Sociedad Colombiana De Cardiología Y Cirugía Cardiovascular

Tel. 523 0012 http://scc.org.co/evento/cardiosur-2018-xxviii-congreso-sudamericano-de-cardiologia/

Corferias Bogotá, Colombia

Asociación Colombiana de Hospitales y Clínicas (ACHC)

Tel: 3124411

XIII Congreso Internacional de Hospitales y Clínicas

Corferias Bogotá, Colombia

Asociación Colombiana de Hospitales y Clínicas (ACHC)

Tel: 3124411

05 al 07 julio de 2018

VII Simposio Internacional de Actualización en Pediatría

Centro de Convenciones - Hotel Las Américas Cartagena, Colombia

Sociedad Colombiana de Pediatría

01 al 04 agosto de 2018

25th Annual Summer Conference on Obstetrics and Gynecology

The Naples Beach Hotel Naples, FL, USA

24 al 25 agosto de 2018

V Simposio Nacional de Crianza y Salud

Armenia Bogotá, Colombia

03 al 08 septiembre de 2018

Congreso-Curso Internacional de Urología

Centro de Convenciones Julio Cesar Turbay Ayala Cartagena, Colombia

17th World Congress on Pain

Boston Convention & Exhibition Center Boston, MA, USA

12 al 16 septiembre de 2018

CONFERENCIA

ANNUAL MEETING ANNUAL MEETING

Tel. 6495352 – 7464706/07 http://plandeactividades.com/eventos/ http://symposiamedicus.org

Sociedad Colombiana de Pediatría

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

Sociedad Colombiana de Urología

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

www.iaspworldcongressonpain.org Asociación Colombiana De Gerontología Y Geriatría (ACGG)

CONFERENCIA

CONGRESO

Tel. 310 699-2532 info@acgh.com.co 26 al 29 septiembre de 2018 21 al 24 octubre de 2018

XV Congreso Colombiano y IX Congreso Internacional de Genética Humana 2018 ASTRO Annual Meeting (American Society for Radiation Oncology)

Hotel Dann Barranquilla, Colombia

Asociación Colombiana De Gerontología Y Geriatría (ACGG)

Henry B. GonzalezConvention Center San Antonio, TX, USA

Astro

Tel. 310 699-2532 info@acgh.com.co www.astro.org

ANNUAL MEETING

Revista Puertorriqueña de Medicina y Salúd Pública

79

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

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

Realizarán los primeros procedimientos de corazones artificiales en Puerto Rico Durante 2018 se protagonizará otro importante capítulo en la historia del Centro Cardiovascular de Puerto Rico, pues colocarán los primeros dispositivos de asistencia ventricular del lado izquierdo del corazón, o los también denominados corazones artificiales.

Rafael Calderón, Cardiólogo.

“Esta será la alternativa para pacientes que no puedan lograr conseguir un corazón para trasplantarlo, bien sea por alguna situación de escasez de corazones, o también, para pacientes que no son candidatos para trasplante de corazón”, explicó el doctor Rafael Calderón, director médico de la Unidad de Cuidado Coronario del Hospital Cardiovascular.

Más información: http://www.medicinaysaludpublica.com/realizaran-los-primeros-procedimientos-de-corazones-artificiales-enpuerto-rico/

Labor de conciencia por los pacientes con Alzheimer en Puerto Rico El Alzheimer es una demencia con impacto tanto en la vida del paciente como en su núcleo familiar, por ello sigue siendo prioridad y un desafío para el país. Esta vez, la alteración neurodegenerativa se presentará a través de una producción cinematográfica Doctor Enrique Vázquez Quintana, expresidente del Colegio puertorriqueña durante el mes de abril, producida de Médicos Cirujanos de Puerto Rico. por el expresidente del Colegio de Médicos Cirujanos, doctor Enrique Vázquez Quintana. “¿Quién eres tú?” se llamará la producción fílmica y de Alzheimer, en este caso, la esposa del doctor Vázquez está acompañado por el libro que contiene la historia de Quintana. una familia compuesta por seis hijos, donde se relatan El filme estará disponible a partir del 19 de abril, en todos los incidentes ocurridos a causa de una paciente los cinemas de Puerto Rico.

Más información: http://www.medicinaysaludpublica.com/labor-de-conciencia-por-los-pacientes-con-alzheimer-en-puerto-rico/ 80

Revista Puertorriqueña de Medicina y Salúd Pública

La medicina puertorriqueña se lucirá en Japón

La vitamina C funciona como cualquier otra medicina

Doctor Humberto Lugo, cirujano pediátrico

Fernando Cabanillas Escalona, director del Centro de Cáncer del Hospital Auxilio Mutuo

Entre los diversos autores de la literatura que hablan sobre el cáncer de tiroides, se destaca el doctor Humberto Lugo, especialista en cirugía pediátrica, formado en las aulas del Recinto de Ciencias Médicas (RCM).

El próximo 13 y 14 de agosto en Japón, el doctor Lugo presentará los avances quirúrgicos en el tumor de tiroides, lo que pondrá en alto el aporte de la medicina puertorriqueña a nivel mundial.

El doctor Cabanillas recalca que la vitamina C es beneficiosa para la salud pero no cuenta con una investigación científica probada en humanos.

También afirmó que sus beneficios se pueden investigar “mediante un estudio aleatorizado donde a la mitad de los pacientes se les suministre la vitamina C y a otros se le da un placebo sin que el paciente sepa lo que está recibiendo. De esa forma no hay ningún prejuicio. Ese tipo de estudio no se ha hecho”.

Más información: http://www.medicinaysaludpublica.com/lamedicina-puertorriquena-se-lucira-en-japon/

Más información: http://www.medicinaysaludpublica.com/lavitamina-c-funciona-como-cualquier-otra-medicina/

FDA aprueba tratamiento de Pfizer contra la artritis psoriásica activa Pfizer anunció un gran avance que beneficia a

Laboratorios Pfizer

pacientes con artritis. Se conoció que la FDA aprobó el uso de Xeljanz 5 mg dos veces al día y Xeljanz XR 11 mg una vez al día (tofacitinib) para tratamiento de adultos con artritis psoriásica activa que no han tenido una buena respuesta o presentaron intolerancia al metotrexato o algún otro tipo de medicamento.

La aprobación se basó en los resultados de los estudios OPAL, que mostraron una respuesta significativamente superior a la de pacientes que recibieron placebo (p&lt;0.05) a los tres meses de tratamiento.

Es importante resaltar que pese a su buena respuesta, hay riesgo de desarrollar una infección.

Más información: http://www.medicinaysaludpublica.com/fda-aprueba-tratamiento-de-pfizer-contra-la-artritis-psoriasica-activa/ Revista Puertorriqueña de Medicina y Salúd Pública

81

Gastroenterólogos se preparan para investigar resistencia de la antibioterapia del H. Pylori

Doctor José Santiago, Gastroenterólogo pediátrico Más información: http://www.medicinaysaludpublica.com/ gastroenterologos-se-preparan-para-investigar-resistencia-dela-antibioterapia-del-h-pylori/

Continúan los nefrólogos el combate clínico de las afecciones renales en la isla

Realizado con éxito el primer trasplante de médula ósea alogénico en paciente con linfoma

José Cangiano, presidente de la Sociedad de Nefrología

Doctor Alexis Cruz Chacón, director del Centro de Trasplante de Médula Ósea del Hospital Auxilio Mutuo

Durante el congreso que se llevó a cabo en San Juan, se resaltaron los desafíos emergentes de la enfermedad crónica renal en Puerto Rico. En el evento se enfatizó sobre los entrenamientos en el avance de herramientas para el diagnóstico de la enfermedad renal, el manejo de la hipertensión y diabetes en esta población, manejo de pacientes renales y diálisis en tiempos de desastre y complicaciones renales de dichas afecciones.

Más información: http://www.medicinaysaludpublica. com/continuan-los-nefrologos-el-combate-clinico-de-lasafecciones-renales-en-la-isla/ 82

La bacteria Helicobacter Pylori sigue constituyendo un reto de salud pública en Puerto debido al aumento de la incidencia del cáncer de estómago en Puerto Rico y de paso, la resistencia mostrada a la antibioterapia.

Según datos del Registro Central de Cáncer de Puerto Rico, para el periodo del 2009 al 2013, el cáncer de estómago fue el noveno cáncer más comúnmente diagnosticado en los hombres, representando un 2.6% de todos los cánceres.

Este escenario clínico de desafío de la bacteria se palpa en la población pediátrica, por lo tanto, prontamente iniciarán protocolos de investigación que de otra parte estudien la resistencia de la bacteria a los antibióticos.

Revista Puertorriqueña de Medicina y Salúd Pública

“Hace dos semanas realizamos el primer trasplante alogénico en un paciente con linfoma agresivo. Su donante fue un hermano 100% compatible. Nunca se había realizado y de ahora en adelante servirá como una nueva alternativa para pacientes con cáncer de linfoma tipo agresivo que muchas veces no responden a quimioterapia. Sería la opción de curar o controlar la enfermedad mediante trasplante alogénico”, declaró el doctor Alexis Cruz Chacón.

Más información: http://www.medicinaysaludpublica.com/ realizado-primer-trasplante-de-medula-osea-en-pacientecon-agresivo-linfoma/

Exitosa primera revisión endoscópica con innovador sistema en paciente bariátrica de Puerto Rico

Carlos Micames y Federico Gregory, gastroenterólogos

Continúan los desafíos de los tumores tipo sarcoma de tejido blando para la oncología científica

Son tumores raros que pueden invadir el hueso o los tejidos blandos del cuerpo, como el cartílago, grasa, músculos, tejido fibroso, entre otros.

Desde las salas quirúrgicas del Hospital Bella Vista de Mayagüez, gastroenterólogos lograron realizar con éxito la primera revisión laparoscópica con el Sistema Overstitch en un paciente con cirugía bariátrica.

El innovador procedimiento figura como la nueva alternativa médica para esta población de pacientes, pues se trata de un sistema que permite revertir la anastomosis.

Los sarcomas constituyen un desafío clínico para la oncología clínica y sobre todo, la medicina primaria, pues estos tumores de tejido blando podrían pasar desapercibidos al ser unas patologías que no presentan dolor y en su mayoría, se comportan de manera agresiva la doctora.

Más información: http://www.medicinaysaludpublica.com/ exitosa-la-primera-revision-endoscopica-con-innovadorsistema-en-paciente-bariatrica-de-puerto-rico/

Más información:http://www.medicinaysaludpublica.com/ continuan-los-desafios-de-los-tumores-tipo-sarcoma-detejido-blando-para-la-oncologia-cientifica/

Uso de famoso ungüento provoca pulmonía en una paciente

¡Somos más de 335.000!

Luis Piñeiro, médico interno del Hospital Auxilio Mutuo

Ungüento a base de mentol y eucalipto, figuró como causante de una pulmonía lipoidea en una paciente de Puerto Rico. Contrario a todos los beneficios contra resfriados, catarros, asma y sinusitis, médicos del Hospital Auxilio Mutuo hallaron que provocó un raro cuadro clínico en mujer de 63 años.

Más información: http://www.medicinaysaludpublica.com/ uso-de-famoso-unguento-provoca-pulmonia-en-unapaciente/

Por más de 12 años MSP sigue posicionada como la primera revista impresa con lo último en información científica

Más de 335.000 personas encuentran en la Revista de Medicina y Salud Pública los últimos avances y logros del campo científico.

La invitación es a seguir haciendo parte de #MedicinaySaludPública #MSP Más información: www.facebook.com/revistamsp Revista Puertorriqueña de Medicina y Salúd Pública

83

Endocrinólogos advierten aumento de casos de tiroides en la isla

Luis Ruiz Rivera, presidente de la Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED) realizó un llamado a la ciudadanía a realizarse la prueba de sangre TSH que mide la cantidad de la hormona estimulante del tiroides para la detección de hipotiroidismo o hipertiroidismo temprano debido al elevado aumento de casos que se vienen presentando. http://www.medicinaysaludpublica.com/endocrinologosadvierten-aumento-de-casos-de-tiroides-en-la-isla/

84

Las mujeres que lideran la ciencia en Puerto Rico

Este grupo de mujeres ha puesto el nombre de Puerto Rico en alto gracias a sus valiosos aportes en el campo de la investigación científica y clínica realizada en laboratorios boricuas, ellas son las doctoras Marcia Cruz, Carmen Zorrilla, Idhaliz Flores, Bárbara Rosado, Kenira Thomson y Michelle Martínez.

Resaltamos también las labores académicas y clínicas de las doctoras Yocasta Brugal, patóloga molecular y presidenta de la Escuela de Medicina San Juan Bautista de Caguas; Olga Rodríguez, pediatra y decana de la Escuela de Medicina de la Ponce Health Science University y recientemente, celebramos la ocupación de la doctora Waleska Crespo como presidenta de la Universidad Central del Caribe en Bayamón (UCC).

Más información: http://www.medicinaysaludpublica.com/lasmujeres-que-lideran-la-ciencia-en-puerto-rico/

Evoluciona el campo de la cirugía ortopédica en Puerto Rico

Cerco a las trombosis en los pacientes con cáncer

Ariel Dávila, cirujano ortopedista

Las trombosis venosas son un problema mayúsculo entre las personas que sufren cáncer

La cirugía ortopédica en Puerto Rico continúa solidificando sus cimientos en el escenario quirúrgico con modalidades que buscarán que los pacientes tengan intervenciones de mayor rigurosidad.

Esa es la labor del doctor Ariel Dávila, quien este año llegó como el único cirujano ortopeda subespecializado en preservación de caderas.

La segunda causa de mortalidad en pacientes oncológicos son los accidentes vasculares, que afectan a uno de cada cinco. Para evitarlos se aplican anticoagulantes que pueden provocar hemorragias graves. Por eso, el reto médico es identificar qué individuos tienen mayor probabilidad de sufrir trombos.

Más información: http://www.medicinaysaludpublica.com/ evoluciona-el-campo-de-la-cirugia-ortopedica-en-puertorico/

Más información: http://www.medicinaysaludpublica.com/ cerco-a-las-trombosis-en-los-pacientes-con-cancer/

Revista Puertorriqueña de Medicina y Salúd Pública

Hacen llamado para educar sobre importancia de detectar a tiempo la endometriosis

Debaten los candidatos a la presidencia del Colegio de Médicos Cirujanos de Puerto Rico

La endometriosis ocurre cuando el endometrio, el tejido que recubre el útero, crece fuera de este órgano

El presidente de PROGyn, Nabal Bracero, informó que la endometriosis ocurre en cerca de 5 millones de mujeres en Estados Unidos y agregó que la prevalencia en Puerto Rico es de un 4% (1 de cada 25 mujeres).

De igual modo, explicó que “El diagnóstico y tratamiento temprano pueden ayudar a manejar los síntomas de la enfermedad”.

Más información: http://www.medicinaysaludpublica.com/ hacen-llamado-para-educar-sobre-importancia-de-detectara-tiempo-la-endometriosis/

Dr. Víctor Ramos Otero (A la izquierda) Dr. Carlos Mellado López (A la derecha)

La impericia médica, la situación con las aseguradoras, el éxodo de médicos y la necesidad de un mejor plan universal de salud, fueron los principales temas de discusión en el debate para la presidencia del Colegio de Médicos Cirujanos de Puerto Rico Más información: http://www.medicinaysaludpublica.com/ debaten-los-candidatos-a-la-presidencia-del-colegio-demedicos-cirujanos-de-puerto-rico/

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

Inauguración Centro de la Mujer

En el marco del Día Internacional de la Mujer, el Centro Comprensivo de Cáncer (CCC) inauguró el Centro de la Mujer, un espacio único con la tecnología más avanzada para el diagnóstico del cáncer de mama.

Este servicio está disponible para el público general desde el 15 de marzo de 2018 y será el primero dentro del nuevo Hospital del CCC, que continuará abriendo servicios en los próximos meses.

El Centro de la Mujer cuenta con dos máquinas de mamografías digital con herramientas de oncología diagnóstica que permiten realizar imágenes con contraste y en 3D por tomosíntesis. También, se podrán realizar biopsias y sonomamografías, entre otros servicios.

Más información: http://www.medicinaysaludpublica.com/centro-comprensivo-de-cancer-inaugura-centro-de-imagenes-para-dardiagnostico-temprano-a-cancer-de-mama/ Revista Puertorriqueña de Medicina y Salúd Pública

85

Dr. Víctor Ramos: El joven que se convirtió en pediatra y en Presidente del Colegio de Médicos Cirujanos de Puerto Rico

E

l Doctor Ramos, natural de Vega Baja, supo desde muy temprano que iba a ser médico y escogió ser Pediatra. Desde muy temprano también, tuvo una gran conciencia social que heredó de su madre y sus tíos. Como estudiante sobresalió por su aprovechamiento académico y por su activismo a los organismos estudiantiles.

Fue miembro de la Junta Estudiantil Nacional en el Senado Académico, cuando se gestó el primer paro estudiantil en el Recinto de Ciencias Médicas. Posteriormente pertenece a la MUPE, el Movimiento Universitario Pro Estadidad. Su activismo continuó mientras ya ejercía su profesión al participar en el movimiento Todo Puerto Rico con Vieques, para el cese de los bombardeos en la isla municipio y la salida de la Marina.

Su experiencia y liderato lo ayudó a

86

Revista Puertorriqueña de Medicina y Salúd Pública

convertirse en el 2014, en el Presidente del Colegio de Médicos Cirujanos de Puerto Rico más joven de su historia y revalidó dos años más tarde a un segundo término.

Pertenece al Colegio desde el 2002 y ha sido su Tesorero, Secretario y Presidente del Senado Médico. Durante su incumbencia logró la inauguración de una nueva sede del Colegio de Médicos Cirujanos, ubicada en la Avenida Muñoz Rivera en Río Piedras y gesta la creación de un plan médico, donde los médicos también puedan ser inversionistas.

Hoy el doctor Ramos deja su nombre en la historia de la medicina en Puerto Rico no tan solo por haber sido electo su presidente más joven sino también por ser el primero en lograr la victoria en tres ocasiones consecutivamente.

www.bestoptionpr.com www.bestoptionpr.com

Cuando necesites necesites la la mejor Farmacia Cuando Farmacia Especializada Especializada paramanejar manejar tu tu condici贸n, condici贸n, recuerda recuerda que para que somos, somos, tu tu mejor mejoropci贸n opci贸n