Revista Medicina y Salud Pública (MSP)

LXXII Año XI 2018

Reacciones

Dermatológicas a causa del uso de medicamentos Actualización en Hidradenitis Supurativa aspectos terapéuticos

Psoriasis

Eficiencia de los nuevos tratamientos

Avances en el

tratamiento contra

la caída de cabello una perspectiva dermatológica

@revistamsp

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Symptom relief in as little as

for nearly 6 out of 10 people

RENFLEXIS® (infliximab-abda)

for injection, for intravenous use 100 mg

RENFLEXIS® (infliximab-abda)

for injection, for intravenous use 100 mg

D

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

urante el transcurso de nuestras vidas tendremos que firmar muchos contratos. Como por ejemplo, el contrato de arrendamiento de un apartamento, el préstamo de un auto, un contrato de empleo y hasta la hipoteca de nuestro primer hogar. Sin embargo, durante la planificación financiera tenemos que evaluar y firmar muchos contratos de productos financieros que, en los momentos más cruciales, podrían ayudarnos o perjudicarnos si no prestamos atención a “las letras pequeñas”.

Cuando concretamos un contrato, estos incluyen los costos de manejo y en ocasiones, costos internos administrativos de los productos que, en múltiples ocasiones, se incrementan gradualmente y provocan una erosión en nuestras ganancias.

Los contratos también pueden incluir posibles cláusulas de penalidad a la hora de retiro prematuro y endosos muy costosos, que benefician más a las compañías que a los mismos individuos, que son quienes más lo necesitan. Es por esto que en el momento más crucial, necesitamos que nuestros contratos estén a nuestro favor y no, en nuestra contra.

Por tal razón, las hojas de trabajo sobre lo pactos escritos son interesantes y requieren pensamiento. Sin embargo, realizar un buen análisis de un contrato, entender su lenguaje, términos y condiciones así como entender las estrategias financieras que trae consigo, será la diferencia entre el éxito y las sorpresas que puedan surgir a la hora de tomar una decisión de futuro.

Basado en una experiencia de 16 años y con un amplio peritaje en análisis de contratos, exhortamos a exigir a los profesionales de servicios financieros que le presenten todas las opciones existentes, siempre con un enfoque educativo encaminado a trabajar en las metas trazadas a corto, mediano y largo plazo.

En Trust MD, nuestros clientes reciben de manera gratuita un análisis profundo financiero el cual incluye una radiografía financiera y análisis de “cash flow”. De esta manera nos asegurarnos que se cumplan todos los objetivos.

Para más información, puede llamarnos al 787-507-2237 ó 7875 07-2236. También puede escribirnos un correo electrónico a info@trustmdcorp.com.

www.trustmdcorp.com

CONTENIDO 32

Melanoma cutáneo (MC): diagnóstico y tratamiento en la actualidad médica

12

Reacciones dermatológicas a causa del uso de medicamentos

76

Lo último sobre “gluten-free” y enfermedad celíaca

23

Actualización en hidradenitis supurativa: aspectos terapéuticos

89

Síndrome Metabólico

28

Psoriasis: eficiencia de los nuevos tratamientos

101

El sistema inmunitario y las alergias

36

Avances en el tratamiento contra la caída del cabello: una perspectiva dermatológica

114

La voluntad del paciente, la eutanasia y el suicidio médicamente asistido

48

Infografía cáncer de próstata en Puerto Rico

136

54

Análisis de supervivencia en pacientes diagnosticados con cáncer de pulmón y bronquios durante el periodo 2008 - 2012 en Puerto Rico

Noticias de medicina ysaludpublica.com

142 A ciencia cierta

Comité Editorial Científico

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

COMITÉ EDITORIAL

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

PRINCIPAL OFICIAL EJECUTIVA

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PROPIEDAD

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Revista Puertorriqueña de Medicina y Salúd Pública

VICTOR RAMOS Presidente del Colegio de Médicos Cirujanos de Puerto Rico.

Nuevas leyes fortalecen la labor de los médicos puertorriqueños Recientemente el gobernador de Puerto Rico, Ricardo Rosselló Nevares, estampó su firma en dos leyes relacionadas la impericia médica y al trabajo voluntario durante temporadas de emergencia.

Una es sobre los periodos de emergencia, incluido el huracán María. Esta ley dispone que los que realizaron trabajo voluntario y no cobraron por ello, tienen inmunidad ante demandas. Esto aplica tanto a los voluntarios extranjeros como a los voluntarios puertorriqueños que llegaron a las distintas comunidades durante el período de emergencia que dejó el huracán. La ley será aplicada en situaciones futuras, cuando el gobernador (a) declare el estado de emergencia en la isla.

En esa misma ley se especifica que, para los que practicaron trabajos en condiciones subóptimas desde el 17 de septiembre del año pasado hasta el 31 de diciembre, solo podrán hacer reclamaciones por el valor de los topes del Estado. El Estado otorga unos topes especiales durante el período de emergencia, acción que también se llevará a cabo en emergencias posteriores.

Esta ley ha sido aprobada durante el periodo de emergencia del huracán Katrina en los Estados Unidos.

La segunda ley aprobada busca frenar demandas frívolas, a través de paneles de impericia médica. Para verificar la veracidad de una demanda, se establecerá un comité compuesto por un abogado, un profesional de la salud y un representante del interés público que evaluarán los méritos. Estos paneles no sólo convienen a los médicos para reducir demandas, sino que también conviene a los pacientes que tienen casos de negligencia real, porque probablemente va a recibir una compensación en cuestión de meses y no en años como es ahora.

Aún así, quedan dos leyes pendientes que son muy importantes para los médicos puertorriqueños. Una es

la P. 841 del Senado y la otra, P. 1546 de la Cámara de Representantes.

Las aseguradoras están peleando la ley l P. 841, porque ahora mismo se han cancelado alrededor de 3000 contratos de médicos sin causa desde el año 2014.

Esa ley dispondría que no se puede hacer eso.

Por su parte, la P. 1546 establece que organizaciones de servicios de salud no podrán denegar la solicitud de un médico para convertirse en proveedor de la misma, siempre y cuando éste cumpla con los requisitos necesarios para ejercer la profesión médica y esté autorizado por las entidades competentes a proveer servicios de cuidado de salud.

Esto beneficia a todo el mundo, pero mayoritariamente a los médicos jóvenes, a quienes chantajean las aseguradoras con el argumento de contrato rápido por un menor tiempo de trabajo. Es inaceptable que esto siga pasando a los que salen de la escuela con una deuda que puede ascender hasta un cuarto de millón de dólares, no les den contratos para trabajar y los jóvenes tengan que emigrar de Puerto Rico.

Más allá de la nueva legislación, un evento para destacar es la participación en múltiples conferencias de cerca de 4000 médicos en la convención anual del Colegio de Médicos Cirujanos de Puerto Rico, acontecimiento que se extendió durante todo el fin de semana y del que también hizo parte el gobernador con una ponencia científica sobre la importancia de las células madre para la medicina actual. Todos los que participaron se sintieron satisfechos con la presentaciones y las actividades que sirvieron para confraternizar con otros colegas, aproximadamente 600 provenientes de Estados Unidos. Los asistentes quedaron satisfechos con las conferencias, exhibidores y actividades.

Revista Puertorriqueña de Medicina y Salúd Pública

11

MSP ARTÍCULO ORIGINAL

Reacciones

dermatológicas

a causa del uso de medicamentos Por: Rocío Mandry Pagán, MD, FAAD Dermatóloga Egresada de la Universidad de Pennsylvania, Philadelphia Graduada de Medicina en Columbia University College of Physicians and Surgeons Residencia en Medicina Interna en Columbia U Medical Center Residencia de Dermatología en el Recinto de Ciencias Médicas, Río Piedras Facultativa en el Departamento de Dermatología UPR Práctica privada en Guaynabo desde hace más de 20 años en medicina dermatológica general y quirúrgica Dermatóloga cosmética

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Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Resumen Se ha estimado que 1-2% de los tratamientos médicos pueden verse asociados a reacciones adversas por medicamentos. Algunos fármacos, tales como las penicilinas y la sulfa, tienen un mayor potencial de causar reacciones dermatológicas y/o sistémicas.

También es importante reconocer que ciertos pacientes, como aquellos infectados con VIH, son más propensos a desarrollar erupciones por drogas o a exacerbaciones de sus condiciones de la piel debido al uso de ciertas medicinas.. Una reacción por medicamento se debe considerar en cualquier paciente que presente una erupción simétrica mientras se le esté administrando una droga o hasta aproximadamente 2 semanas después de haber terminado un fármaco. Algunos medicamentos también pueden agravar condiciones existentes de la piel, como sucede por ejemplo con la psoriasis, que es agravada por B-bloqueadores y por interferón. Además, algunas drogas pueden causar reacciones que imitan condiciones dermatológicas, tales como: el acné, el lupus, la dermatomiositis o el liquen plano.

Abstract It has been estimated that 1 - 2% of medical treatments could be associated with adverses drug reactions. Some medicines, as penicilins and sulfas have a greater potential to cause dermatological or systemical reactions in the body. Also, it is important recognize that certain patients - such as those infected with HIV, are more likely to develop drug rash or exacerbations of their skin conditions due to medications. A reaction to medications should be considered in any patient who has a symmetric rash while a drug is being administered or until approximately 2 weeks after a medication has been completed.Some medications can also aggravate existing skin conditions, as for example with psoriasis, which is aggravated by B-blockers and interferon. In addition, some drugs can cause reactions that mimic dermatological conditions, such as: acne, lupus, dermatomyositis or lichen planus.

Palabras clave: Dermatología, Reacciones Dermatológicas, Efectos secundarios, Administración de fármacos.

Keywords: Dermatology, Skin Reactions, Secondary effects, Drugs administration

Revista Puertorriqueña de Medicina y Salúd Pública

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MSP ARTÍCULO ORIGINAL

"Se ha estimado que 1-2% de los tratamientos médicos pueden verse asociados a reacciones adversas por medicamentos"

E

ntrar en los detalles de las múltiples posibles reacciones dermatológicas asociadas a medicamentos sería una labor inmensa que no estaría al alcance de esta publicación.

Por lo tanto, nos concentraremos en aquellas reacciones asociadas a me d ic a ment o s u s a do s comúnmente en la práctica médica que pueden causar consecuencias adversas en los pacientes o reacciones diversas que vale la pena reconocer.

Entre las reacciones de la piel asociadas a medicamentos sistémicos, recalcaremos las reacciones de fotosensitividad, las reacciones ampollosas y las reacciones que imitan condiciones dermatológicas primarias.

Las reacciones fotosensitivas se dividen entre aquellas de fototoxicidad, que se presentan como una quemadura, y las de fotoalergia, parecidas a una dermatitis de contacto con cambios eccematosos.

Las reacciones fototóxicas son mucho más comunes. También se observan reacciones liquenoides parecidas al liquen plano o reacciones tipo lupus eritematoso causadas por la exposición al sol en asociación al uso de algún medicamento sensitizante.

Tal vez el medicamento más importante en este grupo, debido a su uso extremadamente común, es la hidroclortiazida. Las tiazidas se asocian clásicamente con

14

Revista Puertorriqueña de Medicina y Salúd Pública

fotosensitividad. Recientemente se ha asociado su uso con una mayor predisposición a cáncer de la piel. Un estudio en la población danesa investigó la incidencia de cáncer de la piel en sujetos entre los años de 1989 a 2003, analizando a su vez los medicamentos que recibían y sus condiciones de salud. Se demostró que el uso de diuréticos -en particular las tizidasaumentaba el riesgo a desarrollar cáncer escamoso y en menor escala melanoma maligno, sobre todo en pacientes que llevaban 6 años o más en estos medicamentos. El riesgo a desarrollo de cáncer de la piel era dependiente de las dosis usadas y del tiempo de uso. Se concluye en dicho estudio que cada paciente que comience tratamiento con diuréticos debe observar protección solar rutinaria, e implementar el uso de bloqueador solar de amplio espectro con factor de protección solar (SPF, por sus siglas en inglés) de 30 o mayor. Dichos pacientes deben referirse a cernimientos de piel por un dermatólogo anualmente.

Las tiazidas también se pueden asociar con reacciones cutáneas parecidas al lupus, especialmente en su presentación subaguda con lesiones escamosas, pruríticas, anulares o psoriasiformes en áreas expuestas al sol. Otros medicamentos que se asocian con menor frecuencia al desarrollo de lupus subagudo y con fotosensitividad son los bloqueadores de canales

de calcio (diltiazem), inhibidores de angiotensina (captopril) y antifungales como la griseofulvina y la terbinafina. Aunque no es común, las estatinas, tales como, atorvastatin y simvastatina, también se han reportado como causantes de enfermedades autoinmunes, mayormente de lupus subagudo.

E stos pac ientes present a n normalmente ANA positivo y el anticuerpo anti-Ro positivo en su serología.

Finalmente, las tiazidas también se han asociado con enfermedades ampollosas con fotosensitividad como la pseudoporfiria cutánea tarda. La pseudoporf iria se manifiesta con ampollas en el dorso de las manos que aparecen después de una exposicisión al sol en un paciente que haya tomado el medicamento fototóxico. En contraste a la porfiria cutánea, De hecho, esta condición no se asocia con anormalidades en las porfirinas, ni con fallo hepático.

La pseudoporf iria se asocia más comúnmente con el uso de naproxeno.

Muchos med icamentos recetados con frecuencia tienen el potencial de causar enfermedades ampollosas, pudiendo ser reacciones extremadamente serias. Se catalogan como eccematosas, pustulosis exantematosa generalizada aguda, erupción fija por medicamento, eritema multiforme/ StevensJohnson/ necrólisis tóxica epidermal

MSP ARTÍCULO ORIGINAL

Penfigoide ampolloso, amlopidine

(TEN), pénf igo y penf igoide, dermatosis lineal por inmunoglobulina A (IgA) y pseudoporfiria cutánea tarda (PCT). La mayor parte de estas reacciones resultan por inflamación generada por una respuesta inmunológica. Es importante reconocer los medicamentos más comúnmente asociados a reacciones ampollosas de la piel.

Por el contrario, las pustulosis exantematosas se asocian a antibióticos B-lactams, macrólidos y quinolonas, furosemida, antiinf lamarorios no esteroidales, bloqueadores de canal de calcio como diltiazem. La reacción consta de una erupción aguda con zonas extensas de enrojecimiento y pústulas estériles generalizadas que ocurre usualmente 5 días después del comienzo del medicamento

asociado, nor ma l mente un antibiótico. Puede asociarse con fiebre y malestar, elevación de glóbulos blancos y dolor en la piel. Una vez el medicamento es removido, el paciente recupera con descamación de la piel en unas 2 semanas. El tratamiento es sintomático.

Las erupciones fijas medicamentosas se asocian con aspirina, barbitúricos, tetraciclinas, diazepam, fenolftaleina, sulfas y azoles (fluconazole). Estos casos se manifiestan con placas rojizas con centros grisáceos en áreas definidas de la piel. Dichas placas se presentan siempre en los mismos lugares y pueden ampollar en el centro, especialmente si el paciente ha sido expuesto a la misma droga varias veces. Estas lesiones usualmente se asocian a un medicamento recetado o “OTC” que el paciente toma esporádicamente. Hay que tomar un historial extenso, incluyendo remedios caseros, para identificar el medicamento causante y evitarlo. De no ser así, cada vez la erupción será más severa y habrá más lesiones.

El er itema mu l t i fo r m e mayormente se asocia con agentes infecciosos, tales como, herpes simplex o micoplasma, pero Stevens-Johnson/TEN se asocia comúnmente con varios medicamentos. Entre ellos resaltan los antibióticos (sulfonamidas, pen ic i l i n a s , cefa los por i n a s , c l or a n fe n i c o l , macról idos, quinolonas, griseofulvina, rifampin, tetraciclinas), antiinf lamatorios

no esteroidales, anticonvulsivantes (fenobarbital, carbamazepina, fen itoi n), a nt i h iper ten s ivos , alopurinol. Hoy en día se estima que el Stevens-Johnson y el TEN pueden ser dos polos de un espectro de reacción descamativa inmune severa. En el caso de TEN, la morbibilidad y mortalidad son más altas pues se asocia a un grado más alto de pérdida de la epidermis, y por tanto, a más complicaciones como sepsis. Obviamente el paso más importante en el cuidado de estos pacientes es la remoción inmediata del medicamento causante, seguido por cuidado sintomático y de soporte, preferiblemente en una unidad de quemados.

El pénf igo es una erupción ampollosa autoinmune que puede asociarse con exfoliación extensa de la piel y mucosas. Aunque usualmente ocurre de forma espontánea, la condición también puede ocurrir relacionada al uso de drogas con un grupo tiol, tales como amoxicilina, cefalosporinas y captopril. El penfigoide ampolloso, donde las ampollas se asocian con ronchas eritematosas y prurito severo, también es de origen autoinmune y puede ser inducida por medicamentos. En este caso la droga causante más común es la furosemida, pero también puede asociarse al uso de penicilinas, bloqueadores beta, y terbinafina.

La dermatosis lineal por IgA es otra condición autoinmune ampollosa que puede ser secundaria

Revista Puertorriqueña de Medicina y Salúd Pública

15

MSP ARTÍCULO ORIGINAL

MUCHOS DE LOS MEDICAMENTOS QUE USAMOS A DIARIO TIENEN EL POTENCIAL DE CAUSAR EFECTOS CUTÁNEOS O ERUPCIONES EN LA PIEL.

al uso de drogas -principalmente vancomicina- aunque también se ha asociado con el uso de litio, fenitoina, diclofenac, captopril y penicilinas.

Reacciones usualmente no ampollosas, pero con potencial a serlo, tales como el liquen plano o reacciones liquenoides, pueden verse asociadas al uso de drogas, pa r t icu la r mente i n h ibidores de angiotensina, pero también bloqueadores beta, diuréticos, y antiinf lamatorios no esteroidales, entre otros.

Aparte de las erupciones ya mencionadas, hay varias condiciones dermatológicas que se presentan o se exacerban cuando el paciente se expone a ciertos medicamentos. A continuación, se detallan algunas asociaciones que debemos tener en mente antes de escoger la terapia más adecuada para nuestros pacientes.

• Reacciones acneiformes:

complejos vitamina B, corticosteroides • Ulceraciones de la mucosa: metotrexato • Necrosis cutánea: warfarina.

• Vasculitis: alopurinol, antiinflamatorios no esteroidales, penicilinas.

• Eritema nodoso: sulfonamidas, pastilla anticonceptiva, estrógenos .

• “Serum sickness”: cefaclor, minociclina, penicilinas, propranolol.

• Melasma: quinolonas, minociclina, tiazidas.

• Lupus: hidralazina, agentes fototóxicos/fotoalérgicos (ver discusión arriba).

• Dermatomiositis: 16

Revista Puertorriqueña de Medicina y Salúd Pública

antiinflamatorios no esteroidales, d-penicilamina, fenilbutazone, estatinas.

• Escleroderma: bleomicina.

• Psoriasis: interferón, bloqueadores beta, litio, antiinflamatorios no esteroidales, terbinafina En conclusión, cuando un paciente se presenta con una erupción aguda o con el desarrollo nuevo o la exacerbación de una condición de la piel, nunca debemos descartar la posibilidad de una reacción a drogas. Muchos de los medicamentos que usamos a diario tienen el potencial de causar efectos cutáneos o erupciones en la piel.

Es nuestro deber reconocer estas asociaciones y evitar complicaciones en nuestros pacientes. En algunos casos, como el TEN, diagnosticar el paciente correctamente y remover el agente nocivo con premura puede ser la diferencia entre la vida y la muerte.

Referencias

Roujeau JC, Stern RS. Severe adverse cutanous reactions to drugs. N Engl J Med 1994; 331:1272 Hong J, Bernstein D. A review of drugs that induce or exacerbate psoriasis. Psoriasis Forum 2012; 18(1):1-10 Zhang A, Elston D. Drug induced photosensitivity. Emedicine.medscape. com/article/1049648-overview,2018 Jensen AØ, Thomsen HF, et al. Use of photosensitizing diuretics and risk of skin cancer: a population based case-control study. Br J Cancer. 2008 Nov 4; 99(9): 152228ó Ahronowitz I, et al. Severe drug-induced dermatoses. Semin Cutan Med Surg. 2014 Mar; 33(1):49-58 Smith JD. Drug-induced skin disorders. US Pharm 2012(4): 23

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80 mg/mL

MOVING. TOUCHING. MOMENTS. Taltz is indicated for adults with active psoriatic arthritis (PsA).

Taltz is also indicated for adults with moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

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

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

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

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

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

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

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

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

IX HCP ISI 01DEC2017 References: 1. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018. 2. Nash P, Kirkham B, Okada M, et al; on behalf of SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet.

2017;389:2317-2327. 3. Mease PJ, van der Heijde D, Ritchlin CT, et al; on behalf of SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase 3 trial SPIRIT-P1. Ann Rheum Dis. 2017;76(suppl):1-30.

IN PATIENTS WITH PSORIATIC ARTHRITIS

Taltz provided powerful improvement in joint symptoms at week 241 EVEN IN THOSE WHO FAILED/WERE INTOLERANT TO 1 OR 2 TNFis SPIRIT-P1 (BIOLOGIC-NAIVE): ACR RESPONSE RATES AT WEEK 24, NRI*

58 ACR20

%

vs 30%

40 ACR50

%

vs 15%

23 ACR70

%

vs 6%

SPIRIT-P2 (TNFi-EXPERIENCED): ACR RESPONSE RATES AT WEEK 24, NRI†

53 ACR20

%

vs 20%

Taltz

Placebo

35 ACR50

%

vs 5%

22 ACR70

%

vs 0%

*Taltz 80 mg every 4 weeks n=107; placebo n=106. †Taltz 80 mg every 4 weeks n=122; placebo n=118.

Primary endpoint=ACR20 response at week 24. Inadequate responders (<20% improvement in tender and in swollen joint counts) at week 16 were analyzed as nonresponders after week 16 until the primary endpoint. Nonresponder imputation (NRI) of intent-to-treat population through week 24.1

Taltz helped stop the progression of joint damage at week 16 vs placebo1 In SPIRIT-P1 (biologic-naive), adjusted mean change from baseline in mTSS at week 16 was 0.13 for Taltz vs 0.36 for placebo* Inhibition of progression of structural damage was assessed radiographically and expressed as the adjusted mean change in mTSS and its components, the joint space narrowing score and bone erosion score, at week 16 vs baseline. The mTSS score was modified for psoriatic arthritis by addition of hand distal interphalangeal (DIP) joints.1 SPIRIT-P2 (TNFi-experienced) did not include an assessment of radiographic progression.2 Taltz 80 mg every 4 weeks n=107; placebo n=106.

SPIRIT-P1 AND -P2 TRIAL DESIGN SPIRIT-P1 (N=417) and SPIRIT-P2 (N=363) were phase 3, randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of Taltz compared with placebo in patients with active psoriatic arthritis. Patients in SPIRIT-P1 were biologic-naive. Patients in SPIRIT-P2 were tumor necrosis factor inhibitor (TNFi)-experienced, having had an inadequate response and/or intolerance to 1 or 2 prior TNFis. In both trials, the primary efficacy endpoint was the proportion of patients achieving ACR20 response at week 24. All patients were ≥18 years of age and had ≥3 swollen and ≥3 tender joints. Patients were randomized to placebo or Taltz 80 mg every 2 or 4 weeks following a 160 mg starting dose. In SPIRIT-P1, an active reference arm of adalimumab 40 mg every 2 weeks was included. Patients in all study arms were allowed to continue taking stable background medications during the trial. Inadequate responders (as defined by blinded criteria of <20% improvement in tender and in swollen joint counts) at week 16 received rescue therapy and were analyzed as nonresponders after week 16 until the primary endpoint. After receiving rescue therapy, inadequate responders in the placebo and adalimumab arms were re-randomized to Taltz 80 mg every 2 or 4 weeks. Nonresponder imputation (NRI) methods were used for categorical efficacy analyses during the double-blind treatment period.1-3

Learn more about The Taltz Clear Access Program, which helps assure access so your commercially insured patients can confidently get Taltz.‡ Visit taltzsavings.com Government beneficiaries excluded. Terms and conditions apply.

‡

Taltz® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries and affiliates.

PP-IX-US-1919 06/2018 ©LILLY USA, LLC 2018. ALL RIGHTS RESERVED.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

163 (14)

23 (8)

101 (13)

23 (2) 17 (2)

1 (<1) 0

5 (1) 1 (<1)

Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection.

U.S. approved etanercept.

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

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

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

Taltz® (ixekizumab) injection

IX HCP BS 01DEC2017

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

Plaque Psoriasis Population

By Week 12, approximately 9% of subjects treated with Taltz every 2 weeks developed antibodies to ixekizumab. Approximately 22% of subjects treated with Taltz at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response.

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

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

The detection of antibody formation is highly dependent on the sensitivity and speciicity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be inluenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Taltz across indications or with the incidences of antibodies to other products may be misleading.

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

Immune system disorders: anaphylaxis (Contraindications and Warnings and Precautions) Taltz® (ixekizumab) injection

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ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: t *OGFDUJPOT (Warnings and Precautions) t )ZQFSTFOTJUJWJUZ 3FBDUJPOT (Contraindications and Warnings and Precautions) t *OþBNNBUPSZ #PXFM %JTFBTF (Warnings and Precautions) Clinical Trials Experience—Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not relect the rates observed in practice.

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

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

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

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

Specific Adverse Drug Reactions: Injection Site Reactions : The most frequent injection site reactions were erythema and pain. Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of Taltz.

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

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

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

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

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

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

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

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

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

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

T:8.5”

DRUG INTERACTIONS Live Vaccinations—Avoid use of live vaccines in patients treated with Taltz (Warnings and Precautions).

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

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

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

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

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

Ixekizumab crossed the placenta in monkeys.

In a pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week).

These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical signiicance of these indings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age.

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

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

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

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

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

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

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

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

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

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

IX HCP BS 01DEC2017 Taltz® (ixekizumab) injection

IX HCP BS 01DEC2017

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

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En el campo de la neurociencia, estamos trabajando en conjunto con colaboradores, entre ellos investigadores de renombre, centros académicos, colegas en la industria y pacientes, hacia nuestra meta de descubrir y desarrollar terapias novedosas y transformativas para algunas de las condiciones neurodegenerativas más difíciles de tratar, como la enfermedad de Alzheimer, la esclerosis múltiple y la enfermedad de Parkinson.

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PERSONAS. PASIÓN. POSIBILIDADES. ©2017 AbbVie North Chicago Il 60064 31A-1926616 Septiembre 2017 Impreso en EE.UU.

MSP ARTÍCULO DE REVISIÓN

Actualización en hidradenitis supurativa: aspectos terapéuticos Por: Luis Ortiz Espinosa, MD, FAAD Dermatólogo

Palabras claves: Hidradenitis Supurativa, Oclusión Folicular, Citoquinas Proinflamatorias, Secuelas, Comorbilidades, Biológicos

Keywords: Hydradenitis Suppurativa, Follicular Occlusion, Pro Inflammatory Citokines, Sequels, Comorbilities, Biologics Resumen: La hidradenitis supurativa es una condición crónica inflamatoria que principalmente afecta las áreas ricas en glándulas apocrinas. Clínicamente va a presentar nódulos, abscesos, tractos o fístulas que drenan un fluido maloliente. Con el tiempo las lesiones producen cicatrización excesiva que puede llevar a contracción y fibrosis. Su origen es multifactorial incluyendo factores genéticos, hormonales e inmunológicos.

Una gran variedad de alternativas de tratamiento y manejo que se han utilizado son: antibióticos tópicos y sistémicos, manejo hormonal, inmunodepresores y métodos quirúrgicos, entre las opciones. Recientemente el uso de biológicos se ha añadido al armamentario de tratamientos trayendo un nuevo interés en la investigación y manejo de tan importante condición que afecta física, emocional y socialmente a los que la padecen.

Director Médico, NOVADERM Presidente de la Fundación Puertorriqueña para el Mejoramiento de la Dermatología

Abstract: Hidradenitis Suppurativa is a chronic inflammatory condition of the apocrine-rich areas of the skin.

Clinically presents with nodules, abscess and tracts that drains a purulent, foul smelling discharge. Eventually, excessive cicatrization and inflammation developed on affected areas that can results in diffuse scarring, contraction and fibrosis. The exact etiology is still unproven, but it is known that is multifactorial including genetic, hormonal and inmunobiological factors. A wide variety of treatment alternatives have been used in the management of the Hidradenitis Suppurativa.

Among these alternatives are topical and systemic antibiotics, hormonal treatment, inmunosupressors and surgical methods. Recently the use of a new medication called Biologics has been added to the treatment armamentarium. That brings a new interest in the research and management of this condition that affect physically and emotionally the people who suffers it.

Revista Puertorriqueña de Medicina y Salúd Pública

23

MSP ARTÍCULO DE REVISIÓN

La hidradenitis supurativa también conocida como acné inversa, es una cond ición crónica inf lamatoria que afecta primariamente las áreas ricas en glándulas apocrinas en el cuerpo. Ésta va a presentar nódulos, abscesos, tractos o fístulas que drenan un f luido purulento maloliente. Con el tiempo, las lesiones producen cicatrización excesiva que puede conducir a contracción, desfiguración y la posibilidad de desarrollar cáncer de piel del tipo escamoso en el área afectada. A parte del efecto físico, la calidad de vida y estima propia del paciente se ven grandemente laceradas.

La hidradenitis supurativa hasta hace poco tiempo se mantenía como una enfermedad huérfana que pocos prestaban atención, y cada cual manejaba de acuerdo a su criterio propio. Sin embargo, recientemente con el advenimiento de nuevas terapias que pueden ayudar en ésta importante condición, un nuevo interés se ha levantado para entender y tratar más efectivamente 24

Revista Puertorriqueña de Medicina y Salúd Pública

la hidradenitis supurativa.

En cuanto a la historia natural de la condición, se estima que la prevalencia fluctúa entre un 0.1% a un 4.0% de la población general con una preponderancia en el sexo femenino y sin predilección racial.

Mayormente aparece después de la pubertad en la segunda y tercera década de la vida con algunos casos en niños y envejecientes. La causa de la hidradenitis supurativa no se ha podido descifrar por completo, pero se sabe qué factores genéticos y ambientales tienen mucho que ver.

Dentro de estos factores, se ha visto historial familiar en un 30-40% de los casos. Hábitos como el fumar, el sobrepeso y desórdenes hormonales también se han identificado como factores de riesgo.

El curso de la enfermedad es uno prolongado con periodos de actividad y remisión alternados.

Los signos y síntomas que presenta la hidradenitis supurativa son múltiples y se basan principalmente en el problema de inf lamación, oclusión folicular e infección secundaria que ocurre. El proceso

LA HIDRADENITIS SUPURATIVA TAMBIÉN CONOCIDA COMO ACNÉ INVERSO, ES UNA CONDICIÓN CRÓNICA INFLAMATORIA QUE AFECTA PRIMARIAMENTE LAS ÁREAS RICAS EN GLÁNDULAS APOCRINAS EN EL CUERPO.

MSP ARTÍCULO DE REVISIÓN

inflamatorio primario está basado principalmente en una respuesta inmune aberrante mediada por niveles elevados de varias citoquinas pro-inf lamatorias como el TNFA (Factor Tumoral Necrótico Alpha, por sus siglas en inglés), Interleukina 17 y 10, entre otras que provocan una estimulación exagerada del sistema inmune.

A nivel histopatológico, la oclusión folicular e inf lamación lleva a la dilatación seguida por la ruptura y secreción del contenido folicular en la piel. Este contenido incluye keratinas y bacterias. Todo este proceso provoca la formación de abscesos y destrucción de las unidades pilosebáceas y tejido alrededor responsables de la descarga purulenta, maloliente característica de ésta condición.

Clínicamente se van a observar nódulos dolorosos o pápulas rojizas molestosas con secreción localizados mayormente en la axila, área inguinal, perineal, mamaria, glúteos, región púbica, pecho, cuero cabelludo y párpados. Síntomas sistémicos como: fiebre, malestar general y cansancio pudieran aparecer en algunos casos.

Con el propósito de un mejor diagnóstico y protocolos de tratamientos e investigación, varias clasificaciones se han propuesto. De éstas, una de las más utilizadas en la práctica o clínica es la de Hurley.

En ésta clasificación descrita por Hurley, la hidradenitis supurativa se divide en 3 estadios o etapas basadas en signos clínicos.

En el Estadio I tenemos la formación de abscesos simples o múltiples sin tractos, fisuras o cicatrización.

Estadio II – abscesos recurrentes

con formación de tractos y cicatrización en lesiones dispersas.

Estadio III – implica un envolvimiento generalizado difuso con tractos que se interconectan y múltiples abscesos en el área completa.

La clasificación de Hurley es una sencilla y práctica para el clínico, pero al no ser cuantitativa no se apropia para estudios de investigación o protocolos de tratamientos. Para esto, otras clasificaciones más detalladas y cuantitativas se han propuesto.

En el diagnóstico diferencial de la hidradenitis supurativa se deben considerar las siguientes condiciones: • Abscesos comunes • Forunculos • Carbúnculos • Quistes Epidermales Inflamados • Bartolina infectada • Quistes pilonidales • Linfogranuloma Venereum • Enfermedad de Crohn

deben tener en cuenta. Dentro de estos, tenemos la localización, severidad y condición general del paciente. También tener en cuenta y entender que esta es una enfermedad inflamatoria de origen inmunológico y no simplemente una infección con abscesos.

En el manejo del paciente, se debe siempre incluir la modificación de los estilos de vida y evitar hábitos malsanos según sea el caso. En aquellos que presentan sobrepeso, la dieta, ejercicio y en algunos la cirugía puede beneficiar. También es aconsejable dejar o disminuir el hábito de fumar por su efectivo negativo en la condición y salud en general.

Dependiendo de la severidad y estadio, se debe establecer el tratamiento más adecuado. En general a nivel tópico se utilizan antibióticos como la Clindamicina y limpiadores con peróxido de Benzoilo o formulaciones antibacteriales.

En el campo de los tratamientos En general, un buen examen físico sistémicos, el armamentario es e historial médico familiar pueden enorme debido a la naturaleza de ser suficientes para el diagnóstico. esta condición. El uso de estos está Sin embargo, en algunos casos otras dirigido más a los casos más activos pruebas diagnósticas como cultivo de intensidad moderada o severa. de la lesión o biopsia pudieran ser Las siguientes terapias sistémicas necesarias.

Por otro lado, es importante tener pueden considerarse: Antibióticos en cuenta en el diagnóstico y manejo • Clindamicius 300mg dos de esta condición, que se han veces al día combinada con identificado otras comorbibilidades Rifampin 600mg por 10 asociadas. Dentro de éstas, se han semanas. mencionado la obesidad, síndrome • Tetraciclina 500mg dos metabólico, diabetes, depresión y veces al (aun cuando no se ha enfermedad inf lamatoria de los demostrado gran efectividad) intestinos (IBD).

• Combinación de Rifamp Referente a las opciones de tratamiento en la hidradenitis • in, Moxifloxacion y supurativa, varios factores se Metronidazol seguidos de Revista Puertorriqueña de Medicina y Salúd Pública

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Trimetropin-sulfa methoxazole o cloxicilens.

Terapia hormonal • Antiandrogenos como ciproterone, spironolactona, finasteride y anticonceptivos orales.

Retinoides o derivados de la Vitamina A • Se han utilizado con poca efectividad comprobada.

Gluconato de Zinc • Dosis de 90 mg diarias pueden ayudar en el control Biológicos Estos nuevos medicamentos llamados Biológicos presentan una alternativa novel de tratamiento basados en su acción sobre el sistema inmune disminuyendo la formación de citoquinas pro-inf lamatorias muy importantes en el origen de la condición. Dentro de estos, el Infliximab y el Adalimunab los cuales son anticuerpos monoclonales contra el TNF-alpha cuentan con estudios clínicos que demuestran su efectividad en la hidradenitis supurativa. Primeramente, el Infliximab en dosis de 5mg, 1kg administrado por vía intravenosa en periodos de 2 horas en los días 0, 2 y 6 cada 8 semanas mostró respuesta positiva en estudios Fase II. Sin embargo, el Adalimunab administrado por inyección subcutánea, se convirtió en el primer biológico en ser aprobado por el FDA (Administración de Drogas y Narcóticos Federal) para el tratamiento de hidradenitis supurativa en adultos. El tratamiento se comienza con 160mg de Adalimunab seguido de 80mg a las 2 semanas y luego 40mg en la semana cuarta continuando entonces con 40mg semanalmente de manera indefinida. La terapia es continua y requiere de seguimiento mediante examen físico y laboratorios regularmente. Al presente, se evalúan otros biológicos que puedan ser efectivos de manera que se espera disponer de más alternativas en el futuro cercano.

Otros tratamientos sistémicos en base a agentes inmunosupresores como el metotrexato, dapsona y la ciclosporina, se han estudiado y utilizado con resultados variados.

El manejo mediante técnicas quirúrgicas o tecnología también puede tener su lugar en el tratamiento de la hidradenitis supurativa. Por ejemplo, el láser de Neudinium (Ndyag) y el de carbono se utilizan para reducir o eliminar tejido afectado. La cirugía también puede jugar un papel importante dependiendo de la severidad y localización de la condición. En algunos casos, incisión y drenaje y marsupialización son de gran 26

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ayuda. Otros requieren de excisión parcial o radical de las áreas afectadas seguido de reconstrucción con colgajos cutáneos, trasplante de piel, cierre primario o sanación por segunda intención.

A todo lo antes mencionado, hay que añadir el manejo de los efectos emocionales y sociales que la condición provoca además de ayudar en la disminución del dolor e incomodidad que puede padecer el paciente en adición de las posibles complicaciones o secuelas secundarias.

De manera que como se puede entender la hidradenitis supurativa es una condición muy compleja que hasta hace muy poco tiempo figuraba entre las casi huérfanas y que hoy día con el advenimiento de nuevas terapias como los biológicos ha ganado gran atención y estudio.

Esto se ha traducido en múltiples investigaciones y nueva data en cuanto al origen, diagnóstico y mejores alternativas de tratamiento de tan importante condición que impacta no sólo al paciente sino también a sus familias y seres queridos.

Referencias

1.Woodruff, Carina M., Abbas, Charlie M., Leslie, Kieron S., Hidrenitis Suppurativa: A Guide for the Practicing Physician, Mayo Clinic Proc.December 2015:90(12):1679-1693.

2.Napolitano, M., Megna, M., Timoshchuk, Patruno, C., Balato, N., Fabrbrocini, G., and Monfrecola, G. Hidradenitis Suppurativa: from pathogenesis to diagnosis and treatment. Clin Cosmetc investig Dermatol. 2017: 10:105-115 3.Van der Zee HH, de Ruiter L, van den Broecke DG, Dik WA, Laman JD, Prens EP, Elevated levels of tumour necrosis factor (TNF)-alpha, interluikin (IL)- IB and IL-10 in hidrenitis suppurativa sin: a rationale for targeting TNF-alpha and (IL)- IB. Br J Dermatol.

2011:164(6):1292-1298.

4.Hurley HJ. Axilliary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial benign pemphigus:surgical approach. In: Roenigk RK, Roenigk HH, editors. Dermatologic Surgery. New York:Marcel Dekker; 1996. pp. 623-645.

5.Shlyankevich, J., Chen, A., Kim, G. and Kimball, A. Hidrandenitis Suppurativa is a systemic disease with substantial comorbidity burden: A chart-verified case-control analysis. J Am Acad Dermatol.

December 2014;71: 1144-150 Grant A, Gonzalez T, Montgomery MO, Cardenas V, Kerdel FA. Infliximab therapy for patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind, placebo-controlled crossover trial. J Am Acad Dermatol. 2010; 62:205-217 6.Van der Zee HH, Laman JD, de Ruiter L, Dik WA, Prens EP. Adalimunab (antitumour necrosis factor-alplha) treatment of hidradenitis suppurativa ameliorates skin inflmamation: an in situ and ex vivo study. Br J Dermatol. 2012; 166:298-305.

HIDRADENITIS SUPURATIVA (HS)

¿Nódulos o Abscesos Recurrentes?

Escuche sus HISTORIAS La HIDRADENITIS SUPURATIVA (HS) es una condición crónica, a menudo dolorosa, relacionada con el sistema inmunitario que se caracteriza por zonas inflamadas, generalmente localizadas alrededor de las axilas, la ingle, bajo los senos, los glúteos y en la parte interior de los muslos. Estas áreas muchas veces incluyen lesiones, como nódulos y abscesos y por lo general ocurren donde hay muchas glándulas que producen grasa y sudor y donde una parte de la piel roza con otra.1, 2

¿A QUIÉN AFECTA LA HS? SE CALCULA QUE AFECTA, AL MENOS A LAS MUJERES SON LAS INVESTIGACIONES MÉDICAS SUGIEREN QUE HAY UNA RELACIÓN ENTRE LA HS Y

1%

de la población adulta en general1,2

MÁS PROPENSAS A DESARROLLAR HS QUE LOS HOMBRES 3

FUMAR OBESIDAD 2,4

CASOS LEVES Hay una o pocas lesiones aisladas sin trayectos fistulosos ni tejido cicatricial.2-3,5

CASOS MODERADOS Hay lesiones recurrentes con tejido cicatricial y trayectos fistulosos en múltiples zonas.2-3,5

CASOS SEVEROS Hay lesiones generalizadas, lo que puede producir secreción de pus maloliente y tejido cicatricial con muchos trayectos fistulosos interconectados.2-3,5

©2015 AbbVie Inc. North Chicago, IL 60064 5590-1820901 Octubre de 2015 Impreso en EE.UU.

La HS puede ser progresiva en algunas personas, así que es importante diagnosticarla y manejarla a tiempo.6 Esto puede ser difícil, y muchas personas con HS experimentan una larga demora en el diagnóstico y el tratamiento.2,5 Es importante que los pacientes de HS y las personas que crean que pueden estar afectadas vean un dermatólogo que está adiestrado para reconocer y tratar la enfermedad.6

1. Mayo Health Clinic. Hidradenitis Suppurativa. Disponible en: http://www.mayoclinic.com/health/hidradenitis-suppurativa/DS00818.

Publicado el 9 de abril de 2013. Accedido el 27 de septiembre de 2013.

2. Jemec G. Hidradenitis Suppurativa. N Engl J Med. 2012; 366:158-64.

3. Collier F., Smith R., Morton C. Diagnosis and management of hidradenitis suppurativa. BMJ. 2013; 346:f2121.

4. Zouboulis CC, Tsatsou F (2012) Disorders of the apocrine sweat glands. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K (eds) Fitzpatrick’s Dermatology in General Medicine. 8th ed, McGraw Hill, New York Chicago, pp 947-959.

5. Dufour DN, Emtestam L, Jemec GB. Hidradenitis suppurativa: a common and burdensome, yet under-recognized, inflammatory skin disease. Postgrad Med J. 2014; 90(1062): 216-221; quiz 220.doi:10.1136/postgradmedj-2013-131994.

6. American Academy of Dermatology. Hidradenitis suppurativa. Disponible en: http://www.aad.org/dermatology-a-to-z/diseases-and-treatments/e---h/hidradenitis-suppurativa

MSP ARTÍCULO ORIGINAL

Psoriasis

Eficiencia de los nuevos tratamientos Por:Eneida M. De La Torre Lugo, MD, FAAD Dermatóloga Dermatóloga acreditada por la Academia Americana de Dermatología Parte de la Facultad Médica del Hospital HIMA San Pablo en Bayamón Catedrática Auxiliar del Departamento de Medicina de la Escuela de Medicina de la Universidad Central del Caribe Pasada Presidenta de la Sociedad Dermatológica de Puerto Rico.

Vocal de la Fundación Puertorriqueña para el Mejoramiento de la Dermatología

Palabras claves: Psoriasis, Comorbilidades, Agentes biológicos Keywords: psoriasis, comorbidities, biological agents

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Resumen La psoriasis es una condición de la piel que afecta alrededor de 7.4 millones de adultos en Estados Unidos.

Se caracteriza por ser una condición multisistémica que demuestra múltiples variaciones fenotípicas y grados de severidad que se evalúan de acuerdo con las lesiones cutáneas que presenta el paciente y el área de aparición, frecuentemente en las articulaciones.

L

a psoriasis es una condición de la piel común que afecta alrededor de 7.4 millones de adultos en los Estados Unidos.1 Es una enfermedad genética (heredada), crónica (de larga duración) e inflamatoria que afecta a aproximadamente el 2% a 3% de la población global.1 En Puerto Rico no se han realizado estudios sobre la prevalencia de la psoriasis, pero un estudio publicado en el 2014 reportó la epidemiología de la psoriasis en clínicas multidisciplinarias. El estudio sugirió que la prevalencia de la psoriasis en Puerto Rico podría ser mayor que en los Estados Unidos con un 6%.2 La psoriasis es una condición multisistémica que afecta predominantemente la piel y las articulaciones, y se caracteriza por demostrar múltiples variaciones fenotípicas y grados de severidad. Se presenta como parchos, pápulas, y placas escamosas, eritematosas que comúnmente son pruriginosas y en algunos casos se pueden presentar pústulas. Estas lesiones comúnmente afectan la piel en las articulaciones (rodillas, codos), pero la psoriasis puede afectar el cuero cabelludo, las uñas y, en algunos casos, afectar todo el cuerpo.

Aproximadamente el 80% de los pacientes con psoriasis tienen una enfermedad leve a moderada, mientras que el 20% tienen enfermedad moderada a severa, que puede afectar significativamente su calidad de vida.

La psoriasis se presenta en diversas formas clínicas que incluye la psoriasis en placa, psoriasis guttata, psoriasis pustular, psoriasis eritrodérmica, psoriasis inversa, la psoriasis ungueal (uñas) y la psoriasis palmo-plantar.3 La psoriasis puede parecer contagiosa, pero no lo es. En la mayoría de los casos el diagnóstico de esta condición es clínico y se puede realizar con un historial médico y un examen físico de la piel, las uñas y el cuero cabelludo. En algunas ocasiones el dermatólogo necesita realizar una biopsia de piel para confirmar el diagnóstico.

Los pacientes de psoriasis pueden presentar otras condiciones que se conocen como comorbilidades. Estos

Abstract Psoriasis is a skin condition that affects around 7.4 million adults in the United States. It is characterized as a multi systemic condition that demonstrates multiple phenotypic variations and degrees of severity that are evaluated according to the skin lesion presented by the patient and the appearance area, frequently in the joints. pacientes tienen una mayor incidencia de linfoma, enfermedades cardiovasculares (infarto cardiaco, accidentes cerebrovasculares), obesidad, diabetes tipo II, y del síndrome metabólico. La depresión y el suicidio, el fumar y el consumo de alcohol también son más comunes en pacientes con psoriasis.

El primer paso en el tratamiento de la psoriasis es abordar las necesidades psicosociales de los pacientes, esto incluye la necesidad de comprender su enfermedad.

La asesoría inicial comienza brindando materiales educativos para el paciente sobre cómo manejar los síntomas y mejorar su calidad de vida.

La artritis psoriásica (PsA) es común en pacientes con psoriasis (hasta un 30%) y tiende a comenzar años después de que comienza la psoriasis.

Los dermatólogos pueden detectar la artritis psoriásica (PsA) temprano. Preguntar a los pacientes sobre rigidez en las articulaciones, dolor en las articulaciones o dolor de espalda es una forma sensible de identificar posibles pacientes con PsA. Cuando se sospecha artritis, el examen físico debe incluir un examen musculoesquelético completo que incluya la evaluación del rango de movimiento y la evaluación por rayos X de las articulaciones afectadas. Una sospecha de artritis merece una consulta a un reumatólogo. Los dermatólogos y reumatólogos pueden colaborar en la elección de los tratamientos ideales para pacientes con psoriasis y artritis psoriásica.

El primer paso antes de comenzar el tratamiento es clasificar la psoriasis del paciente entre psoriasis limitada o extensa, dependiendo de si es factible o no aplicar tratamientos tópicos en todas las áreas afectadas. Esto nos ayudará a determinar el algoritmo de tratamiento para cada paciente. (Tabla 1) El tratamiento de la psoriasis incluye modalidades tópicas (esteroides, análogos de vitamina D, tazaroteno, brea, ácido salicílico, inhibidores de calcineurina, etc.), terapia con luz ultravioleta, agentes sistémicos (methotrexate, ciclosporina, acitretin) y terapia con agentes biológicos. En los últimos 10 años debido al Revista Puertorriqueña de Medicina y Salúd Pública

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mejor entendimiento de la inmunopatogénesis de la psoriasis, se han introducido varios agentes biológicos que se dirigen a combatir moléculas específicas necesarias para el desarrollo de la placa psoriática.

Durante este tiempo, estudios a largo plazo han confirmado la seguridad de los inhibidores del factor de necrosis tumoral alfa (TNF-α) como etanercept (Enbrel®, Amgen), adalimumab (Humira®, Abbvie) y inf liximab (Remicade®, Janssen). Más reciente, los descubrimientos que envuelven las interleucinas (IL) han llevado al desarrollo de agentes como el ustekinumab (Stelara®, Janssen) que es un inhibidor de las interleucinas 12 y 13 (IL-12/IL-23). Todos estos agentes han demostrado ser seguros, bien tolerados y mejoran la calidad de vida de los pacientes con psoriasis y artritis psoriática. Los nuevos avances en el tratamiento de la psoriasis incluyen inhibidores de la interleucina 17 (IL-17) como secukinumab (Consentyx®, Novartis), ixekizumab (Taltz®, Lilly) y brodalumab (Siliq®, Ortho). La terapia oral de inhibidores de la fosfodiesterasa-4 (PDE-4) (Otezla®, Celgene) es una opción de tratamiento para pacientes que no desean inyecciones y no requiere monitoreo de laboratorios.

Recientemente fueron aprobados guselkumab (Tremfya®, Janssen) y tildrakizumab (Ilumya,® Sun Pharma) que son inhibidores más específicos de la interleucina 23 (IL-23). El certolizumab pegol (Cimzia®), es un anticuerpo monoclonal humanizado conjugado con polietilenglicol y dirigido al factor de necrosis tumoral alfa (TNF-α) que también recibió recientemente una actualización de la etiqueta y ahora incluye la aprobación de la FDA para psoriasis y artritis psoriásica. Continúan en estudios y próximos para aprobación por la FDA para la psoriasis los inhibidores de la kinasa janus ( JAK) tofacitinib e inhibidores de la interleucina 23 (IL-23) mirikizumab. Esta nueva generación de medicamentos prometen ser una nueva dirección en el tratamiento de la psoriasis, y aunque su eficacia está probada, más estudios son necesarios para confirmar su seguridad.

En conclusión, la psoriasis es una enfermedad de la piel común asociada a múltiples comorbilidades que necesita un diagnóstico temprano y tratamiento agresivo. Los agentes biológicos han revolucionado el tratamiento de la psoriasis debido a que proveen una eficacia evidente y sustancial.

Tabla 1. Algoritmo de Tratamiento

Primera línea de tratamiento

Psoriasis Localizada Moderada a Severa

Esteroides tópicos

Fototerapia, agentes sistémicos y biológicos (en pacientes donde la fototerapia no esté indicada)

Referencias

Segunda línea de tratamiento Combinación de esteroides tópicos con otras modalidades tópicas y fototerapia Combinación de agentes sistémicos y biológicos

1.Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol.

2014;70(3):512-6.

2.Ramirez Fort M, Gottlieb A, Doan H, et al. A cross-sectional study of Fitzpatrick’s skin type and psoriasis in Puerto Rico. J Am Acad Dermatol. 2014;70(5)Supp1:AB79.

3.Voorhees AV, Feldman S, Lebwohl M, Mandelin A, Ritchlin C. The Psoriasis and Psoriatic Arthritis Pocket Guide: Treatment Algorithms and Management Options. 4th ed. Portland, OR: National Psoriasis Foundation; 2017. Accessed September 3, 2018.

4.Página web de la Academia Americana de Dermatología. www.aad.org. Accessed September 3, 2018. s

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6 mm

Evolución

Color

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Melanoma cutáneo (MC): diagnóstico y tratamiento en la actualidad médica Por: Hiram Ruiz, MD, FAAD American Board of Dermatology American College of Mohs Surgery Secretario de la Fundación Puertorriqueña para el Mejoramiento de la Dermatología

Asimetría Palabras claves: melanoma, biopsia de nódulo centinela, terapia adyuvante para melanoma avanzado, biopsia de piel, tratamiento quirúrgico del melanoma.

Keywords: melanoma, sentinel lymph node biopsy, adjuvant therapy for advanced melanoma, skin biopsy, surgical treatment of melanoma

Resumen: El melanoma es un tipo de cáncer en la piel con potencial alto de metástasis. Identificar las personas de alto riesgo y hacer un diagnóstico temprano son esenciales para poder prevenir y curar esta temible enfermedad.

Abstract: Melanoma is a skin cancer with real metastatic potential. The identification of high risk patients as well as an early diagnosis are key in preventing and curing this terrible disease Revista Puertorriqueña de Medicina y Salúd Pública

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El melanoma es el cáncer de la piel más peligroso, no solo porque puede ser mortal sino porque puede afectar a personas relativamente jóvenes. En los EE. UU. es el sexto cáncer más común, con una incidencia de 19.7 por cada 100,000 personas y una mortalidad de 9,000 pacientes al año. La incidencia en Puerto Rico es menor: aproximadamente 3.5 por cada 100,000 habitantes1.

La tasa de supervivencia depende principalmente de la profundidad del tumor y de ahí la importancia de un diagnóstico temprano. Los factores de riesgo a desarrollar melanoma incluyen: 1. Cambios en la apariencia de un lunar o un lunar distinto a los demás del cuerpo 2. Historial personal o familiar de melanoma u otro tipo de cáncer de piel 3. Exposición excesiva a luz solar o "tanning beds" 4. Piel blanca, pelirrojos u ojos claros 5.Lunares atípicos -lunares que comparten Biopsia en escisión características clínicas con el melanoma (bordes y/o color irregular) 6. Tener 50 lunares o más Aunque el número de lunares se considera un factor de riesgo, la mayoría de los melanomas aparecen "de novo"2. El examen clínico (ABCDE) sigue siendo la mejor herramienta para detectar tempranamente el melanoma: A. Asimetría: si se biseca la lesión, las mitades no son idénticas B. Bordes irregulares C. Color variado Biopsia en paralelo "shave" D. Diámetro >6mm E. Evolución: cambio en tamaño, color o nueva lesión más expertos, diferenciar histológicamente entre un lunar benigno y un melanoma puede ser, en ocasiones, de rápido crecimiento. sumamente difícil. En los casos en que no se pueda Un lunar que no se parezca al resto de los lunares, descartar con certeza el diagnóstico de melanoma, se también se considera un hallazgo clínico importante. Se debe remover la lesión completa.

Siempre que sea posible, la biopsia debe incluir toda el área pigmentada con un margen de 1 a 3 mm de simetría orde Asimétricos piel normal. Uno de los hallazgos histopatológicos más Irregular importantes para diferenciar entre neoplasias malignas y benignas en la piel, es la simetría que suelen tener las iámetro olor neoplasias benignas, versus la asimetría de las malignas.

Superior Color no a 6 mm homogéneo Por otra parte, si no se remueve en su totalidad, no se puede medir con exactitud la profundidad del melanoma, siendo este el factor pronóstico más importante. La tasa de supervivencia a 10 años es de volución 92% en pacientes con melanomas <1mm de espesor y de solo 50% en melanomas >4mm de espesor. Además, debe hacer una biopsia a cualquier lesión sospechosa y como veremos a continuación, la profundidad del que sea evaluada por un dermatopatólogo o patólogo melanoma es uno de los factores más importantes para con experiencia en lesiones pigmentadas. Aún para los determinar el margen quirúrgico y la terapia adyuvante.

A

B

C

D

E

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El tratamiento del melanoma primario es la escisión quirúrgica con márgenes amplios hasta la fascia.

Dependiendo de la profundidad del tumor, el margen varía de 0.5cm hasta 2.0cm. No son necesarios márgenes mayores a 2.0cm, ya que no afectan la tasa de recurrencia.

Profundidad tumor

Margen quirúrgico

In situ

0.5 - 1.0 cm

1.0 mm 1.01 - 2.0 mm 2.0 mm

1 cm

1 - 2 cm

2 cm

Las guías del "American Society of Clinical Oncology" (ASCO) y el "Society for Surgical Oncology" recomiendan la biopsia de nódulo centinela (SLNB) en melanomas de grosor intermedio (1-4mm) o melanomas <1mm ulcerados. También la recomiendan en melanomas de >4mm como valor pronóstico3,4.

Si se va a realizar el SLNB, debe hacerse simultáneamente a la escisión del tumor, ya que al remover el tejido se podría modificar el flujo linfático e interferir con la localización precisa del nódulo centinela.

Aunque no se ha visto un aumento en la tasa de supervivencia, el SLNB ofrece información importante para la clasificación (estadio), el pronóstico y las terapias adyuvantes. Si el nódulo centinela está positivo, se recomendaba la remoción completa de los demás nódulos del área; sin embargo, dos estudios aleatorios

recientes comparan la escisión completa de todos los nódulos al momento de remover el nódulo centinela, versus remover solo el nódulo centinela, y no se demostraron diferencias significativas en la tasa de supervivencia5,6.

El tratamiento del melanoma avanzado ha mejorado dramáticamente en los últimos años con la inclusión de la inmunoterapia y la terapia dirigida ("targeted therapy"). Aunque este artículo no pretende discutir detalladamente el tema, es importante mencionar los recientes avances en este campo. El 20 de diciembre de 2017, la FDA aprobó el uso de nivolumab (inhibidor de PD-1) como terapia adyuvante. Se puede utilizar en la mayoría de los casos con envolvimiento de nódulo linfático o metástasis (estadíos III y IV), independientemente de la mutación BRAF7. Otro medicamento de efectividad similar es el pembrolizumab, pero aún no ha sido aprobado por el FDA como terapia adyuvante8.

Ambos medicamentos han demostrado su efectividad en aumentar la longevidad de los pacientes y evitar la progresión del cáncer. En estudios a largo plazo, 90 % de los pacientes que consiguieron una respuesta completa al pembrolizumab alcanzaron 2 años sin evidencia de recurrencia luego de descontinuar la terapia9.

Como en cualquier tipo de cáncer, la prevención y el diagnóstico temprano son las mejores estrategias para vencerlo. Los pacientes de alto riesgo de desarrollar melanoma deben ser evaluados al menos una vez al año. Muchas veces el mejor cernimiento lo realiza la pareja del paciente, por lo que la educación a ambos es esencial. El ABCDE y el signo del "patito feo" son guías sencillas pero efectivas en el diagnóstico temprano. Por último, debemos tener en cuenta que vivimos donde el índice de luz ultravioleta es alto prácticamente todo el año, y debemos educar a los pacientes sobre la importancia de la protección solar.

Referencias

1.Valentin SM, Sánchez JL, Figueroa LD, et al. PRSHSJ 2007; 26(4): 343-348.

2.J Am Acad Dermatol. 2017;77(5):938. Epub 2017 Aug 29.

3.J Clin Oncol. 2012;30(23):2912.

4.Ann Surg Oncol. 2012 Oct;19(11):3313-24.

5.Lancet Oncol. 2016;17(6):757.

6.N Engl J Med. 2017;376(23):2211.

7.Weber JS, Mandala M, Del Veccio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238) (Abstract 9502). American Society of Clinical Oncology annual meeting.

8.N Engl J Med. 2018;378(19):1789.

9.J Clin Oncol. 2018;36(17):1668.

Revista Puertorriqueña de Medicina y Salúd Pública

35

MSP ARTÍCULO ORIGINAL

Avances en el tratamiento contra la caída de cabello una perspectiva dermatológica Por: Rosbel González Rivera, MD, FAAD Eneida M. De La Torre, MD, FAAD

Resumen La caída del cabello es una afección causada comúnmente por la la alopecia androgénica o alopecia androgenética (AGA), provocada por un desorden genético que padecen hombres y mujeres alrededor del mundo.

Abstract Hair loss is an affection commonly caused by androgenic alopecia or androgenetic alopecia (AGA), caused by a genetic disorder that affects men and women around the world.

Palabras clave Alopecia androgénica, Alopecia androgenética, Caída del cabello, Dermatología, Tratamientos.

Keywords Androgenic alopecia, androgenetic alopecia, hair loss, dermatology, treatments.

L

a caída del cabello afecta tanto a hombres como a mujeres y puede tener un impacto significativo en su calidad de vida. El tipo más común de pérdida de cabello es la alopecia androgénica o alopecia androgenética (AGA). La misma surge usualmente luego de la pubertad y afecta hasta el 50% de los individuos blancos a los 50 años y cerca del 50% de las mujeres a lo largo de su vida. Los hombres y mujeres que experimentan calvicie pueden baja autoestima, falta de confianza y creciente vergüenza, factores que que influyen negativamente en sus relaciones interpersonales e incluso su crecimiento profesional.

Aunque los hombres y las mujeres se ven afectados por la pérdida de cabello, existen muchas diferencias, como la presentación, la prevalencia y la fisiopatología.

En los hombres, se acentúa la pérdida de cabello en la zona frontal y superior del cuero cabelludo. Por otro lado, las mujeres pueden tener afinamiento difuso en la coronilla con preservación de la línea frontal del cabello, o recesión en área bitemporal como es visto en los hombres.

El afinamiento del cabello y por consiguiente la alopecia androgénica es causada por un factor genético fundamental que hace que el folículo piloso sea sensible a 36

Revista Puertorriqueña de Medicina y Salúd Pública

un metabolito de la hormona de la testosterona llamado dihidrotestosterona (DHT). La alopecia androgénica es progresiva, lo que lleva a una disminución en la densidad y el diámetro del cabello, miniaturización del folículo piloso y calvicie potencialmente significativa.

La clave para evitar la pérdida de cabello tanto en hombres como mujeres es obtener una evaluación médica temprana. Antes de comenzar tratamiento, el paciente debe comprender que requiere una terapia continua para poder alcanzar una respuesta adecuada. De hecho, el paciente no debe interrumpir el tratamiento, de lo contrario continuará la pérdida de cabello. Algunos de los tratamientos indicados para la alopecia androgénica son: minoxidil 5%, finasteride, terapia de luz de baja intensidad, terapia de plasma rico en plaquetas, o trasplante de pelo, entre otras.

El minoxidil 5% es un tratamiento tópico que puede prolongar la fase de crecimiento del pelo. El finasteride es una terapia oral que inhibe las hormonas responsables de causar la pérdida de cabello. La terapia de plasma rico en plaquetas es un procedimiento mínimamente invasivo que estimula el crecimiento del cabello a través de la liberación de varias sustancias, incluyendo factores de crecimiento. Las técnicas de trasplante de pelo en el presente incluyen el trasplante de unidad

MSP ARTÍCULO ORIGINAL

folicular (TUF), donde se realiza una escisión del área posterior del cuero cabelludo y se trasplantan las unidades foliculares al área afectada. Sin embargo, la principal desventaja con esta técnica es la cicatriz linear que permanece en el área occipital del cuero cabelludo.

La técnica de extracción de unidad folicular (EUF) es una técnica mínimamente invasiva que consiste en la extracción directa del área donante de las unidades foliculares, utilizando un pequeño sacabocado. La principal desventaja de la técnica es que requiere una extracción manual precisa y consistente para no dañar los injertos, lo que está sujeto a la fatiga del técnico que esta realizando el procedimiento y la calidad del injerto puede disminuir con el tiempo de cirugía debido a que el procedimiento es de larga duración.

Avances en la tecnología han logrado el desarrollo del Sistema Robótico ARTAS para procedimientos de trasplante de cabello, siendo éste lo último en tecnología aprobado por la FDA para trasplante de pelo en hombres. El Sistema Robótico ARTAS analiza el cuero cabelludo del paciente y escoge sólo los mejores cabellos para ser trasplantados. El Sistema extrae unidades foliculares de alta calidad y viabilidad, las cuales son implantadas en las áreas afectadas. Dicho procedimiento sólo debe ser realizado por un médico

completamente adiestrado en el uso del robot con el que se realiza la intervención. Es importante que visite a su dermatólogo para que pueda ser evaluado y orientado sobre cual tratamiento es la mejor opción para usted.

La doctora González es dermatóloga acreditada por la Academia Americana de Dermatología y forma parte de la Facultad Médica del Hospital HIMA San Pablo en Bayamón. Para más información se puede comunicar al 787-269-7233.

La doctora De La Torre es dermatóloga acreditada por la Academia Americana de Dermatología, forma parte de la Facultad Médica del Hospital HIMA San Pablo en Bayamón, es Catedrática Auxiliar del Departamento de Medicina de la Universidad Central del Caribe School of Medicine y miembro de la Directiva de la Sociedad Dermatológica de Puerto Rico.

Ambas médicas son dermatólogas certificadas por la Academia Americana de Dermatología, forman parte de la Facultad Médica del Hospital HIMA San Pablo en Bayamón. La doctora De La Torre es Catedrática Auxiliar del Departamento de Medicina de la Universidad Central del Caribe School of Medicine y miembro de la Directiva de la Sociedad Dermatológica de Puerto Rico. Para más información se puede comunicar al 787-269-7233.

Revista Puertorriqueña de Medicina y Salúd Pública

37

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

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

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

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

EVOLVE-1 (over Months 1 to 6)

EVOLVE-2 (over Months 1 to 6) 100

80

60

40

62%a 39% 39%a

19%

20

0

≥50%

16%a 6%

80

60

59%a 36% 34%a

40

18%

20

0

100%

≥75%

Mean Percentage of Patients

Mean Percentage of Patients

100

≥50%

Level of Reduction Emgality 120 mg (N=210)

100%

≥75%

Level of Reduction

Placebo (N=425) a

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

12%a 6%

Emgality 120 mg (N=226)

Placebo (N=450)

p<0.001 vs placebo.

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

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

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

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

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

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

240 mg is an unapproved dose.

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

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

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

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

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

Please see Instructions for Use included with the device.

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

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

All rights reserved.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

All rights reserved.

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

NOW APPROVED�

For the first time in over a decade, a new oral treatment option for the management of moderate to severe pain associated with endometriosis.

• Available in 2 oral dosages (150 mg QD and 200 mg BID)1

Dysmenorrhea (150 mg or 200 mg)

Nonmenstrual Pelvic Pain (150 mg or 200 mg)

The first and only oral GnRH antagonist specifically developed for women with moderate to severe endometriosis pain1

Dyspareunia* (200 mg only)

*Statistical significance for dyspareunia was not achieved with the 150-mg dose of ORILISSA.1

INDICATION1

ORILISSA™ (elagolix) is indicated for the management of moderate to severe pain associated with endometriosis.

IMPORTANT SAFETY INFORMATION1

CONTRAINDICATIONS • ORILISSA is contraindicated in women who are pregnant (exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss), in women with known osteoporosis or severe hepatic impairment (due to risk of bone loss), or with concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil).

WARNINGS AND PRECAUTIONS Bone Loss • ORILISSA causes a dose-dependent decrease in bone mineral density (BMD), which is greater with increasing duration of use and may not be completely reversible after stopping treatment.

• The impact of ORILISSA-associated decreases in BMD on longterm bone health and future fracture risk is unknown. Consider assessment of BMD in patients with a history of low-trauma fracture or other risk factors for osteoporosis or bone loss, and do not use in women with known osteoporosis.

• Limit the duration of use to reduce the extent of bone loss.

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy • Women who take ORILISSA may experience a reduction in the amount, intensity, or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of pregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected, and discontinue ORILISSA if pregnancy is confirmed.

Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders • Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with ORILISSA in the endometriosis clinical trials.

• ORILISSA users had a higher incidence of depression and mood changes compared to placebo and ORILISSA users with a history of suicidality or depression had an increased incidence of depression.

Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits. Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health professional, as appropriate.

©2018 AbbVie Inc. North Chicago, IL 60064

400-1939046

• Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing ORILISSA if such events occur.

Hepatic Transaminase Elevations • In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3 times the upper limit of the reference range occurred with ORILISSA. • Use the lowest effective dose and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice.

• Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks.

Reduced Efficacy with Estrogen-Containing Contraceptives • Based on the mechanism of action of ORILISSA, estrogencontaining contraceptives are expected to reduce the efficacy of ORILISSA. The effect of progestin-only contraceptives on the efficacy of ORILISSA is unknown.

• Advise women to use non-hormonal contraceptives during treatment and for one week after discontinuing ORILISSA. ADVERSE REACTIONS • The most common adverse reactions (>5%) in clinical trials included hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions, and mood changes.

These are not all the possible side effects of ORILISSA. Safety and effectiveness of ORILISSA in patients less than 18 years of age have not been established.

REFERENCE: 1. Orilissa [package insert]. North Chicago, IL: AbbVie Inc; 2018.

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

Learn more about this new treatment option at ORILISSA.com/hcp

Printed in the U.S.A.

July 2018

DO NOT RE-SIZE 400-1939046

ORILISSA™ (elagolix) tablets, for oral use

Dosing Regimen

Maximum Treatment Coexisting Duration Condition

Initiate treatment with 24 months ORILISSA 150 mg once daily

None

Consider initiating treatment 6 months with ORILISSA 200 mg twice daily

Dyspareunia

Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended.

Moderate hepatic impairment (ChildPugh Class B)

6 months

Hepatic Impairment No dosage adjustment of ORILISSA is required in women with mild hepatic impairment (Child-Pugh A).

Compared to women with normal liver function, those with moderate hepatic impairment had approximately 3-fold higher elagolix exposures and those with severe hepatic impairment had approximately 7-fold higher elagolix exposures. Because of these increased exposures and risk for bone loss: • ORILISSA 150 mg once daily is recommended for women with moderate hepatic impairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of ORILISSA 200 mg twice daily is not recommended for women with moderate hepatic impairment [see Use in Specific Populations].

• ORILISSA is contraindicated in women with severe hepatic impairment (Child-Pugh C) [see Contraindications and Use in Specific Populations].

Missed Dose Instruct the patient to take a missed dose of ORILISSA on the same day as soon as she remembers and then resume the regular dosing schedule.

• 150 mg once daily: take no more than 1 tablet each day.

• 200 mg twice daily: take no more than 2 tablets each day.

CONTRAINDICATIONS ORILISSA is contraindicated in women: • Who are pregnant [see Use in Specific Populations]. Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss.

• With known osteoporosis because of the risk of further bone loss [see Warnings and Precautions] • With severe hepatic impairment because of the risk of bone loss [see Use in Specific Populations] • With concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil) [see Drug Interactions] WARNINGS AND PRECAUTIONS Bone Loss ORILISSA causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment [see Adverse Reactions].

The impact of these BMD decreases on long-term bone health and future fracture risk are unknown. Consider assessment of BMD in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss, and do not use in women with known osteoporosis. Limit the duration of use to reduce the extent of bone loss.

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy Women who take ORILISSA may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner [see Adverse Reactions]. Perform pregnancy testing if pregnancy is suspected, and discontinue ORILISSA if pregnancy is confirmed.

Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with ORILISSA in the endometriosis clinical trials. ORILISSA subjects had a higher incidence of depression and mood changes compared to placebo, and ORILISSA subjects with a history of suicidality or depression had a higher incidence of depression compared to subjects without such a history [see Adverse Reactions]. Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits [see Adverse Reactions]. Patients with new or worsening depression, anxiety or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing ORILISSA if such events occur.

Hepatic Transaminase Elevations In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3-times the upper limit of the reference range occurred with ORILISSA. Use the lowest effective dose of ORILISSA and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks [see Adverse Reactions].

03-B671 ORILISSA PB 7.625 x 10.5(2-1/3).indd 1

Table 2. Percentage of Subjects in Studies EM-1 and EM-2 with Treatment-Emergent Adverse Reactions Occurring in at Least 5% of Subjects (either ORILISSA Dose Group) and at a Greater Incidence than with Placebo

Hot Flush or Night Sweats Headache Nausea Insomnia Mood altered, mood swings Amenorrhea Depressed mood, depression, depressive symptoms and/or tearfulness Anxiety Arthralgia

ORILISSA 150 mg Once Daily N=475 % 24 17 11 6 6 4

ORILISSA 200 mg Placebo Twice Daily N=734 N=477 % % 46 9 20 12 16 13 9 3 5 3 7 <1

3

6

2

3 3

5 5

3 3

Less Common Adverse Reactions: In Study EM-1 and Study EM-2, adverse reactions reported in ≥ 3% and < 5% in either ORILISSA dose group and greater than placebo included: decreased libido, diarrhea, abdominal pain, weight gain, dizziness, constipation and irritability.

The most commonly reported adverse reactions in the extension trials (EM-3 and EM-4) were similar to those in the placebo-controlled trials.

Bone Loss The effect of ORILISSA on BMD was assessed by dual-energy X-ray absorptiometry (DXA).

In Studies EM-1 and EM-2, there was a dose-dependent decrease in BMD in ORILISSA-treated subjects compared to an increase in placebo-treated subjects.

In Study EM-1, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -0.9% (95% CI: -1.3, -0.4) with ORILISSA 150 mg once daily and -3.1% (95% CI: -3.6, -2.6) with ORILISSA 200 mg twice daily (Table 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was 2% with ORILISSA 150 mg once daily, 7% with ORILISSA 200 mg twice daily and < 1% with

placebo. In the blinded extension Study EM-3, continued bone loss was observed with 12 months of continuous treatment with ORILISSA. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 8% with continuous ORILISSA 150 mg once daily and 21% with continuous ORILISSA 200 mg twice daily.

In Study EM-2, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -1.3% (95% CI: -1.8, -0.8) with ORILISSA 150 mg once daily and -3.0% (95% CI: -3.5, -2.6) with ORILISSA 200 mg twice daily (Table 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was < 1% with ORILISSA 150 mg once daily, 6% with ORILISSA 200 mg twice daily and 0% with placebo. In the blinded extension Study EM-4, continued bone loss was observed with 12 months of continuous treatment with ORILISSA. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 2% with continuous ORILISSA 150 mg once daily and 21% with continuous ORILISSA 200 mg twice daily.

Table 3. Percent Change from Baseline in Lumbar Spine BMD at Month 6 ORILISSA ORILISSA 150 mg 200 mg Once Daily Twice Daily Placebo EM-1 N

183

180

277

Percent Change from Baseline, %

-0.3

-2.6

0.5

Treatment Difference, % (95% CI)

-0.9 (-1.3, -0.4)

-3.1 (-3.6, -2.6)

EM-2 N

174

183

271

Percent Change from Baseline, %

-0.7

-2.5

0.6

Treatment Difference, % (95% CI)

-1.3 (-1.8, -0.8)

-3.0 (-3.5, -2.6)

To assess for recovery, the change in lumbar spine BMD over time was analyzed for subjects who received continuous treatment with ORILISSA 150 mg once daily or ORILISSA 200 mg twice daily for up to 12 months and who were then followed after cessation of therapy for an additional 6 months. Partial recovery of BMD was seen in these subjects (Figure 1).

In Study EM-3, if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip at the end of treatment, follow-up DXA was required after 6 months off-treatment. In Study EM-4, all subjects were required to have a follow-up DXA 6 months off treatment regardless of change in BMD and if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip after 6 months off treatment, follow-up DXA was required after 12 months off-treatment.

Figure 2 shows the change in lumbar spine BMD for the subjects in Study EM-2/EM-4 who completed 12 months of treatment with ORILISSA and who had a follow-up DXA 12-months off treatment.

Figure 1. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and Had Follow-up BMD 6 Months off Therapy in Studies EM-2/EM-4 1% 0%

Percent Change (95% CI) from Baseline

Table 1. Recommended Dosage and Duration of Use

Reduced Efficacy with Estrogen-Containing Contraceptives Based on the mechanism of action of ORILISSA, estrogen containing contraceptives are expected to reduce the efficacy of ORILISSA. The effect of progestin-only contraceptives on the efficacy of ORILISSA is unknown.

Advise women to use non-hormonal contraceptives during treatment with ORILISSA and for one week after discontinuing ORILISSA [see Use in Specific Populations, Drug Interactions].

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: • Bone loss [see Warnings and Precautions] • Change in menstrual bleeding pattern and reduced ability to recognize pregnancy [see Warnings and Precautions] • Suicidal ideation, suicidal behavior, and exacerbation of mood disorders [see Warnings and Precautions] • Hepatic transaminase elevations [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of ORILISSA was evaluated in two six-month, randomized, double-blind, placebo-controlled clinical trials [EM-1 (NCT01620528) and EM-2 (NCT01931670)] in which a total of 952 adult women with moderate to severe pain associated with endometriosis were treated with ORILISSA (475 with 150 mg once daily and 477 with 200 mg twice daily) and 734 were treated with placebo. The population age range was 18-49 years old.

Women who completed six months of treatment and met eligibility criteria continued treatment in two uncontrolled, blinded six-month extension trials [EM-3 (NCT01760954) and EM-4 (NCT02143713)], for a total treatment duration of up to 12 months.

Serious Adverse Events Overall, the most common serious adverse events reported for subjects treated with ORILISSA in the two placebo-controlled clinical trials (Studies EM-1 and EM-2) included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%). In these trials, 0.2% of subjects treated with ORILISSA 150 mg once daily and 0.2% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to serious adverse reactions compared to 0.5% of those given placebo.

Adverse Reactions Leading to Study Discontinuation In the two placebo-controlled clinical trials (Studies EM-1 and EM-2), 5.5% of subjects treated with ORILISSA 150 mg once daily and 9.6% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to adverse reactions compared to 6.0% of those given placebo.

Discontinuations were most commonly due to hot flushes or night sweats (1.1% with 150 mg once daily and 2.5% with 200 mg twice daily) and nausea (0.8% with 150 mg once daily and 1.5% with 200 mg twice daily) and were dose-related. The majority of discontinuations due to hot flushes or night sweats (10 of 17, 59%) and nausea (7 of 11, 64%) occurred within the first 2 months of therapy.

In the two extension trials (Studies EM-3 and EM-4), discontinuations were most commonly due to decreased BMD and were dose-related. In these trials, 0.3% of subjects treated with ORILISSA 150 mg once daily and 3.6% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to decreased BMD. Common Adverse Reactions: Adverse reactions reported in ≥ 5% of women in the two placebo-controlled trials in either ORILISSA dose group and at a greater frequency than placebo are noted in the following table.

-1% -2% -3% -4% -5% -6%

# of Subjects Placebo 150 mg Once Daily 200 mg Twice Daily

271 79 79 Month 0

271 79 79

79 79

79 79

Month 6 Month 12 On Treatment

Month 6 Off Treatment

Placebo ORILISSA 150 mg Once Daily ORILISSA 200 mg Twice Daily

Figure 2. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and Had Follow-up BMD 12 Months off Therapy in Studies EM-2/EM-4 1% 0%

Percent Change (95% CI) from Baseline

INDICATIONS AND USAGE ORILISSA is indicated for the management of moderate to severe pain associated with endometriosis.

DOSAGE AND ADMINISTRATION Important Dosing Information • Exclude pregnancy before starting ORILISSA or start ORILISSA within 7 days from the onset of menses.

• Take ORILISSA at approximately the same time each day, with or without food.

• Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives [see Warnings and Precautions].

• Limit the duration of use because of bone loss (Table 1) [see Warnings and Precautions].

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

-1% -2% -3% -4% -5% -6%

# of Subjects 150 mg Once Daily 200 mg Twice Daily

30 51

Month 0

30 51

30 51

Month 6 Month 12 On Treatment

29 48

30 51

Month 6 Month 12 Off Treatment

ORILISSA 150 mg Once Daily ORILISSA 200 mg Twice Daily

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Suicidal Ideation, Suicidal Behavior and Exacerbation of Mood Disorders In the placebo-controlled trials (Studies EM-1 and EM-2), ORILISSA was associated with adverse mood changes (see Table 2 and Table 4), particularly in those with a history of depression.

Table 6. Mean Bleeding/Spotting Days and Mean Intensity Scores at Month 3 ORILISSA 150mg Once Daily

Table 4. Suicidal Ideation and Suicidal Behavior in Studies EM-1 and EM-2 ORILISSA

Adverse Reactions

150 mg Once Daily (N=475) n (%)

200 mg Twice Daily (N=477) n (%)

Placebo (N=734) n (%)

Completed suicide

1 (0.2)

0

0

Suicidal ideation

1 (0.2)

1 (0.2)

0

A 44-year-old woman received 31 days of ORILISSA 150 mg once daily then completed suicide 2 days after ORILISSA discontinuation. She had no relevant past medical history; life stressors were noted.

Among the 2090 subjects exposed to ORILISSA in the endometriosis Phase 2 and Phase 3 studies, there were four reports of suicidal ideation. In addition to the two subjects in Table 4, there were two additional reports of suicidal ideation: one subject in EM-3 (150 mg once daily) and one in a Phase 2 study (75 mg once daily, an unapproved dose). Three of these subjects had a history of depression. Two subjects discontinued ORILISSA and two completed the clinical trial treatment periods.

Hepatic Transaminase Elevations In the placebo-controlled clinical trials (Studies EM-1 and EM-2), dosedependent asymptomatic elevations of serum ALT to at least 3-times the upper limit of the reference range occurred during treatment with ORILISSA (150 mg once daily – 1/450, 0.2%; 200 mg twice daily – 5/443, 1.1%; placebo – 1/696, 0.1%). Similar increases were seen in the extension trials (Studies EM-3 and EM-4).

Changes in Lipid Parameters Dose-dependent increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and serum triglycerides were noted during ORILISSA treatment in EM-1 and EM-2.

In EM-1 and EM-2, 12% and 1% of subjects with mildly elevated LDL-C (130-159 mg/dL) at baseline had an increase in LDL-C concentrations to 190 mg/dL or higher during treatment with ORILISSA and placebo, respectively. In EM-1 and EM-2, 4% and 1% of subjects with mildly elevated serum triglycerides (150-300 mg/dL) at baseline had an increase in serum triglycerides to at least 500 mg/dL during treatment with ORILISSA and placebo, respectively. The highest measured serum triglyceride concentration during treatment with ORILISSA was 982 mg/dL. Table 5. Mean Change and Maximum Increase from Baseline in Serum Lipids in Studies EM-1 and EM-2 ORILISSA 150 mg Once Daily N=475

ORILISSA 200 mg Twice Daily N=477

Placebo N=734

Mean change at Month 6

5

13

-3

Maximum increase during Treatment Period

137

107

122

Mean change at Month 6

2

4

1

Maximum increase during Treatment Period

43

52

45

Mean change at Month 6

<1

11

-3

Maximum increase during Treatment Period

624

484

440

LDL-C (mg/dL)

HDL-C (mg/dL)

Triglycerides (mg/dL)

Lipid increases occurred within 1 to 2 months after the start of ORILISSA and remained stable thereafter over 12 months.

Hypersensitivity Reactions In Studies EM-1 and EM-2, non-serious hypersensitivity reactions including rash occurred in 5.8% of ORILISSA treated-subjects and 6.1% of placebotreated subjects. These events led to study drug discontinuation in 0.4% of ORILISSA-treated subjects and 0.5% of placebo-treated subjects.

Endometrial Effects Endometrial biopsies were performed in subjects in Study EM-1 and its extension at Month 6 and Month 12. These biopsies showed a dosedependent decrease in proliferative and secretory biopsy patterns and an increase in quiescent/minimally stimulated biopsy patterns. There were no abnormal biopsy findings on treatment, such as endometrial hyperplasia or cancer.

Based on transvaginal ultrasound, during the course of a 3-menstrual cycle study in healthy women, ORILISSA 150 mg once daily and 200 mg twice daily resulted in a dose-dependent decrease from baseline in mean endometrial thickness.

Effects on menstrual bleeding patterns The effects of ORILISSA on menstrual bleeding were evaluated for up to 12 months using an electronic daily diary where subjects classified their flow of menstrual bleeding (if present in the last 24 hours) as spotting, light, medium, or heavy. ORILISSA led to a dose-dependent reduction in mean number of bleeding and spotting days and bleeding intensity in those subjects who reported menstrual bleeding.

03-B671 ORILISSA PB 7.625 x 10.5(2-1/3).indd 2

ORILISSA 200mg Twice Daily

Placebo

Baseline Month 3 Baseline Month 3 Baseline Month 3 Mean bleeding/ spotting days in prior 28 days

5.3

2.8

5.7

0.8

5.4

4.6

Mean Intensity scorea

2.6

2.2

2.5

2.0

2.6

2.4

aIntensity

for subjects who reported at least 1 day of bleeding or spotting during 28 day interval. Scale ranges from 1 to 4, 1 = spotting, 2 = light, 3 = medium, 4 = heavy ORILISSA also demonstrated a dose-dependent increase in the percentage of women with amenorrhea (defined as no bleeding or spotting in a 56-day interval) over the treatment period. The incidence of amenorrhea during the first six months of treatment ranged from 6-17% for ORILISSA 150 mg once daily, 13-52% for ORILISSA 200 mg twice daily and less than 1% for placebo. During the second 6 months of treatment, the incidence of amenorrhea ranged from 11-15% for ORILISSA 150 mg once daily and 46-57% for ORILISSA 200 mg twice daily.

After 6 months of therapy with ORILISSA 150 mg once daily, resumption of menses after stopping treatment was reported by 59%, 87% and 95% of women within 1, 2, and 6 months, respectively. After 6 months of therapy with ORILISSA 200 mg twice daily, resumption of menses after stopping treatment was reported by 60%, 88%, and 97% of women within 1, 2, and 6 months, respectively.

After 12 months of therapy with ORILISSA 150 mg once daily resumption of menses after stopping treatment was reported by 77%, 95% and 98% of women within 1, 2, and 6 months respectively. After 12 months of therapy with ORILISSA 200 mg twice daily resumption of menses after stopping treatment was reported by 55%, 91% and 96% of women within 1, 2, and 6 months respectively.

DRUG INTERACTIONS Potential for ORILISSA to Affect Other Drugs Elagolix is a weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with ORILISSA may decrease plasma concentrations of drugs that are substrates of CYP3A. Elagolix is an inhibitor of efflux transporter P-glycoprotein (P-gp).

Co-administration with ORILISSA may increase plasma concentrations of drugs that are substrates of P-gp (e.g., digoxin).

Potential for Other Drugs to Affect ORILISSA Elagolix is a substrate of CYP3A, P-gp, and OATP1B1.

Concomitant use of ORILISSA 200 mg twice daily and strong CYP3A inhibitors for more than 1 month is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and strong CYP3A inhibitors to 6 months.

Co-administration of ORILISSA with drugs that induce CYP3A may decrease elagolix plasma concentrations.

The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of ORILISSA is unknown. Co-administration of ORILISSA with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Concomitant use of ORILISSA and strong OATP1B1 inhibitors (e.g., cyclosporine and gemfibrozil) is contraindicated.

Drug Interactions - Examples and Clinical Management Table 7 summarizes the effect of co-administration of ORILISSA on concentrations of concomitant drugs and the effect of concomitant drugs on ORILISSA. Table 7. Established Drug Interactions Based on Drug Interaction Trials

Concomitant Drug Class: Drug Name

Effect on Plasma Exposure of Elagolix or Concomitant Drug

Clinical Recommendations

↑ digoxin

Clinical monitoring is recommended for digoxin when co-administered with ORILISSA.

Antimycobacteria ↑ elagolix rifampin

Concomitant use of ORILISSA 200 mg twice daily and rifampin is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and rifampin to 6 months.

Antiarrhythmics digoxin

Benzodiazepines oral midazolam

↓ midazolam

Consider increasing the dose of midazolam and individualize therapy based on the patient’s response.

Statins rosuvastatin

↓ rosuvastatin

Consider increasing the dose of rosuvastatin.

The direction of the arrow indicates the direction of the change in the area under the curve (AUC) (↑= increase, ↓ = decrease).

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss. Use of ORILISSA is contraindicated in pregnant women.

Discontinue ORILISSA if pregnancy occurs during treatment.

The limited human data with the use of ORILISSA in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with ORILISSA, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups (see Data).

When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the maximum recommended human dose (MRHD).

Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively (see Data).

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

Data Human Data There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with ORILISSA for up to 12 months. These pregnancies occurred while the women were receiving ORILISSA or within 30 days after stopping ORILISSA. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 15 days of pregnancy.

Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in ORILISSA clinical trials, there were no apparent decreases in birth weights associated with ORILISSA in comparison to placebo.

Animal Data Embryofetal development studies were conducted in the rat and rabbit.

Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/ dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).

In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest, maternally toxic dose, which was 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD. No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development.

The rat study is still expected to provide information on potential non-targetrelated effects of elagolix.

In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were unaffected.

Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.

Lactation Risk Summary There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. There are no adequate animal data on the excretion of ORILISSA in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORILISSA and any potential adverse effects on the breastfed child from ORILISSA. Data There are no adequate animal data on excretion of ORILISSA in milk.

Females and Males of Reproductive Potential Based on the mechanism of action, there is a risk of early pregnancy loss if ORILISSA is administered to a pregnant woman [see Use in Specific Populations].

Pregnancy Testing Exclude pregnancy before initiating treatment with ORILISSA. Perform pregnancy testing if pregnancy is suspected during treatment with ORILISSA [see Warnings and Precautions].

Contraception Advise women to use effective non-hormonal contraception during treatment with ORILISSA and for one week after discontinuing ORILISSA [see Warnings and Precautions and Drug Interactions].

Pediatric Use Safety and effectiveness of ORILISSA in patients less than 18 years of age have not been established.

Renal Impairment No dose adjustment of ORILISSA is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis).

Hepatic Impairment No dosage adjustment of ORILISSA is required for women with mild hepatic impairment (Child-Pugh A). Only the 150 mg once daily regimen is recommended for women with moderate hepatic impairment (Child-Pugh B) and the duration of treatment should be limited to 6 months.

ORILISSA is contraindicated in women with severe hepatic impairment (Child-Pugh C) [see Contraindications].

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OVERDOSAGE In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies conducted in mice (50, 150, or 500 mg/kg/day) and rats (150, 300, or 800 mg/kg/day) that administered elagolix by the dietary route revealed no increase in tumors in mice at up to 19-fold the MRHD based on AUC. In the rat, there was an increase in thyroid (male and female) and liver (males only) tumors at the high dose (12 to 13-fold the MRHD). The rat tumors were likely species-specific and of negligible relevance to humans.

Elagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus assay.

In a fertility study conducted in the rat, there was no effect of elagolix on fertility at any dose (50, 150, or 300 mg/kg/day). Based on AUC, the exposure multiple for the MRHD in women compared to the highest dose of 300 mg/kg/day in female rats is approximately 5-fold. However, because elagolix has low affinity for the GnRH receptor in the rat [see Use in Specific Populations], and because effects on fertility are most likely to be mediated via the GnRH receptor, these data have low relevance to humans.

03-B671 ORILISSA PB 7.625 x 10.5(2-1/3).indd 3

PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Advise patients on contraceptive options, not to get pregnant while using ORILISSA, to be mindful that menstrual changes could reflect pregnancy and to discontinue ORILISSA if pregnancy occurs [see Contraindications and Warnings and Precautions].

• Inform patients that estrogen containing contraceptives are expected to reduce the efficacy of ORILISSA. • Inform patients about the risk of bone loss. Advise adequate intake of calcium and vitamin D [see Warnings and Precautions].

• Advise patients to seek immediate medical attention for suicidal ideation and behavior. Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention [see Warnings and Precautions].

• Counsel patients on signs and symptoms of liver injury [see Warnings and Precautions].

• Instruct patients who miss a dose of ORILISSA to take the missed dose on the same day as soon as she remembers and then resume the regular dosing schedule: ° 150 mg once daily: no more than 1 tablet each day should be taken. ° 200 mg twice daily: no more than 2 tablets each day should be taken.

• Instruct patients to dispose of unused medication via a take-back option if available or to otherwise follow FDA instructions for disposing of medication in the household trash, www.fda.gov/drugdisposal, and not to flush down the toilet.

Manufactured by AbbVie Inc. North Chicago, IL 60064 © 2018 AbbVie Inc. All rights reserved.

Ref: 03-B671 Revised: July, 2018 206-1956816 MASTER

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CÁNCER DE PRÓSTATA EN PUERTO RICO

Agentes infecciosos

Bacteria

Virus

En cifras: de los diagnósticos en Puerto Rico son por cáncer de próstata.

En 2017 se diagnosticó cáncer de próstata a 180.000 hombres en Estados Unidos.

39 %

de todas las 17,6 % muertes por cáncer en la isla del 2008 - 2012, estuvieron asociadas al cáncer de próstata.

En promedio, cada año mueren 515 hombres a causa de la enfermedad.

El cáncer de próstata es el tipo de cáncer más común en hombres. Le siguen el cáncer de vejiga y cáncer de riñón, respectivamente.

Factores de riesgo 40 años es la edad ideal en Puerto Rico para que los hombres visiten al urólogo debido a la mortalidad y la agresividad de este cáncer que es mayor en la isla que en otros países.

50 años. A partir de esta edad se diagnostica con mayor frecuencia.

Lugar de procedencia: El cáncer de próstata es una enfermedad común en Norteamérica, las islas del Caribe, Europa y Australia.

Grupo étnico: Los hombres africanos o con ascendencia africana que viven en el Caribe son más propensos a este tipo de cáncer.

Ocupación: Hombres con exposición al cadmio (trabajo de soldaduras, producción de baterías alcalinas y similares).

Estilo de vida: Fumar, consumir alimentos ricos en grasas y alcohol, obesidad y diabetes. En Puerto Rico, hay un 78% de prevalencia de obesidad y una tasa de 13.8% de diabetes.

Heridas

Alcohol

Hipotermia

Obesidad

6 de 10 casos se detectan en hombres mayores de 65 años.

Se cree que la población puertorriqueña presenta un fenotipo de cáncer de próstata más agresivo que el de la población residente en Estados Unidos.

La tasa de supervivencia de 5 años de la mayoría de los hombres con cáncer de próstata es del 99%. El 98% está vivo después de 10 años, y el 95% vive 15 años o más.

Hormonas

Estres

Estilo de vida

Fuentes: RICARDO SÁNCHEZ-ORTIZ, MD - ESPECIALISTA EN UROLOGÍA - ONCOLOGÍA // HOSPITAL HIMA SAN PABLO - BAYAMÓN DR. RAÚL MORALES BORGES // Especialista en Hematología - Oncología DR. William Román Torreguitart // Especialista en Urología Sociedad Americana Contra el Cáncer

Hongos

Necesidad de orinar con mayor frecuencia, sobre todo en la noche.

Sangrado al orinar

Dolo r / ardor al orinar o eyacular

Dificultad para lograr una erección

Pérdida del control en la vejiga o los intestinos

Diagnósticos y tratamiento: Examen rectal: El médico realiza la palpación de la próstata en busca de agrandamiento o áreas firmes.

Biopsia: Extracción del tejido de la próstata que se analiza en laboratorio en búsqueda de células cancerosas.

Prueba sanguínea del antígeno prostático: Las células sanas y cáncerosas producen el antígeno. A mayor nivel de antígeno, mayor probabilidad de padecer cáncer de próstata.

Cirugía: Consiste en la extracción de la glándula, tejido circundante afectado, incluyendo las vesículas seminales.

Monitoreo clínico: A través de diferentes técnicas se previene y chequea el crecimiento del cáncer.

Radioterapia o Quimioterapia Terapia hormonal: Se reduce hormonalmente la producción del antígeno prostático.

En Puerto Rico se evalúan nuevas opciones de tratamiento. Algunos estudios sugieren que el tratamiento hormonal no es efectivo en ciertos pacientes así que se buscan nuevos tratamientos hormonales y nuevos medicamentos orales.

Etapa I

Etapa II

Etapa III

Diseño: Pablo Andrés Bermúdez Robayo Textos: Susana María Rico Barrera

Etapa IV

BACK ON PROGRESSION

FOR PATIENTS WITH NON-METASTATIC CRPC On ADT With a rapidly rising PSA*

In the SPARTAN study†: ERLEADA™ (apalutamide) + ADT improved median metastasis-free

And no radiographically detectable metastases

(40.5 months vs 16.2 months; HR=0.28; 95% CI: 0.23, 0.35; P<0.0001)

survival (MFS) by 2 YEARS (24.3 months) vs placebo + ADT 1

��INTRODUCING��

• An androgen receptor inhibitor indicated for the treatment of patients with non-metastatic CRPC1 • Once-daily oral dosing with no additional laboratory monitoring requirements 1

*PSA doubling time ≤10 months.

Study Design: SPARTAN was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of patients with non-metastatic CRPC (N=1207). Patients had a PSA doubling time to be ≤10 months and serum testosterone levels <50 ng/dL. All patients in the SPARTAN trial received a concomitant GnRH analog or ha non-metastatic by blinded central imaging review. Patients were randomized 2:1 to receive ERLEADA™ 240 mg orally once daily + ADT or placebo orally once daily + ADT. The primary endpoint was oft 1-3 tissue lesions or enlarged lymph nodes above the iliac bifurcat ADT = androgen-deprivation therapy; CRPC = castration-resistant prostate cancer; GnRH = gonadotropin-releasing hormone; HR = h e Prostate Androgen Receptor Targeting with ARN-509.

3. Smith MR, Saad F, Chowdhury S, et al; for the SPARTAN Investigators.

References: 1. ERLEADA™ [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc. 2.

Apalutamide treatment and metastasis-free survival in prostate cancer [published online February 8, 2018]. N Engl J Med. doi:10.1056/NEJMoa1715546.

†

Please see brief summary of full Prescribing Information for ERLEADA™ on subsequent pages.

Visit erleadahcp.com

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Análisis de supervivencia en pacientes diagnosticados con cáncer de pulmón y bronquios en Puerto Rico Por: Programa Graduado de Maestría en Salud Pública, Escuela de Medicina San Juan Bautista: Yettdalí Williams Robles, Mariana D. Padilla Velázquez, María González Solís, Isa D. Torres Santiago, Amarilis Rosario Guzmán, María del Sol Cotto López, Camila Vera Gay, Francisco Javier Parga, PhD, Alexis Vera, DBA, Yaritza Díaz Algorri, DrPH

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Resumen Antecedentes: En Puerto Rico se utilizan aproximadamente $12 billones en fondos para el Plan de Salud del Gobierno. Se necesita evaluar la efectividad del acceso a los servicios de salud y el impacto que esto tiene en la supervivencia de los pacientes diagnosticados con cáncer de pulmón y bronquios.

Objetivo: Determinar la supervivencia total por etapa específica a dos años de los residentes en Puerto Rico con cáncer de pulmón y bronquios por tipo de seguro médico y tratamiento durante el periodo 2008-2012.

Método: Estudio de cohorte retrospectivo, utilizando los datos del Registro Central de Cáncer de Puerto Rico (N=2,660). Se realizó un análisis univariado describiendo las características sociodemográficas y clínicas de la población, análisis bivariado asociando las variables sociodemográficas y clínicas por tipo de seguro médico y estado vital. Para el análisis multivariado se utilizó la regresión de Cox para riesgos proporcionales,

comparando el riesgo de mortalidad por tipo de seguro médico. Resultados: La mayoría de los pacientes fueron diagnosticados en etapa de metástasis distante (38.92%).

La mediana de supervivencia para los usuarios del Plan de Salud del Gobierno fue de 5 meses, mientras que la mediana de supervivencia entre los usuarios de Medicare fue de 7 meses y en los participantes usuarios de seguro privado fue de 12 meses. La diferencia en supervivencia fue mayor por sexo, específicamente en hombres (HR= 1.39; IC 95%: 1.25-1.55; p <0.001), grupo de edad igual o mayor a 69 años (HR=1.54; IC 95%: 1.36-1.74; p <0.001) y tipo de seguro médico. Se observó mayor riesgo de mortalidad en los participantes usuarios del Plan de Salud del Gobierno (HR= 1.34; IC 95%: 1.14-1.59; p <0.001). Conclusiones: Se observó que existe disparidad en la supervivencia por etapa del tumor y tipo de seguro médico en los pacientes diagnosticados con cáncer de pulmón y bronquios de Puerto Rico.

Palabras Clave: Tratamiento, Seguro médico, Etapa del tumor, Supervivencia, Mortalidad, Disparidad.

Abstrac: Treatment, Health Insurance, tumor stage, survival, mortality, disparity.

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Abstract Background: In Puerto Rico $12 billion in funds are destined to the Government Health Plan. It is necessary to evaluate the access to the health services and the impact that this has on the survival of patients diagnosed with lung cancer. Objective: To determine the overall survival by stage of the residents of Puerto Rico with lung cancer by insurance type and treatment between 2008 and 2012. Methods: The study was a retrospective cohort, using the data from the Puerto Rico Central Cancer Registry (N=2,660). A univariate analysis describing the sociodemographic and clinical characteristics of the population was performed, as well as a bivariate analysis to evaluate associations between sociodemographic and clinical variables by insurance type and vital status. Cox proportional hazards regression models were used to compute and compare hazard ratios (HR) and 95% confidence intervals

Introducción El cáncer de pulmón y bronquios tanto a nivel mundial, en los Estados Unidos y en Puerto Rico representa una de las principales causas de muerte por cáncer; esta condición no conoce grupo étnico, sexo y/o nivel socioeconómico. Durante el periodo 2008–2012 en Puerto Rico, se observaron 3,732 casos de cáncer de pulmón y bronquios, y se registraron 3,052 muertes (Registro Central de Cáncer de Puerto Rico, 2016). En Puerto Rico el cáncer de pulmón y bronquios representa la segunda causa de muerte por cáncer en hombres y la tercera causa de muerte en mujeres (Registro Central de Cáncer de Puerto Rico, 2016). Esta investigación, va dirigida a analizar la supervivencia de cáncer de pulmón y bronquios de acuerdo al tipo de seguro médico. Los cuidados de salud dependen de la capacidad económica de la persona para cubrir el costo de los mismos, lo que deja a un sector de la población en desventaja al momento de costear los tratamientos y otros gastos médicos (Oficina de Gerencia y Presupuesto, 2015).

En Puerto Rico -durante el año 2011- el 7.6% de la población carecía de la cobertura de un seguro de 56

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(IC) for long-term mortality by insurance type.

Results: A 38.92% of the patients were diagnosed at distant metastasis stage. The median survival for patients with the Government Health Care Plan was 5 months, for patients with Medicare the median survival was 7 months, and for the patients with Private insurance was 12 months.

Difference in survival was observed by sex, specifically in men (HR= 1.39; IC 95%: 1.251.55; p <0.001), and age group ≥ 69 (HR=1.54; IC 95%: 1.36-1.74; p <0.001) and insurance type. Patients with the Government Health Plan had statistically significant increase in the risk of death (HR= 1.34; IC 95%: 1.141.59; p <0.001). Conclusion: Disparities in survival were observed by stage of the tumor and insurance type in the patients diagnosed with Lung cancer in Puerto Rico. Key words: Lung cancer, Puerto Rico, treatment, health insurance, stage, survival, mortality, disparity.

salud (Rodríguez, Geerman, & Pesante, 2012). Además, el 57.7% de la población contaba con la cobertura del seguro del estado (Rodríguez, Geerman, & Pesante, 2012). Mientras que la población que contaba con un seguro de salud privado representaba el 40.8% (Rodríguez, Geerman, & Pesante, 2012). La población asegurada por el plan público de salud se redujo en el 2007, y en años posteriores aumentó la cantidad de personas cubiertas (Rodríguez, Geerman, & Pesante, 2012). De acuerdo a los datos de abril de 2012, la distribución por sexo de la población cubierta por el seguro público de salud, era de un 54.8% mujeres y un 45.2% hombres (Rodríguez, Geerman, & Pesante, 2012).

El nivel socioeconómico representa una disparidad al acceso de los servicios de salud. El tipo de seguro médico es el determinante principal al momento de diagnóstico y el tipo de tratamiento que el paciente recibe. En Puerto Rico se utilizan aproximadamente $12 billones en fondos para el seguro médico del Gobierno (Ortiz, Ramírez, Cruz, Ríos, & Ortiz, 2014). Se necesita evaluar la efectividad del acceso a los servicios de

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salud y el impacto que esto tiene en la supervivencia de los pacientes diagnosticados con cáncer de pulmón y bronquios en la isla. Esto a su vez representaría una diferencia en la supervivencia del paciente con cáncer de pulmón y bronquios. Es de gran importancia lograr identificar posibles limitaciones en los servicios de salud del país, para pacientes con el tipo de cáncer que tratamos en este artículo. De esta manera se podrá reforzar el sistema de servicios de salud y ofrecer una mejor calidad de vida a estos pacientes.

Es por esto que el propósito de esta investigación es estudiar si existe diferencia en la supervivencia de pacientes diagnosticados con cáncer de pulmón y bronquios en el periodo 2008–2012 por tipo de seguro médico y tratamiento. Como primer objetivo se planteó describir las características epidemiológicas, clínicas y sociodemográficas de los residentes en Puerto Rico con un diagnóstico de cáncer de pulmón y bronquios utilizando los datos del Registro Central de Cáncer de Puerto Rico (RCCPR) durante el periodo 2008– 2012.Como primer objetivo se planteó describir la supervivencia total por etapa específica a dos años de los residentes en Puerto Rico con cáncer de pulmón y bronquios utilizando los datos del RCCPR durante el periodo 2008–2012. Finalmente, determinar la supervivencia total por etapa de cáncer específica a dos años de los residentes en Puerto Rico con cáncer de pulmón y bronquios de acuerdo al tipo de seguro médico (Plan de Salud del Gobierno, Medicare y privado) y tratamiento utilizando los datos del RCCPR durante el periodo 2008–2012.

Métodos El diseño de estudio fue un cohorte retrospectivo.

Para este estudio se evaluaron hombres y mujeres residentes de Puerto Rico con 21 años o más. Estos participantes fueron diagnosticados con cáncer de pulmón y bronquios en el periodo 2008–2012. La población de estudio fueron 2,660 casos de cáncer de pulmón y bronquios, se excluyeron 287 casos que no contaban con el criterio de información de seguro médico, 3 casos que pagaban por su atención médica y 119 casos que se desconocía el tipo de seguro médico.

Para una población elegible de 2,251 participantes. Este estudio fue aprobado por el Institutional Review Board de la Escuela de Medicina San Juan Bautista IRB # EMSJB 19-2016.

Se incluyeron todos los tipos histológicos de cáncer de pulmón y bronquios. Los casos fueron extraídos de la base de datos del Registro Central de Cáncer de Puerto Rico y fueron categorizados por tipo histológico de acuerdo al ICD-O-3. Los sujetos fueron residentes de Puerto Rico de 21 años o más y diagnosticados con cáncer de pulmón y bronquios primario durante el periodo 2008–2012. Los participantes contaban con la información de seguro médico al momento del diagnóstico. Se excluyeron los sujetos que fueron diagnosticados en Puerto Rico y recibieron tratamiento, pero no residen en la Isla. No se incluyeron casos con cáncer de pulmón y bronquios in-situ y aquellos casos que fueron diagnosticados mediante autopsia.

Las variables sociodemográficas utilizadas en el estudio fueron las siguientes: sexo, edad, índice socioeconómico, tipo de seguro médico y municipio. Las variables clínicas fueron: histología, etapa, lateralidad, tratamiento, fecha de diagnóstico y fecha de último contacto.

Se extrajeron las variables por etapa al momento del diagnóstico y tratamiento en las instalaciones del RCCPR mediante los programas Path Plus y Claims.

Al finalizar el trabajo de recuperación de datos se realizó un control de calidad del 5% de los datos. En este proceso se evaluó que la información obtenida se reportó correctamente. Además se usó la información secundaria obtenida del RCCPR para determinar la etapa del tumor al momento de diagnóstico, el tipo de seguro médico, el tipo histológico y el tratamiento en los residentes de Puerto Rico con cáncer de pulmón y bronquios, durante el periodo 2008–2012. Estos datos fueron provistos por el RCCPR de manera encriptada y de-identificada a través de una conexión segura (Secure File Transfer Protocol o SFTP) en formato de Microsoft Excel©.

Se realizó un análisis de supervivencia por medio del programa estadístico STATA (StataCorp. 2015.

Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). Para el cumplimiento del primer objetivo se realizó un análisis univariado en las siguientes variables categóricas: histología, sexo, etapa al momento del diagnóstico, lateralidad, índice socioeconómico (SEP) y tratamiento (quimioterapia, radioterapia y combinación de radioterapia y quimioterapia). De acuerdo al segundo objetivo, se determinó la supervivencia total por etapa específica a Revista Puertorriqueña de Medicina y Salúd Pública

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dos años de los residentes en Puerto Rico con cáncer de pulmón y bronquios utilizando los datos del RCCPR durante el periodo 2008–2012. Para la evaluación de este objetivo, se realizó un análisis bivariado para evaluar la asociación entre las variables sociodemográficas y las variables clínicas por tipo de seguro médico y estado vital. La significancia estadística se determinó utilizando la prueba de Pearson’s chi-square o la prueba exacta de Fisher, según fuera necesario. Para las variables cuya asociación resultara estadísticamente significativas se calculó la estadística de Cramer’s V para evaluar la fuerza de asociación.

El método de Kaplan-Meier se utilizó para evaluar la supervivencia por todas las causas, por etapa específica de cáncer de pulmón y bronquios al momento del diagnóstico, por sexo y por tipo de seguro médico.

Este método se utiliza para determinar las tasas de supervivencia de los pacientes de cáncer. En esta etapa del análisis, se eliminaron 399 casos en los que se desconocía la etapa del tumor al momento del diagnóstico. Para comparar las curvas en las gráficas de Kaplan-Meier se realizó la prueba de igualdad de Log-Rank.

Por último, se determinó la supervivencia total por etapa específica del tumor a dos años de los residentes en Puerto Rico con cáncer de pulmón y bronquios de acuerdo al tipo de seguro médico (Plan de Salud del Gobierno, Medicare y privado) y tratamiento utilizando los datos del RCCPR durante el periodo 2008–2012.

Se realizó un análisis multivariado para evaluar la supervivencia a dos años de los pacientes con cáncer de pulmón y bronquios, considerando la variable principal de tipo de seguro médico, categorizada por: Plan de Salud del Gobierno, Medicare y privado. Se realizó una comparación entre la variable principal con la variable de tratamiento, etapa del tumor al momento del diagnóstico, edad al momento del diagnóstico y sexo. El método que se utilizó para realizar el análisis multivariado fue la regresión de Cox para riesgos proporcionales.

Resultados La tabla 1, describe las características sociodemográficas de la población de pacientes con cáncer de pulmón y bronquios durante el periodo de estudio del 2008-2012. En la población se encontró que fueron más los hombres diagnosticados con cáncer de pulmón y bronquios 1,365 (60.64%) en comparación con las mujeres 886 (39.36%). Por otra parte, el grupo 58

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etario con mayor cantidad de pacientes fue el de 69 años o más 1,191 (52.91%), mientras que los menores de 69 años representaban el 47.09% con un total de 1,060 participantes. Al momento del diagnóstico, la mayor cantidad de pacientes residían en municipios con el nivel socioeconómico más alto 1,017 (45.20%), mientras que la menor cantidad de pacientes residían en municipios categorizados con el índice de nivel socioeconómico más bajo, 185 (8.22%). En la población de estudio hubo 398 pacientes vivos (17.68%) y 1,853 muertos (82.32%).

Cuando se diagnosticaron, la mayoría de pacientes contaban con el tipo de seguro médico Medicare 1,266 (56.24%), seguido del tipo de seguro médico Plan de Salud del Gobierno (Medicaid) 628 (27.90%).

Los resultados en la tabla 2, muestran que al momento del diagnóstico la mayoría de los pacientes Variable

Sexo

Frecuencia n (%)

Hombre

1,365 (60.64)

Mujer

886 (39.36)

Total

2,251 (100.00)

Edad al momento del diagnóstico ‹69

1,060 (47.09)

69 Total

1,191 (52.91) 2,251 (100.00)

Índice Socioeconómico 1

185 (8.22)

2 3 4 5

217 (9.64) 322 (14.31) 509 (22.62) 1,017 (42.20)

Total

2,250 (100.00)

Estado Vital Vivo

398 (17.68)

Muerto

1,853 (82.32)

Total

2,251 (100.00)

Tipo de seguro médico Privado

357 (15.86)

Medicaid

628 (27.90) 1,266 (56.24) 2,251 (100.00)

Medicaid Total

Tabla 1 Características sociodemográficas de los pacientes diagnosticados con cáncer de pulmón y bronquios durante el periodo 2008-2012 (N=2,251)

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se encontraban en etapa de metástasis distante 876 (38.92%). Al evaluar la variable tratamiento, se observó que el tratamiento más utilizado fue quimioterapia 568 (25.23%), seguido de radioterapia 425 (18.88%) y cirugía 428 (19.01%). El tratamiento menos utilizado fue la combinación de quimioterapia y radioterapia.

Durante el periodo 2008-2012 la mayor cantidad de pacientes dentro de la población de estudio fueron diagnosticados con una lateralidad derecha 1,081 (48.02%). La clasificación histológica más frecuente en los pacientes fue adenocarcinoma 948 (42.11%), seguido por el carcinoma de células no pequeñas 519 (23.06%).

Al describir la edad en años al momento de diagnóstico, se observó que el rango de edad de la población de estudio fluctúa entre 29 a 99 años y la mediana de edad fue 69 años.

Se realizó un análisis de asociación por tipo de seguro médico, para las variables sociodemográficas. En este se encontró que las variables estadísticamente significativas fueron: la edad al momento del diagnóstico, el índice socioeconómico y el estado vital (valor de p <0.001).

Para las variables sociodemográficas con significancia estadística se reportó el resultado de la estadística de Cramer's V. La asociación más fuerte se encontró en la variable edad al momento de diagnóstico (V = 0.4535). Por otra parte, no se encontró asociación estadísticamente significativa entre sexo y tipo de seguro médico (valor de p = 0.082).

La tabla 4 describe el análisis de asociación por tipo de seguro médico de las variables clínicas. Las variables estadísticamente significativas fueron: quimioterapia (valor de p = 0.037), radioterapia (valor de p = 0.001), combinación de quimioterapia y radioterapia (valor de p = 0.021), cirugía (valor de p <0.001), lateralidad (valor de p = 0.002), e histología (valor de p = 0.001).

La asociación más fuerte se encontró en la variable histología (V = 0.0875). Sin embargo, la variable etapa del tumor no resultó estadísticamente significativa (valor de p = 0.220).

La figura 1 ilustra la supervivencia por grupo etario.

Se observó que el grupo etario de edad igual o mayor a 69 años al momento del diagnóstico de cáncer de pulmón y bronquios tiene menor supervivencia en comparación al grupo etario de menores de 69 años. La supervivencia mediana en el grupo etario de menores de 69 años luego del diagnóstico fue de 15 meses, mientras que en el grupo etario de igual o mayor a 69 años fue de 5 meses. Se observó diferencia estadísticamente significativa en la supervivencia por grupos de edad al

Variable

Frecuencia n (%)

Etapa del tumor Localizado

580(25.77)

Regional

369(16.39)

Metástasis distante

876(38.92)

Etapa desconocida

426(18.92)

Total

2,251(100.00)

Quimioterapia Sí

568(25.23)

No

820(36.43)

Desconocido

863(38.34)

Total

2,251(100.00)

Radioterapia Sí

425 (18.88)

No

1,218(54.11)

Desconocido

608(27.01)

Total

2,251(100.00)

Combinación de quimioterapia y radioterapia Sí

240(10.66)

No

2,011(89.34)

Total

2,251(100.00)

Cirugía Sí

428(19.01)

No

1,090(48.42)

Desconocido

733(32.56)

Total

2,251(100.00)

Lateralidad Bilateral

13(0.58)

Un solo lado involucrado; no especificado

34(1.51)

Sitio pareado; desconocido

327(14.53)

Izquierdo

796(35.36)

Derecho

1,081(48.02)

Total

2,251(100.00)

Histología

Carcinoma de células escamosas

461(20.48)

Carcicoma de células pequeñas

186(8.26)

Adenocarcicoma

948(42.11)

Carcinoma de células grandes

35(1.55)

Tumor carcinode

82(3.64)

Carcinoma de células no pequeñas

519(23.06)

Carcicoma adenoescamoso

20(0.89)

Total

2,251(100.00)

Tabla 2 Características clínicas de los pacientes diagnosticados con cáncer de pulmón y bronquios durante el periodo 2008-2012 (N=2,251) Revista Puertorriqueña de Medicina y Salúd Pública

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Variable

Frecuencia n (%)

Valor-P

Cramer`s

diagnóstico (valor de p <0.0001).

En la figura 4 se ilustran las curvas de supervivencia Hombre 1,365 (60.64) Kaplan-Meier por tipo de seguro médico. Se observó Mujer 886 (39.36) que los participantes usuarios del Plan de Salud del Total 2,251 (100.00) Gobierno tienen menor supervivencia en comparación 0.4535 Edad al momento ‹0.001 a los participantes usuarios del seguro médico del diagnóstico ‹69 1,060 (47.09) Medicare y usuarios de seguro privado. La mediana 69 1,191 (52.91) de supervivencia en los participantes usuarios del Plan Total 2,251 (100.00) de Salud del Gobierno fue de 5 meses. Mientras que la mediana de supervivencia en los participantes usuarios 0.1093 ‹0.001* Índice Socioeconómico de Medicare fue de 7 meses y en los participantes 1 185 (8.22) usuarios de seguro médico privado fue de 12 meses. Se 2 217 (9.64) observó una diferencia estadísticamente significativa 322 (14.31) 3 entre los grupos por tipo de seguro médico (valor de p 509 (22.62) 4 1,017 (42.20) <0.0001).

5 2,250 (100.00) Total En los resultados del análisis multivariado (figura 5.), utilizando la Regresión de Cox, se observó que los 0.1044 ‹0.001* Estado Vital Vivo 398 (17.68) participantes usuarios del Plan de Salud del Gobierno Muerto 1,853 (82.32) al momento del diagnóstico de cáncer de pulmón y 2,251 (100.00) Total bronquios, tienen 34% mayor riesgo de mortalidad ----Tipo de seguro en comparación a los participantes usuarios de seguro médico médico privado. Por otra parte, los hombres tienen Privado 357 (15.86) 39% mayor riesgo de mortalidad en comparación a Medicaid 628 (27.90) 1,266 (56.24) Medicaid las mujeres diagnosticadas con cáncer de pulmón y 2,251 (100.00) Total bronquios. Mientras que los pacientes diagnosticados en *Prueba exacta de Fisher etapa regional tienen 31% mayor riesgo de mortalidad en comparación a los pacientes diagnosticados en etapa Tabla 3 Variables sociodemográficas asociadas a tipo de seguro médico localizada. Además, los pacientes diagnósticados en (N=2,251) etapa metástasis distante tienen aproximadamente dos veces mayor riesgo de mortalidad en comparación a los pacientes diagnosticados en etapa localizada. En el momento del diagnóstico (valor de p <0.0001).

La figura 2 muestra las curvas de supervivencia modelo ajustado por la variable cirugía, se observó que por sexo. Se observó que los hombres tienen los pacientes que no fueron sometidos al procedimiento menor supervivencia en comparación a las mujeres tienen dos veces mayor riesgo de mortalidad en diagnosticadas con cáncer de pulmón y bronquios. La comparación a los pacientes que fueron intervenidos mediana de supervivencia en hombres fue de 6 meses quirúrgicamente. y en mujeres 11 meses. Se observó una diferencia estadísticamente significativa por sexo (valor de p Discusión El cáncer de pulmón y bronquios en Puerto Rico <0.0001).

La figura 3, muestra la supervivencia por etapa. Se representa la segunda causa de muerte en hombres y la observó que los pacientes que fueron diagnosticados en tercera causa de muerte por cáncer en mujeres (Zavala etapa de metástasis distante tienen menor supervivencia et al., 2015). Por lo que estudiar la supervivencia de en comparación con los pacientes que fueron aquellas personas diagnosticadas con esta enfermedad diagnosticados en etapa regional y en etapa localizada. puede tener serias repercusiones en su tratamiento y en La mediana de supervivencia en la etapa de metástasis el diagnóstico de la misma. Los datos recopilados en el distante fue de 4 meses, en la etapa regional fue de presente estudio indican que la mortalidad asociada con 13 meses y en la etapa localizado fue de 14 meses. Se un diagnóstico por este tipo de cáncer puede ser afectado observó una diferencia estadísticamente significativa por características sociodemográficas y clínicas. En en los grupos por etapa del tumor al momento del un estudio realizado en Brasil por Araujo y colegas, Sexo

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0.082

---

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Variable

Etapa del tumor

Frecuencia n (%)

Valor-P

Cramer`s V

por sus siglas en inglés), se comparó la supervivencia de los pacientes con este diagnóstico por tratamiento en Regional 369(16.39) una institución privada. Se observó que la histología Metástasis distante 876(38.92) más común dentro de la población de estudio fue Etapa desconocida 426(18.92) adenocarcinoma (59.0%), similar a la población de Total 2,251(100.00) este estudio donde la histología de adenocarcinoma Quimioterapia 0.037 0.0477 predominó (42.11%), hallazgo que es consistente con Sí 568(25.23) la literatura. En esta investigación se encontró que la No 820(36.43) mayoría de los pacientes fueron diagnosticados en etapa Desconocido 863(38.34) avanzada (79.6%), hallazgo similar al presente estudio, Total 2,251(100.00) en el que se observó que el (38.92%) de los pacientes Radioterapia 0.001 0.0665 fueron diagnosticados en etapa de metástasis distante.

Sí 425 (18.88) Con este descubrimiento se enfatiza la necesidad de No 1,218(54.11) implementar estrategias de prevención primaria para el Desconocido 608(27.01) cáncer de pulmón y bronquios (Araujo et al., 2014).

Total 2,251(100.00) Por otra parte, los hallazgos de este estudio son Combinación de 0.021 0.0585 similares a los de la investigación realizada por quimioterapia y radioterapia Elchoufani y colegas durante el periodo 2001-2010, Sí 240(10.66) en el que se observó disparidad en la supervivencia No 2,011(89.34) por tipo de seguro médico en los Estados Unidos. Se Total 2,251(100.00) encontró que la población con seguro médico Medicaid y un nivel socioeconómico bajo tienen mayor riesgo de Cirugía 0.001 ‹0.0731 Sí 428(19.01) mortalidad. En este estudio se encontró una diferencia No 1,090(48.42) estadísticamente significativa en la supervivencia por Desconocido 733(32.56) sexo y grupo etario (HR= 1.20; IC 95%: 1.04-1.3; p Total 2,251(100.00) <0.05). Por otra parte, en un estudio retrospectivo del Lateralidad 0.002 0.0736 periodo 2003-2006, realizado por Khullar y colegas, Bilateral 13(0.58) utilizando el National Cancer Data Base en los Estados Un solo lado involucrado; 34(1.51) Unidos encontraron, al igual que este estudio, que los no especificado pacientes con índice socioeconómico bajo, no fueron 327(14.53) Sitio pareado; desconocido intervenidos quirúrgicamente, debido al diagnóstico 796(35.36) Izquierdo tardío. La mayoría de los pacientes que no fueron Derecho 1,081(48.02) 2,251(100.00) Total tratados con cirugía fueron diagnosticados en etapa de metástasis distante.

Histología 0.001 0.0875 En resultados comparables a los de este estudio los 461(20.48) Carcinoma de células escamosas pacientes con seguro médico del gobierno tuvieron 186(8.26) Carcicoma de células pequeñas mayor riesgo de mortalidad (HR=1.55; IC 95%: 948(42.11) Adenocarcicoma 35(1.55) Carcinoma de células grandes 1.52-1.58) en comparación a los pacientes con seguro 82(3.64) Tumor carcinode médico privado. Además, en la presente investigación Carcinoma de células no pequeñas 519(23.06) se encontró que el mayor número de pacientes 20(0.89) Carcicoma adenoescamoso diagnosticados con cáncer de pulmón y bronquios 2,251(100.00) Total residían en un municipio de índice socioeconómico *Prueba exacta de Fisher alto. La diferencia en supervivencia fue mayor por sexo, específicamente en hombres (HR= 1.39; IC 95%: 1.25Tabla 4 1.55; p <0.001), grupo de edad igual o mayor a 69 años Variables clínicas asociadas a tipo de seguro médico (N=2,251) (HR=1.54; IC 95%: 1.36-1.74; p <0.001) y tipo de seguro médico, se observó mayor riesgo de mortalidad en los evaluando el periodo de 1998-2010 en la población de participantes usuarios del Plan de Salud del Gobierno pacientes de cáncer de pulmón y bronquios (NSCLC, (HR= 1.34; IC 95%: 1.14-1.59; p <0.001). No se Localizado

580(25.77)

0.220

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Figura 1 75

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observó una diferencia estadísticamente significativa en el riesgo de mortalidad entre los participantes usuarios del seguro médico Medicare y los participantes usuarios con seguro médico privado (HR= 1.02; IC 95%: 0.861.20; p= 0.809).

Niu y colegas (2013), realizaron un estudio para evaluar la disparidad en la supervivencia de acuerdo al tipo de seguro médico. El estudio comparó los siete cánceres más comunes, entre ellos cáncer de pulmón y bronquios. Durante un periodo de investigación comprendido entre 1999 -2004 en los Estados Unidos, excluyendo los pacientes de 65 años o más, ya que son asegurados de Medicare. Se encontró que los participantes usuarios de Medicaid con diagnóstico de cáncer de pulmón y bronquios tienen mayor riesgo de mortalidad (HR= 1.21; IC 95%: 1.08-1.35) en comparación a los participantes usuarios de seguro médico privado. Hallazgo que es similar al observado en este estudio.

Luego de evaluar y ajustar por estas variables se encontró que el riesgo mayor de mortalidad es en hombres, en el grupo etario de 69 años o más y participantes del Plan de Salud del Gobierno (Medicaid).

Se observó que sí existe disparidad en la supervivencia por etapa del tumor y tipo de seguro médico en los pacientes diagnosticados con cáncer de pulmón y bronquios residentes de Puerto Rico. Los participantes que fueron diagnosticados en etapa regional (HR=1.31; IC 95%: 1.12-1.53; p= 0.001) y etapa metástasis distante (HR=1.87; IC 95%: 1.65-2.13; p <0.001), tienen mayor riesgo de mortalidad. Los participantes usuarios del Plan de Salud del Gobierno tienen mayor riesgo de mortalidad, independientemente de la asignación de fondos que provee para mayor acceso a los servicios de salud en Puerto Rico.

La fortaleza principal de este estudio es que los datos pertenecen al RCCPR y son representativos de la población de Puerto Rico. Esto facilitó la realización del diseño de estudio, de naturaleza de cohorte retrospectivo. Como parte de las limitaciones para el estudio, el RCCPR depende de las fuentes que reportan la información. No todas las aseguradoras reportan al RCCPR las reclamaciones con la información del tratamiento que recibieron los participantes. La variable de tratamiento utilizada en el estudio, no considera la dosis, duración y frecuencia. Además, no se recogió información sobre exposición a los factores de riesgo para el desarrollo de cáncer de pulmón y bronquios.

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Figura 4 75

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Edad ‹69

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Figura 5. Resultados Análisis Multivariado

Agradecimientos Queremos agradecer a nuestros mentores: Dra. Yaritza Díaz, Dr. Alexis Vera y Dr. Francisco J. Parga y colaboradores del Registro Central de Cáncer: Dra. Karen J. Ortiz, Carlos Torres, Mariela Alvarado por el apoyo y disposición durante el proceso de nuestra investigación. Además, a las patólogas Dra. Kathia Rosado y Dra. Raisa Balbuena.

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Seminars in Interventional Radiology, 30(2), 93–98. http://doi. org/10.1055/s-0033-1342949 Rodríguez, I., Geerman, K., Pesante, F. Departamento de Salud de Puerto Rico.

54.(2012). Evaluación de la Salud de la Comunidad Puertorriqueña: Perfil de Datos Secundarios. Recuperado de: http:// www.salud.gov.pr/Estadisticas-Registros-yPublicaciones/Publicaciones/Evaluacion%20de%20la%20Salud%20de%20la%20 Comunidad%20Puertorrique%C3%B1a%20Perfil%20de%20 Datos%20Secundarios%20(Espa%C3%B1ol).pdf 55.Sari, A. A., Rezaei, S., Arab, M., Majdzadeh, R., Matin, B. K., & Zandian, H. (2016).

56.Effects of Smoking on Cost of Hospitalization and Length of Stay among Patients with Lung Cancer in Iran: a Hospital-Based Study, 17(9):4421-4426. doi: http://dx.doi.org/10.7314/APJCP.2016.17.9.4421 57.Sebrié, E. M., Schoj, V., & Glantz, S. A. (2008). Smokefree environments in Latin America: on the road to real change? Prevention and Control : The Official Journal of the World Heart Federation, 3(1), 21–35. doi: 10.1016/j.precon.2007.09.001 58.SEER Cancer Statistics Factsheets: Lung and Bronchus Cancer. (2016). National Cancer Institute. Bethesda, MD. Recuperado de: http://seer.cancer.gov/statfacts/html/lungb.html 59.SEER. (2015). ICD-0-3 SEER SITE/HISTOLOGY VALIDATION. Recuperado de: https://seer.cancer.gov/icd-o-3/sitetype.icdo3. d20150918.pdf 60.Shi, R., Diaz, R., Shi, Z., Duvall, E., & Mills, G. (2016). The Effect of Payer Status on Survival of Patients with Stage I/II Nonsmall Cell Lung Cancer: NCDB 1998-2011. 36 (1), 319-26.

61.Sociedad Americana del Cáncer. (2016). Cáncer de Pulmón. Recuperado de: http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancerwhat-is-non-small-cell-lung-cancer 62.Sociedad Americana del Cáncer. (2016). Estadísticas importantes sobre el cáncer de pulmón. Recuperado de: http://www. cancer.org/espanol/cancer/cancerdepulmonnomicrocitico-celulasno/guiadetallada/cancer-de-pulmon-no-microcitico-celulasno-pequenas-what-is-key-statistics 63.Sociedad Americana del Cáncer (2016). Factores de Riesgo del Cáncer de Pulmón. Recuperado de: http://www.cáncer-depulmón-células-pequeñas-causes-risk-factors Sociedad Americana del Cáncer. (2016). Tumor Carcinoide Pulmonar. Recuperado 66

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de: http://www.cancer.org/cancer/lungcarcinoidtumor/index 64.Szabo, E., Mao, J. T., Lam, S., Reid, M. E., & Keith, R. L. (2013).

Chemoprevention of Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 143(5 Suppl),e40S–e60S. http://doi.org/10.1378/chest.12-2348.

65.Taylor, R., Najafi, F., Dobson, A. (2007). Meta-analysis of studies of passive smoking and lung cancer: effects of study type and continent. International Journal of Epidemiology. (36) 1048–1059. doi:10.1093/ije/dym158 66.Thomas, A., Chen, Y., Yu, T., Jakopovic, M., & Giaccone, G. (2015). Trends and Characteristics of Young Non-Small Cell Lung Cancer Patients in the United States. Frontiers in Oncology, 5 (113). doi: 10.3389/fonc.2015.00113 67.Torre, L. A., Siegel, R. L., & Jema, A. (2015). Lung Cancer Statistics. Adv Exp Med Biol., 893, 1-19. doi: 10.1007/978-3-31924223-1_1 68.Torres, M., Ortiz, A. P., Ortiz, K. J., Figueroa, N. R., Perez, J., Díaz, G., … Suárez, E. (2012). Using a Socioeconomic Position Indez to Asses Disparities in Cancer Incidence and Mortality, Puerto Rico, 1995-2004. Preventing Chronic Disease, (9), 100271. doi: http://dx.doi.org/10.5888/pcd9.100271 69.Trédaniel, J., Boffetta, P., Saracci, R., & Hirsch, A. (1994). Exposure to environmental tobacco smoke and risk of lung cancer: the epidemiological evidence. European Respiratory Journal. (7) 1877–1888. doi: 10.1183/09031936.94.07101877 69.Triple-S Salud. (2017). Una Organización del Mantenimiento de la Salud con un producto de Punto de Servicio. Recuperado de: https://www.ssspr.com/wp-content/uploads/2016/11/PolizaFederal-FEHB-SPA-2017.pdf 70.White, C. (1990). Research on Smoking and Lung Cancer: A Landmark in the History of Chronic Disease Epidemiology. The Yale Journal of Biology and Medicine 63 (1990), 29-46.

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Deutsches Ärzteblatt International, 108(10), 163–169. http://doi.org/10.3238/arztebl.2011.0163

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

+

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

+

DVT/PE Demonstrated to be superior to aspirin in reduction in the risk of recurrence†3 †

After 6 months initial treatment.

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

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

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

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

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

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

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

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

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

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

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

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

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

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

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

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

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

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

WARNINGS AND PRECAUTIONS (cont’d)

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

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

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

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

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

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

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

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

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

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

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

®

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

Janssen Pharmaceuticals, Inc.

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

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

DRUG INTERACTIONS

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

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

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

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

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

USE IN SPECIFIC POPULATIONS

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

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

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

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

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

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

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

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

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

OVERDOSAGE

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

ADVERSE REACTIONS IN CLINICAL STUDIES

Most common adverse reactions with XARELTO® were bleeding complications.

cp-62551v2

IMPORTANT SAFETY INFORMATION (cont’d)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Parameter

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

Major Bleeding†

XARELTO vs. Warfarin HR (95% CI)

395 (3.6)

386 (3.5)

1.04 (0.90, 1.20)

55 (0.5)

84 (0.7)

0.67 (0.47, 0.93)

Hemorrhagic Stroke§

36 (0.3)

58 (0.5)

0.63 (0.42, 0.96)

Other ICH

19 (0.2)

26 (0.2)

0.74 (0.41, 1.34)

221 (2.0)

140 (1.2)

1.61 (1.30, 1.99)

27 (0.2)

55 (0.5)

0.50 (0.31, 0.79)

ICH

24 (0.2)

42 (0.4)

0.58 (0.35, 0.96)

Non-intracranial

3 (0.0)

13 (0.1)

0.23 (0.07, 0.82)

Intracranial Hemorrhage (ICH)‡

Gastrointestinal

(GI)¶

Fatal Bleeding#

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

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

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

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

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

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

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

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

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

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

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

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

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

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

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

Total treated patients Major bleeding event

XARELTO 10 mg

Enoxaparin†

N=4487 n (%)

N=4524 n (%)

14 (0.3)

9 (0.2)

Fatal bleeding

1 (<0.1)

0

Bleeding into a critical organ

2 (<0.1)

3 (0.1)

Bleeding that required re-operation

7 (0.2)

5 (0.1)

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

4 (0.1)

1 (<0.1)

261 (5.8)

251 (5.6)

N=3281 n (%)

N=3298 n (%)

Any bleeding event‡ Hip Surgery Studies Major bleeding event

7 (0.2)

3 (0.1)

Fatal bleeding

1 (<0.1)

0

Bleeding into a critical organ

1 (<0.1)

1 (<0.1)

Bleeding that required re-operation

2 (0.1)

1 (<0.1)

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

3 (0.1)

1 (<0.1)

201 (6.1)

191 (5.8)

N=1206 n (%)

N=1226 n (%)

7 (0.6)

6 (0.5)

0

0

Bleeding into a critical organ

1 (0.1)

2 (0.2)

Bleeding that required re-operation

5 (0.4)

4 (0.3)

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

1 (0.1)

0

60 (5.0)

60 (4.9)

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

Any bleeding event‡

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

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

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

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

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

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

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

Parameter Modified ISTH Major Bleeding‡

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

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

144 (0.9)

1.84 (1.50, 2.26)

12 (<0.1)

8 (<0.1)

1.51 (0.62, 3.69)

6 (<0.1) 6 (<0.1)

3 (<0.1) 5 (<0.1)

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

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

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

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

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

7 (<0.1)

6 (<0.1)

1.17 (0.39, 3.48)

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

188 (1.1)

91 (0.5)

2.08 (1.62, 2.67)

117 (0.7)

49 (0.3)

2.40 (1.72, 3.35)

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

Major GI bleeding

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

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

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

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

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

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

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

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

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

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

© 2011 Janssen Pharmaceutical Companies cp-62544v2

MSP ARTÍCULO DE ORIGINAL REVISIÓN

Lo último sobre “gluten-free” y enfermedad celíaca Medicina, nutrición y tecnología

Por: Carlos Micames Cáceres, MD, AGAF, FASGE Presidente de la Asociación Puertorriqueña de Gastroenterología Gastroenterólogo especializado en endoscopía intervencional

Aida N. Sisco Oquendo, RDN, LND, DEPR, DysC

Madeline A. Velázquez Méndez, estudiante de Microbiología Industrial

Resumen Las personas con enfermedad celíaca manifiestan síntomas como resultado de una respuesta autoinmune hacia el intestino y otros órganos al ser expuesto a la proteína del gluten. La terapia médiconutricional es clave dentro del tratamiento de esta condición. Es responsable de evitar deficiencias nutricionales, dado a que la dieta y los productos libre de gluten tienden a ser bajos en vitaminas del complejo B, calcio, vitamina D, hierro, zinc, magnesio y fibra. Dentro del enfoque de la educación se encuentra: identificar las fuentes de gluten y evitar la contaminación cruzada con el gluten antes, durante y después de la preparación de alimentos. El Nutricionista – Dietista en colaboración con el individuo establecen el plan nutricional que responda a las necesidades de tratamiento, preferencias alimentarias, estilo de vida y actividad física.

76

Revista Puertorriqueña de Medicina y Salúd Pública

Abstract Individuals with celiac disease will manifest symptoms as a result of an autoimmune reaction to the intestine and other organs when exposed to gluten in their diet. Medical nutrition therapy is key in the treatment of celiac disease. It is responsible for preventing nutritional deficiencies, due to the low Vitamin B Complex, Calcium, Vitamin D, Iron, Magnesium and Fiber levels present in Gluten Free Products and Gluten Free Diet. The main goals of education are: identifying food sources of gluten and avoidance of gluten crosscontamination before, during and after food preparation. The Registered Dietitian Nutritionist establishes a nutritional plan, which responds to treatment needs, food preferences, lifestyle, and physical activity of the individual diagnosed with this condition.

Palabras claves Enfermedad celíaca, Libre de gluten, Contaminación cruzada, Condición autoinmune, Aplicaciones electrónicas.

Keywords Celiac disease, gluten-free, crosscontamination, autoimmune disease, Apps

MSP ARTÍCULO DE ORIGINAL REVISIÓN

“En Estados Unidos la prevalencia aumentó por un factor de cinco y se estima que el número de casos con enfermedad celiaca (EC) se duplicará cada 15 años.

Este aumento también se ha visto en países y regiones del mundo, en desarrollo, como África y Asia.”

L

as personas con enfermedad celíaca presentan múltiples síntomas a causa de la exposición al gluten. Dicha proteína está presente en el trigo, el centeno y la cebada. Esta enfermedad es sistémica autoinmune, porque el sistema inmunológico ataca células sanas del tracto digestivo y otras partes del cuerpo.

Síntomas y diagnóstico.

Las dietas libre de gluten son más populares en la población a causa de diversos síntomas o condiciones.

De hecho, hay personas que se identifican como “sensitivos” al gluten sin tener enfermedad celíaca (sensibilidad al gluten no celiaca-SGNC).

La incidencia de esta enfermedad incrementó en años recientes. En Estados Unidos la prevalencia aumentó por un factor de cinco y se estima que el número de casos con enfermedad celíaca (EC) se duplicará cada 15 años. Este aumento también se ha visto en países y regiones del mundo, en desarrollo, como África y Asia.

Esto se debe a que adoptan una dieta más “occidental” que contiene una mayor exposición a harinas. En Latinoamérica la prevalencia es similar a la de Europa, en particular en regiones con una población de descendencia caucásica.

El hecho de tener síntomas que se manifiesten o exacerben al ingerir alimentos con gluten, no es suficiente criterio para hacer un diagnóstico. El paciente celíaco tiene susceptibilidad genética y reacción al gluten, lo que resulta en inflamación y daño del intestino delgado. los síntomas clásicos de la EC, contrario a los adultos, a quienes no les sucede tan frecuente. Es común que en niños se manifieste con dolor abdominal

recurrente o problemas de crecimiento (baja estatura, fracaso para prosperar). Se debe tener en cuenta que apenas un 10% de casos pediátricos se presentan con diarreas. En particular, aquellos diagnosticados en edades bien tempranas. Hay algunos niños que son obesos a pesar de tener esta condición.

Aunque la diarrea suele ser un síntoma que hace sospechar al médico, la mayor parte de adultos diagnosticados con EC no padecen de este síntoma. Los adultos celíacos suelen presentar síntomas atípicos como anemia, osteoporosis, “rash” (dermatitis herpetiformis como muestra la Foto A), dolor abdominal, infertilidad, deficiencia de vitaminas y problemas neurosiquiátricos.

Se estima que hasta un 22% de pacientes celiacos desarrollan trastornos neurológicos y siquiátricos.

Algunas manifestaciones incluyen: ataxia, convulsiones, neuropatía periferal, y trastornos siquiátricos como depresión, ansiedad, déficit de atención e hiperactividad, autismo y esquizofrenia. Estudios con números pequeños de pacientes celíacos y SGNCs, demostraron mejoría de estos síntomas neurosiquiátricos al eliminar gluten de la dieta.7 Aunque el resultado de este estudio es prometedor, esperamos que se replique con un mayor número de pacientes. Así se podrá concluir si eliminar el gluten es efectivo o no, para estos síntomas específicos.

Cuando se sospecha padecer la EC, se recomienda una evaluación inicial con pruebas serológicas de sangre. Antes de hacerse estas pruebas, es importante no reducir o eliminar la ingesta de gluten para evitar que se alteren los resultados. La presencia de inmunoglobulina A (IgA) contra la transglutaminasa tisular (TTG - tissue transglutaminase) es la más precisa y debe ser la utilizada. Hay una mayor incidencia de Revista Puertorriqueña de Medicina y Salúd Pública

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MSP ARTÍCULO ORIGINAL

“Los adultos celíacos suelen presentar síntomas atípicos como anemia, osteoporosis, “rash” (dermatitis herpetiformis como muestra la Foto A), dolor abdominal, infertilidad, deficiencia de vitaminas y problemas neurosiquiátricos” comienzo del intestino delgado, individuo. Esta prueba posee un conocido como el duodeno, y valor predictivo negativo de casi se envían para patología a ser un 100%. Por eso, es más útil analizadas. Los cambios patológicos para descartar la posibilidad de la pueden suceder en parches, o sea que EC en pacientes con diagnóstico se recomienda tomar un mínimo incierto. También, es útil para de cuatro muestras de la segunda hacer el diagnóstico en pacientes o tercera porción del duodeno. que eliminan el gluten de su dieta Asimismo, una del bulbo duodenal y no quieren volver a ingerir Dermatitis Herpetiformis en piernas. para aumentar la probabilidad de alimentos regulares. Al no tener esta Foto: Ballena Blanca via Creative detectar la condición. exposición, las pruebas serológicas Commons La EC sucede solo en individuos pueden resultar negativas y no con la predisposición genética. ref lejar los cambios esperados en deficiencia de IgA en pacientes La prueba para determinar la las biopsias de duodeno. Se estima celiacos comparados con la presencia de los alelos HLA-DQ2 que un 20-30% de la población población en general. Si al verificar y –DQ8 ayuda a determinar la en Europa y EEUU contienen los el nivel total de lgA, se detecta un susceptibilidad genética de cada alelos HLA-DQ2/DQ8, lo cual los nivel bajo de esta inmunoglobulina; se recomienda entonces otro tipo de pruebas. En estos casos, las pruebas de anticuerpos contra la gliadina o endomiseo ya no son recomendadas porque tienen una precisión diagnóstica inferior. Se debe medir el nivel de la inmunoglobulina G (IgG) contra el péptido de gliadina deaminado (DGP – deamidated gliadin peptide), porque es más útil en la detección de hasta un 80% de casos con EC y deficiencia de IgA. Es esencial conf irmar los resultados positivos en estas pruebas con una biopsia de intestino delgado para evitar resultados que puedan ser falsamente positivos. Esto se obtiene mediante una endoscopia Identificación de Fuentes de Gluten de tracto digestivo superior, o La educación sobre gluten va desde la selección de alimentos/ esofagogastroduodenoscopia. Este bebidas, leerla etiqueta nutricional e identificar ingredientes, entre estudio que se hace bajo los efectos otros. La Figura A muestra algunas precauciones que se deben tener de sedación intravenosa. Durante para evitar la exposición. el mismo, se obtienen muestras del 78

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MSP ARTÍCULO ORIGINAL

“La EC sucede solo en individuos con la predisposición genética. La prueba para determinar la presencia de los alelos HLA-DQ2 y –DQ8 ayu da a determinar la susceptibilidad genética de cada individuo”

Prevenir la Contaminación Cruzada: El cuidado en la preparación de alimentos libres de gluten es vital para mantenerlos así. Se debe tomar precaución antes, durante y después de la preparación de alimentos: enfoque de la Terapia Médico Nutricional se basa en dos áreas principales: identificar las fuentes de gluten y evitar la contaminación cruzada con partículas de gluten o derivados en la preparación, empaque o ingredientes de comidas.

Al comer o hacer compras de alimentos pueden surgir dudas Hablemos de Nutrición La absorción de nutrimentos están mal los espacios. La tecnología se afecta con la enfermedad podría ser una herramienta muy celíaca (EC). Por eso, una vez es valiosa y de gran ayuda en el diagnosticada, se debe tomar acción empodera m iento. A si m ismo, en la alimentación para evitar un complemento perfecto a las comprometer su estado óptimo intervenciones con su Nutricionista de salud. La dieta y productos sin - Dietista gluten (“gluten-free”) tienden a ser bajos en: vitaminas del complejo Hablemos de Tecnologías B, calcio, vitamina D, hierro, zinc, La puertorriqueña Madeline A. Velázquez Méndez, fue diagnosticada magnesio y fibra.

Su Nutricionista – Dietista con EC a sus 17 años. Al principio, trabajará para la prescripción consideró el diagnóstico devastador: dietaría correcta, educación y “Me apasiona cocinar y comer, pensé seguimientos de tolerancia. El que nunca más disfrutaría de esas hace susceptibles. Sin embargo, solo entre uno y tres por ciento de ellos manifestarán la condición. Esto indica que existen otros factores ambientales o inmunológicos para el desarrollo de esta enfermedad aún sin identificar.

experiencias al tener una nueva dieta limitada”, expresó. Ella supo que no estaba sola. Según la Fundación de Enfermedad Celíaca (CDF, por sus siglas en inglés) un 2% de la población tiene esta condición. Con el tiempo encontró herramientas que le ayudaron a controlar la enfermedad.

“Ahora soy universitaria, y a pesar del ajetreo, considero que es muy fácil llevar una dieta libre de gluten por completo”, añadió. Muchos restaurantes y supermercados ofrecen una variedad de productos “gluten free”. Madeline no se cohíbe en lo absoluto de tener nuevas experiencias gastronómicas. Existen fuentes de información confiables para ayudar a cualquier celiaco. Ella recomienda las siguientes aplicaciones de celular en cualquier momento que tenga alguna duda.

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MSP ARTÍCULO ORIGINAL

Se estima que un 20-30% de la población en Europa y EEUU contienen los alelos HLA-DQ2/ DQ8, lo cual los hace susceptibles.

Sin embargo, solo entre uno y tres por ciento de ellos manifestarán la condición.

“Yo no sufro con la EC porque mis alternativas son ilimitadas” expresó la estudiante de Microbiología Industrial. Aún la comida es parte importante y especial de su vida.

“Aprendí que comer sin gluten es fácil de lograr, nunca me había sentido tan saludable en toda mi vida”añadió.

Madeline aprendió mucho sobre los alimentos que ingiere y retomó el control de su vida y de la enfermedad. De hecho, disfruta de cada experiencia nueva y posit iva. “ L a enfermedad celíaca es solo una “enfermedad” si permites que te controle” concluyó entusiasmada con las herramientas que recomienda sean de gran ayuda a compañeros celíacos.

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MSP ARTÍCULO ORIGINAL

“Aprendí que comer sin gluten es fácil de lograr, nunca me había sentido tan saludable en toda mi vida”

Referencias

1.Lionetti E, Catassi C. New clues in celiac disease epidemiology, pathogenesis, clinical mainfestations, and treatment. International Reviews of Immunology 2011; 30: 219-31.

2. Parra-Medina R, Malaro-Gonzalez N, RojasVillarraga A, et al. Prevalence of celiac disease in Latin America: a systematic review and meta-regression.

PLoS ONE 2015; 10: e0124040.

3. Reilly NR, Aguilar K, Hassid BG, et al. Celiac disease in normal-weight and overweight children: clinical features and growth outcomes following a glutenfree diet. Journal of Pediatric Gastroenterology and Nutrition 2011; 53: 528-31.

4. Lebwohl B, Ludvigsson JF, Green PH. Celiac Disease and non-celiac gluten sensitivity. BMJ 2015; 351: h347.

5. Briani C, Zara G, Alaedani, et al. Neurological complications of celiac disease and autoimmune mechanisms: A prospective study. Journal of Neuroimmunology 2008; 195: 171-75.

6. Hadjivassiliou M, Grunewald R, Sharrack B, et al.

Gluten ataxia in perspective: Epidemiology, genetic susceptibility and clinical characteristics. Brain 2003; 126: 685-91.

7. Chin RL, Latov N, Green PH, et al. Neurologic complications of celiac disease. Journal of Clinical Neuromuscular Disease 2004; 5: 129-37.

8. Hadjivassiliou M, Rao DG, Wharton SB, et al.

Sensory ganglionopathy due to gluten sensitivity.

Neurology 2010; 75: 1003-08.

transglutaminase antibody compared as screening tests for coeliac disase. Alimentary Pharmacology and Therapeutics 2010; 31: 73-81.

10. Ontiveros N, Hardy MY, Cabrera-Chavez F. Assessing of celiac disease and nonceliac gluten sensitivity. Gastroenterology Research and Practice 2015: 723954.

11. Rubio-Tapia A, Hill ID, Kelly CP, et al. Diagnosis and management of celiac disease. American Journal of Gastroenterology 2013; 108: 656-76.

12. Kaukinen K, Partanen J, Maki M, et al. HLA-DQ typing in the diagnosis of celiac disease. American Journal of Gastroenterology 2002; 97: 695-99.

13. Jackson JR, Eaton WW, Cascella NG. Neurologic and psychiatric manifestations of celiac disease and gluten sensitivity. Psychiatric Quaterly2012; 83: 91-102.

14. Hill ID, Dirks MH, Liptak GS. Guidelines for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Journal of pediatric Gastroenterology and Nutrition 2005; 40: 1-19.

15. Kupper C. Dietary Guidelines and Implementation for Celiac Disease. https://www.ncbi.nlm.nih.gov/ pubmed/15825119.Accesado Febrero 1,2018.

16. Academy of Nutrition and Dietetics. Avoid Gluten Cross-Contamination. http://www.eatright. org/resource/health/diseases-and-conditions/ celiac-disease/avoiding-gluten-crosscontamination.

Accesado Febrero 1,2018.

9. Lewis NR, Scott BB. Meta-analysis: deamidatedgliadin peptide antibody and tissue Revista Puertorriqueña de Medicina y Salúd Pública

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THE FIRST AND ONLY ORAL JAK INHIBITOR APPROVED FOR UC1,2

NOW APPROVED FOR THE TREATMENT OF ADULTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS2

JAK=Janus kinase; UC=ulcerative colitis.

Learn more at XELJANZUC.HCP.com

Please see additional Important Safety Information and brief summary of full Prescribing Information, including BOXED WARNING, on the following pages. For current full Prescribing Information, please visit XELJANZPI.com.

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 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.

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

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months.

The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.

Lipid Elevations In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter.

Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

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

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

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

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

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

The clinical significance of the observed serum creatinine elevations is unknown.

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

Common Adverse Reactions* in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis With or Without Concomitant DMARDs (0-3 Months) XELJANZ 5 mg Twice Daily

XELJANZ 10 mg Twice Daily**

Placebo

N = 1336 (%)

N = 1349 (%)

N = 809 (%)

Upper respiratory tract infection

4

4

3

Nasopharyngitis

4

3

3

Diarrhea

4

3

2

Headache

4

3

2

Hypertension

2

2

1

Preferred Team

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

Ulcerative Colitis XELJANZ has been studied in patients with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose ranging UC-V) and an open-label long term extension study (UC-IV).

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

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

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

Common Adverse Reactions* in UC Patients during the Maintenance Trial (Study UC-III)

the following: herpes zoster infections, serious infections, and NMSC. DRUG INTERACTIONS The table below includes drugs with clinically important drug interactions when administered concomitantly with XELJANZ/XELJANZ XR and instructions for preventing or managing them.

Clinical Relevant Interactions Affecting XELJANZ and XELJANZ XR When Coadministered with Other Drugs Strong CP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/ XELJANZ XR is recommended

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

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/ XELJANZ XR is recommended

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

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

Intervention

Coadministration with XELJANZ/ XELJANZ XR is not recommended

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

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

Intervention

Coadministration with XELJANZ/ XELJANZ XR is not recommended

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

XELJANZ 5 mgTwice Daily

XELJANZ 10 mgTwice Daily

Placebo

Preferred Term

N = 198 (%)

N = 196 (%)

N = 198 (%)

Nasopharyngitis

10

14

6

Pregnancy

Elevated cholesterol levels**

5

9

1

Headache

9

3

6

Upper respiratory tract infection

7

6

4

Increased blood creatine phosphokinase

3

7

2

Rash

3

6

4

Diarrhea

2

5

3

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.

Herpes zoster

1

5

1

Gastroenteritis

3

4

3

Anemia

4

2

2

Nausea

1

4

3

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

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

Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 mg twice daily, include

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

The estimated background risks of major birth defects and miscarriage for the indicated

MSP ARTÍCULO ORIGINAL

Síndrome Metabólico Por: Francisco Díaz Lozada, MD, FACP Director Internado Rotario Hospital Auxilio Mutuo Ramón F.A. Grillo Morales MD-I Médico Interno Hospital Auxilio Mutuo

Palabras claves: Síndrome Metabólico, Diabetes Mellitus Tipo 2, Resistencia a la insulina, Enfermedades Cardiovasculares, Obesidad

Keywords: Obesity, Metabolic Syndrome, Insulin Resistance, Diabetes Mellitus Type 2, Cardiovascular Disease Revista Puertorriqueña de Medicina y Salúd Pública

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Resumen El Síndrome Metabólico en la actualidad es posiblemente el fenómeno más subestimado y pasado por alto en el área de la medicina, secundario a su naturaleza insidua, las múltiples variantes existentes para su definición y los criterios para su diagnóstico.

Alrededor del 75% del dinero invertido en el campo de la medicina, circula alrededor de las enfermedades crónicas causadas por el síndrome y los factores de riesgo metabólicos que eventualmente lo causarían.

La obesidad, resistencia a la insulina, hiperglicemia, dislipidemia e hipertensión, son un agrupamiento de factores que aumentan sinergísticamente la incidencia de enfermedades crónicas de tipo cardiovascular y metabólico. Pero su ausencia, a su vez, no cohíbe al paciente de la posibilidad de desarrollar las mismas. Sin embargo, cuando estos factores ocurren simultáneamente en un individuo, se han reconocido internacionalmente como "Síndrome Metabólico", el cual es producto de la coexistencia de los factores patofisiológicos ya mencionados y otros factores sociales que varían de acuerdo con la cultura y hábitos cotidianos del individuo, tales como la actividad física y la dieta. Originalmente la utilidad de identificar a los individuos predispuestos o sufriendo del síndrome estaba dirigida hacia retrasar o prevenir la incepción de enfermedades cardiovasculares, pero también se ha demostrado su utilidad en identificar con precisión significativa a pacientes en riesgo de sufrir de diabetes tipo 2. El tejido adiposo no es un almacén inerte para el depósito de triglicéridos, y por ende debe percibirse como un órgano endocrino. Inclusive, el lugar y forma de almacenamiento del mismo nos proporciona información clínica sobre la gravedad individual de cada paciente. Además de contribuir a la insulinoresistencia, los niveles altos de ácidos grasos aturden la función de las células pancreáticas promoviendo un estado hiperglucémico. La prevención juega un papel pivotal siendo la primera línea en el tratamiento, logrando atrasar o - en algunos casos - anular la emergencia de diabetes o enfermedades cardiovasculares, que en caso de estar presentes en el paciente, se requeriría intervención farmacológica.

A pesar de que la obesidad es prominente en esta población, el 20% restante de los pacientes obesos definidos por el índice de masa corporal (BMI) se considera que mantienen un estado de obesidad que 90

Revista Puertorriqueña de Medicina y Salúd Pública

metabólicamente hablando, se considera saludable y los mismos no manifiestan los signos clínicos de la dislipidemia, hipertensión, o hiperglicemia.

Sin embargo, más de un 90% de los pacientes que conforman esta población no logran adaptarse a los nuevos hábitos recomendados y por ende se aturde la reducción, el retraso, o en algunos casos la prevención de los factores de riesgo y enfermedades crónicas.

Abstract Metabolic Syndrome at present is possibly the most underestimated and overlooked phenomenon in the area of medicine, secondary to its insiduous nature, the multiple existing variants for its definition and the criteria for its diagnosis. About 75% of the money invested in the field of medicine circulates around the chronic diseases caused by the syndrome and the metabolic riskfactorsthatwouldeventually cause it? Obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension are a group of factors that synergistically increase the incidence of chronic cardiovascular and metabolic diseases; but its absence in turn does not inhibit the patient from developing them. However, when these factors occur simultaneously in an individual, they have been recognized internationally as "Metabolic Syndrome", which is a product of the coexistence of the aforementioned pathophysiological factors and other social factors that vary according to the culture and dailyhabitsofthe individual; just as physicalactivity and diet are. The diagnostic criteria provided by the following organizations: International Diabetes Federation (IDF) and National Cholesterol Education Program (ATP-III) have been internationally accepted as the most up-todate and universal definitions and / or criteria since they take into account ethnic and social variables. cultural activities in different populations. Originally the utility of identifying individuals predisposed or suffering from the syndrome was aimed at delaying or preventing the inception of cardiovascular diseases; but it has also been shown to be useful in identifying with significant precision patients at risk of suffering from type 2 diabetes. It should be mentioned that adipose tissue is not an inert storehouse for the storage of triglycerides, and therefore must be perceived as an endocrine organ. Even the place and form of storage

MSP ARTÍCULO ORIGINAL

of it (Intraperitoneal, Subcutaneous, Intrahepatic) provides us with clinical information about the individual severity of each patient. In addition to contributing to insulin resistance, high levels of fatty acids stunning the function of pancreatic cells promoting a hyperglycemic state. Prevention plays a pivotal role being the first line in the treatment, achieving delaying or in some cases canceling the emergence of diabetes or cardiovascular diseases that if present in the patient would require pharmacological intervention. Although obesity is prominent in this population, the remaining 20% of obese patients defined by the body mass index (BMI) are considered to maintain a state of obesity that metabolically speaking is considered healthy and they do not manifest the clinical signs of dyslipidemia, hypertension, or hyperglycemia. However, more than 90% ofthepatientsthatmake up thispopulation do not manage to adapt to the new recommended habits and there for et her eduction, delay, or in some cases the prevention of risk factors and chronic diseases is stunned.

E

l Síndrome Metabólico en la actualidad es debatiblemente el fenómeno más subestimado y pasado por alto en el área de la medicina, secundario a su naturaleza insidua, las múltiples variantes existentes para su definición y criterios para su diagnóstico. Alrededor del 75% del dinero invertido en la medicina circula alrededor de enfermedades crónicas causadas por el síndrome y los factores de riesgo metabólicos que eventualmente lo causarían. Sin embargo; ¿Cómo una agrupación de signos, síntomas y factores de riesgo con etiología compartida no se presentan en un patrón uniforme, cronológico y estático? La obesidad, resistencia a la insulina, hiperglicemia, dislipidemia e hipertensión son un agrupamiento de factores, que aumentan sinergísticamente la incidencia de enfermedades crónicas de tipo cardiovascular y metabólico; pero su ausencia a su vez, no cohíbe al paciente de la posibilidad de desarrollar las mismas. Sin embargo, cuando estos factores ocurren simultáneamente en un individuo, se han reconocido internacionalmente como "Síndrome Metabólico", el cual es producto de la coexistencia de los factores patofisiológicos ya mencionados y otros factores sociales que varían de acuerdo con la cultura y hábitos cotidianos del individuo; tal como lo son la actividad física y la dieta.

Múltiples estudios han examinado los componentes del síndrome de forma individual, algunos de ellos en conjunto; sin embargo, la falta de armonía y cronología entre la naturaleza en la que surgen y complementan los signos, factores de riesgo, y la investigación del síndrome como una entidad completa, es lo que ha forzado la emergencia de múltiples definiciones y criterios para el

diagnóstico del síndrome. Existe un solapamiento de 93% en esta población, según los criterios de diagnóstico proveídos por las siguientes organizaciones: International Diabetes Federation (IDF) y National Cholesterol Education Program (ATP-III). Estas se han aceptado internacionalmente como las definiciones y/o criterios más actualizados y universales, ya que toman en consideración las variables étnicas y culturales en las diferentes poblaciones, y a su vez le proveen al BMI tomar riendas sensitivas sobre el diagnóstico del síndrome. Originalmente la utilidad de identificar a individuos predispuestos o sufriendo del síndrome, estaba dirigida hacia retrasar o prevenir la incepción de enfermedades cardiovasculares; pero también ha demostrado su utilidad en identificar con precisión a pacientes en riesgo de diabetes. Estudios también han demostrado un solapamiento significativo en el riesgo de diabetes y enfermedades cardiovasculares en un

“Más de un 90% de los pacientes que conforman esta población no logran adaptarse a los nuevos hábitos recomendados y por ende se aturde la reducción, el retraso, o en algunos casos la prevención de los factores de riesgo y enfermedades crónicas” Revista Puertorriqueña de Medicina y Salúd Pública

91

MSP ARTÍCULO ORIGINAL

lapso de 10 años, en individuos afectados por el síndrome y de esta manera sosteniendo que el riesgo de sufrir de síndrome es directamente proporcional a la cantidad de componentes patofisiológicos presentes que ya han sido mencionados y sin el control apropiado, promueven el desarrollo de enfermedades crónicas.

Es necesario calcular un estimado del riesgo cardiovascular de cada paciente por individual a través de criterios como el ASCVD y con el mismo se determina el diseño y agresividad individual del tratamiento.

Actualmente se aprecia entre esta población una prevalencia de 5% en individuos con un BMI saludable, 22% en pacientes con sobrepeso y 60% en pacientes obesos. La obesidad central es reconocida como u na ma n i fest ación fundamental para el diagnóstico de síndrome metabólico, la cual debe ser cuantificada a nivel del ombligo y contrastada con el índice de masa corporal del paciente, convirtiéndola en una preocupación sustancial, tomando en consideración el incremento en obesidad a nivel mundial. Cabe mencionar que el tejido adiposo no es un almacén inerte para el depósito de triglicéridos, y por ende debe percibirse como un órgano endocrino. Inclusive, el lugar y forma de almacenamiento del mismo (Intraperitoneal, Subcutánea, Intrahepática, Intramuscular) nos proporciona información clínica sobre la gravedad individual de cada paciente. Metabólicamente hablando, el tejido adiposo intraperitoneal está asociado a una resistencia mayor a la insulina y aumentos en los niveles de triglicéridos, LDL y VLDL. El almacenamiento subcutáneo no 92

Revista Puertorriqueña de Medicina y Salúd Pública

excluye de riesgo al paciente, pero está asociado con menos descontrol metabólico, el cual en hipótesis se atribuye a la accesibilidad disminuida que tienen los órganos a este tipo de tejido adiposo, en comparación al tejido adiposo intraperitoneal. La obesidad entrelaza los factores de riesgo y contribuye a su vez a los estados: proinf lamatorio y protrombótico crónicos, como resultado del estrés oxidativo acumulado en el tejido adiposo; a su vez evidenciado por un aumento en los niveles de citoquinas

“La obesidad también comparte una predispocisión entre la insulinoresistencia y diabetes, la cual se estima que duplicará su prevalencia en los próximos 12 años” inf lamatorias tales como la IL-6, TNF-α, CRP y niveles reducidos de adiponectina, la cual está asociada a una función cardioprotectiva.

La severidad y tiempo de duración de estos estados también están asociados a un riesgo aumentado para el desarrollo de enfermedades cardiovasculares; de nuevo sosteniendo la sinergia y complementación entre la patofisiología causante de este síndrome.

La obesidad también comparte una predispocisión entre la insulinoresistencia y diabetes, la cual se estima que duplicará su prevalencia en los próximos 12 años, y su importancia se torna pivotal cuando se estima que un 30-40% de la población mundial actual es insulino-resistente.

Además de contribuir a la insulino-

resistencia, los niveles altos de ácidos grasos aturden la función de las células pancreáticas promoviendo un estado hiperglucémico. La actividad excesiva de lipasa hormono-sensitiva y el exceso de lipólisis de triglicéridos almacenados en el tejido adiposo, es promovida por la inhabilidad de las células pancreáticas para compensar la insulino-resistencia. De esta manera, se comienza a apreciar un patrón sinergístico que entrelaza y complementa la hiperglicemia con los otros factores de riesgo metabólicos.

La hipertensión se considera un proceso patof isiológ ico multifactorial, parcialmente mediado por la disfunción y daño endotelial causados por la generación de radicales libres producto de ácidos grasos, por la activación del sistema nervioso simpático a consecuencia de la hiperinsulinemia y teniendo como resultado vasoconstricción a través de la activación del sistema de renina-angiotensinaaldosterona, también presente en la obesidad. Usualmente, la hipertensión es diagnosticada en una etapa tardía del proceso en donde ya existen consecuencias irreversibles y/o perjudiciales para la salud del individuo como lo son el daño renal y el fallo cardíaco. A pesar de que la obesidad es prominente en esta población, el 20% restante de los pacientes obesos definidos por el índice de masa corporal (BMI) se considera que mantienen un estado de obesidad que metabólicamente hablando se considera saludable y los mismos no manifiestan los signos clínicos de la dislipidemia, hipertensión, o hiperglicemia.

El tratamiento primario se basa en la prevención a través de cambios en

MSP ARTÍCULO ORIGINAL

el estilo de vida del individuo y monitoreo de múltiples valores de laboratorio anualmente. Se recomienda un monitoreo anual de los valores lipídicos en especial los triglicéridos, los valores de glicemia en sangre, la HbA1c y la presión arterial en visitas individuales al consultorio en cualquier individuo que presente al menos uno de los factores de patofisiológicos mencionados, sobrepeso u obesidad. La pérdida de peso, modificación en la dieta, monitoreo anual de laboratorios y el incremento en la actividad física son la primera línea en el tratamiento, aspirando a la prevención y disminución en la incidencia y prevalencia de Síndrome Metabólico, y consecuentemente de las enfermedades crónicas que vienen acompañadas por el mismo. Sin embargo, más de un 90% de los pacientes que conforman esta población no logran adaptarse a los nuevos hábitos recomendados y por ende, se aturde la reducción, el retraso, o en algunos casos la prevención de los factores de riesgo y enfermedades crónicas. El tratamiento secundario se conforma de la intervención farmacológica la cual va dirigida hacia el control de los factores de la hipertensión, hiperglicemia, dislipidemia (especialmente hipertrigliceridemia), obesidad, resistencia a la insulina, o en varios casos hacia el control de las enfermedades crónicas ya existentes. En los individuos donde la diabetes y la enfermedad cardiovascular están presentes, la intervención farmacológica es imperativa, considerando que la mortalidad de un paciente diabético sin tratamiento médico sorprendentemente es de un 70% y si a su vez consideramos las enfermedades cardiovasculares, las cuales son la causa mas común de muerte en países desarrollados, entendemos el sentido de urgencia que requiere el énfasis sobre este fenómeno. La tercera línea en el tratamiento se compone de procedimientos quirúrgicos tales como la cirugía bariátrica, los cuales solamente se consideran en casos donde el individuo no obtiene una respuesta positiva a las primeras dos líneas del tratamiento.

En síntesis, podemos concluir que el cuidado propio y riguroso del Síndrome Metabólico previo a sus complicaciones, tiene capacidad de disminuir la mortalidad y aumentar el promedio y calidad de vida en dicha población. Cuando incorporamos un cambio en la dieta de cualquier individuo es importante determinar el porcentaje, tipo, y cantidad de calorías; de esta manera se controlan los niveles de leptina, la cual está asociada al sentido de saciedad. Los cambios en el estilo de vida son la manera más efectiva de combatir esta epidemia de una forma efectiva. En comparación, los pacientes que

han logrado cambios en sus hábitos cotidianos, obtienen resultados mucho más beneficiosos, en contraste con pacientes que han requerido intervención farmacológica.

Para obtener resultados permanentes es mandatoria la educación del paciente, la complicidad del mismo, un acercamiento agresivo hacia los cambios en su estilo de vida y hacia los factores que contribuyen a la incepción insidua de la patofisiología del Síndrome Metabólico.

Referencias

1.Alberti, K. G., Eckel, R. H., Grundy, S. M., Zimmet, P. Z., Cleeman, J. I., Donato, K. A., … Fruchart, J. C. (2009). HarmonizingtheMetabolicSyndrome a 2.jointinterimstatementoftheinternational diabetes federationtaskforceonEpidemiology and prevention; nationalheart, lung, and bloodinstitute; etc.

JointScientificStatement, 1640-1645. doi:10.1161/ CIRCULATIONAHA.109.192644 3.Alberti, K. G., Zimmet, P., & Shaw, J. (2005).

Themetabolicsyndrome—a new worldwidedefinition. The Lancet, 366(9491), 1059-1062. doi:10.1016/s0140-6736(05)67402-8 4.Furukawa, S., Fujita, T., Shimabukuro, M., Iwaki, M., Yamada, Y., Nakajima, Y., … Nakayama, O. (2004). Increasedoxidate stress in obesity and itsimpactonmetabolicsyndrome.

TheJournalofClinicalInvestigation, 114(12), 1752-1761. doi:10.1172/ JCI200421625 5.Grundy, S. M., Cleeman, J. I., Daniels, S. R., Donato, K. A., Eckel, R. H., Franklin, B. A., … Gordon, D. J. (2005). Diagnosis and managementofthemetabolicsyndrome. Circulation, 2735-2747. doi:10.1161/CIRCULATIONAHA.105.169404 6.Isomaa, B., Almgren, P., Tuomi, T., Forsen, B., Lahti, K., Nissen, M., … Groop, L. (2001). Cardiovascular Morbidity and MortalityAssociatedWiththeMetabolicSyndrome. Diabetes Care, 24(4), 683-689. doi:10.2337/diacare.24.4.683 7.Meigs, J. B. (2017). Themetabolicsyndrome (insulinresistancesyndromeorsyndrome x). Retrievedfromwww. uptodate.com/contents/the-metabolic-syndrome-insulinresistance-syndrome..

8.O'Neill, S., &O'Driscoll, L. (2014). Metabolicsyndrome: a closerlook at thegrowingepidemic and itsassociatedpathologies.

ObesityReviews, 16(1), 1-12. doi:10.1111/obr.12229 9.Samson, S. L., &Garber, A. J. (2014). MetabolicSyndrome.

Endocrinology and MetabolismClinicsof North America, 43(1), 1-23. doi:10.1016/j.ecl.2013.09.009

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IN YOUR PATIENTS WITH ASTHMA

LOOK BEYOND EOSINOPHIL AND IgE LEVELS TO GET A CLEARER PICTURE OF TYPE 2 INFLAMMATION

EOS

IL-9

IL-4

IL-13

IgE

IL-5

Type 2 asthma encompasses a range of biomarkers driven by Type 2 inflammation.

Gain More Insight at UnderstandingType2Asthma.com

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

US-ILF-14192

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

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

Limitations of Use: Not recommended as first-line therapy for patients inadequately controlled on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans. Prescribe only if potential benefits outweigh potential risks. Has not been studied in patients with a history of pancreatitis; consider another antidiabetic therapy. Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. Not a substitute for insulin. Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. Not for patients with pre-existing severe gastrointestinal disease.

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

It is unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

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

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

Preparation2 •

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

•

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

The key administration steps

Disposal2

2

•

1

2

3

Uncap the pen

Place and unlock

Press and hold

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

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

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

syndrome type 2, and in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components.

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

in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 RA use in humans. If serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging, the patient should be further evaluated.

Yes, I think I can do this

*

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

•

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

•

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

•

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

•

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

•

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

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

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

Please see Instructions for Use included with the pen.

Important Safety Information WARNING: RISK OF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and 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

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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)

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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.

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El sistema inmunitario y las alergias Por: Rafael H. Zaragoza Urdaz Alergista/ Inmunólogo Presidente de la Asociación Puertorriqueña de Médicos Alergistas

Resumen El sistema inmunitario es un conjunto de órganos, tejidos, células y productos derivados de estas células que se encuentran por todo el organismo y de cuyo funcionamiento e integridad depende la supervivencia del mismo. Tiene como misión fundamental el proteger la identidad del individuo efectuando dos procesos especiales: reconocimiento y defensa.

Abstract The immune system is a set of organs, tissues, cells and products derived from these cells that are found throughout the body and whose functioning and integrity depends on its survival. It has the fundamental mission of protecting the identity of the individual by carrying out two special processes: recognition and defense.

Palabras clave Keywords Sistema inmunitario, Reacción, alergia, Immune System, allergic reaction, allergic Condición alérgica, Alteraciones del sistema condition, alterations of the immune system inmunitario

E

l sistema inmunitario es un conjunto de órganos, tejidos, células y productos derivados de estas células que se encuentran distribuidos por todo el organismo y de cuyo funcionamiento e integridad dependerá la supervivencia del mismo. Los órganos que forman parte de él se denominan órganos linfoides: adenoides -comúnmente llamadas vegetaciones-, amígdalas palatinas, timo, apéndice, médula ósea, bazo, ganglios linfáticos, placas de Peyer en el intestino (véase figura 1) y mucosas del aparato digestivo del respiratorio y del genitourinario. Tiene como misión fundamental el proteger la identidad del individuo efectuando dos procesos especiales: reconocimiento y defensa. Su proceso permanente de reconocimiento, registra y acepta todo aquello que es propio del mismo sistema y forma parte del organismo -tejidos y células- y en su proceso de defensa rechaza todo lo extraño y potencialmente perjudicial que pudiese agredir y atacar desde el exterior -bacterias, virus- o internamente -células

degeneradas o tumorales. En condiciones normales, el sistema inmunitario está vigilante para permitir nuestra supervivencia en un medio natural hostil lleno de virus, bacterias, hongos y parásitos -a los cuales es capaz de reconocer y destruir- pero en ocasiones hay alteraciones congénitas o adquiridas que pueden modificar su normal funcionamiento y producir enfermedades como las inmunodeficiencias.

Estas dan lugar a un aumento del número de infecciones, algunas de ellas gravísimas, que pueden conducir a la muerte. Otras veces el sistema inmunitario falla en el reconocimiento de las propias células, considerándolas extrañas y auto reaccionando contra ellas, dando lugar a las llamadas enfermedades autoinmunes como lo es el lupus eritematoso o la artritis reumatoide.

Se calcula que la variedad de posibles sustancias contra las cuales el sistema inmunitario debe reaccionar de forma específica -llamadas genéricamente antígenos- es de -aproximadamente- 109 variedades. Para esta diversidad en la respuesta inmunitaria está perfectamente preparado Revista Puertorriqueña de Medicina y Salúd Pública

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dicho sistema, ya que puede producir tan variado número de anticuerpos diferentes como sea preciso al poseer una habilidad muy específica para discriminar entre moléculas estrechamente relacionadas y porque tiene memoria de forma tal que puede reconocer fácil y rápidamente una segunda exposición a un antígeno contra el cual había generado anteriormente una respuesta.

El sistema inmunitario de los seres humanos es muy similar al que se halla en otros organismos inferiores en la escala filogenética como en el caso de los insectos como la mosca del vinagre o del resto de los mamíferos, entre ellos los ratones de laboratorio. Por esta razón, ambos modelos animales son muy útiles para el estudio de las enfermedades del sistema inmunitario humano.

La alergia, a pesar de ser muy frecuente y causar síntomas de los que todo el mundo habla, es una gran desconocida. Si ante un infarto de miocardio casi todos sabrían identificar al corazón como el órgano dañado, ante una enfermedad alérgica pocos podrían determinar dónde se localiza la alteración que la desencadena. En una enfermedad alérgica lo que se altera es precisamente el sistema inmunitario. Los alérgenos son todas aquellas sustancias capaces de provocar estas reacciones en el organismo. Se caracterizan por dos hechos: por ser sustancias inocuas para el resto de población que no es alérgica y por tener la propiedad de generar un tipo especial de anticuerpos, la inmunoglobulina E (IgE). Prácticamente cualquier sustancia puede ser un alérgeno: medicamentos, alimentos, sustancias que flotan en el aire y se respiran o sustancias que se tocan. Unas son muy frecuentes y otras menos comunes y su identificación puede resultar difícil.

Ejemplos de las primeras son los pólenes, los ácaros del polvo doméstico, determinados hongos, los epitelios de animales -perro, gato, hámster, etc., medicamentos -antibióticos, aspirina, etc., así como numerosos alimentos -leche, huevo, frutas, etc. En cuanto a los alérgenos poco frecuentes se encuentran las garrapatas de las palomas o los caracoles. No obstante, las personas desarrollan la alergia contra aquellas sustancias con las que tienen contacto.

La alergia no está presente en el nacimiento, sino que se va desarrollando con el paso del tiempo y frente a las sustancias que se encuentran en el entorno del paciente.

Por ejemplo, en nuestra área es muy habitual la alergia a los perros o a los gatos, pero no a los leones.

Sin embargo, alguien que trabaje en un circo o en un zoológico puede desarrollar alergia a estos felinos.

Si una de las funciones del sistema inmunitario es la capacidad de distinguir, dentro de lo ajeno, aquello que no supone ninguna amenaza para el organismo que está defendiendo, como sería el caso del polen que entra por la nariz, la leche que bebemos o los pendientes de 102

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bisutería que pudiesen contener níquel, es precisamente este matiz tan importante el que falla cuando el sistema desencadena en la alergia. Como consecuencia de esta alteración del sistema inmunitario, y al encontrarse distribuido por todo e1 organismo, las enfermedades alérgicas pueden producir síntomas en cualquier órgano del cuerpo, aunque sean más frecuentes los problemas respiratorios, digestivos o de piel debido a que son estas zonas las de mayor contacto con los agentes externos.

Los anticuerpos son generados por el sistema inmunitario como una respuesta de defensa contra todas las sustancias que penetran en el organismo y contra los microbios. Son proteínas que circulan por la sangre producidas por el sistema inmunitario, en concreto por los linfocitos B, moléculas cuyo tamaño es de una millonésima de milímetro. Los anticuerpos también son denominados inmunoglobulinas y se abrevian con las letras Ig. Desde el punto de vista estructural, tienen forma de Y griega y hay varias clases de Inmunoglobulinas denomidadas con letras: IgG, IgA, IgM, IgD e IgE. El sistema inmunitario dispone de este repertorio de inmunoglobulinas capaces de interaccionar con un gran número de estructuras químicas diferentes Se calcula que existen más de 1010 clones de linfocitos B de especificidad distinta, y se dispone incluso de anticuerpos capaces de reconocer compuestos sintéticos que son inexistentes en la naturaleza. Si estas sustancias externas son reconocidas por e1 sistema inmunitario como no perjudiciales resultan toleradas y se producen Ig del tipo G (IgG) como, por ejemplo, se generan anticuerpos IgG frente a los pólenes que son inhalados por las personas sanas. Por el contrario, las personas alérgicas producen, además de anticuerpos, IgG, inmunoglobulinas del tipo E (IgE). La inmunoglobulina E es una clase de anticuerpo denominado así porque forman parte de su estructura unas cadenas llamadas Epsilon. Esta inmunoglobulina es la concentración más baja de todas las clases de inmunoglobulinas. A pesar de ello resulta ser el anticuerpo más importante en la resistencia y lucha contra las enfermedades parasitarias sobre todo en las producidas por helmintos o gusanos. La IgE posee la capacidad de activar unas células que contienen en su interior productos muy tóxicos y sustancias letales capaces de eliminar a tales parásitos. Gracias a los avances higiénicos en el mundo occidental, han disminudido notablemente las enfermedades infecciosas producidas por parásitos, pero nos encontramos con la curiosa situación de tener un sistema inmunitario capaz de sintetizar anticuerpos IgE y sin enemigos naturales que combatir. Por el contrario, existen sustancias inofensivas o inocuas para la mayoría

MSP ARTÍCULO ORIGINAL

de las personas, como los pólenes, ante los que el sistema inmunitario sintetiza IgE específico frente a ellos. Esta respuesta enérgica del sistema inmunitario no sólo es inútil sino, lo que es más importante, resulta peligrosa para el individuo pues puede incluso ocasionarle la muerte.

La concentración de IgE en la sangre circulante se eleva notablemente cuando se desarrollan las enfermedades alérgicas. Las reacciones alérgicas técnicamente se denominan reacciones de hipersensibilidad inmediatas. Tras tener un primer contacto con el alérgeno como por ejemplo el polen, se produce una captación de éste por parte de unas células llamadas células presentadoras de antígeno, que lo procesan en su interior y lo presentan a los linfocitos T, y que a su vez interaccionan con los linfocitos B que producen IgE específica frente a ese polen concreto.

Esta IgE se unirá a los mastocitos y los basófilos, células que contienen receptores para la IgE en su superficie.

Hasta aquí el paciente no siente nada ni experimenta ningún síntoma de alergia, pero el proceso puede durar varios días, meses o años y se denomina sensibilización en el cual el individuo se hace sensible a ese alérgeno: el polen, en el caso que hemos puesto de ejemplo. Éste es el punto de inflexión a partir del cual el individuo se ha hecho alérgico y es muy importante, ya que, aunque se nazca con predisposición genética para hacerse alérgico, la enfermedad no se desarrollará si no se ha estado durante un cierto tiempo en contacto con el alérgeno responsable. Esto determina un hecho fundamental que será la regla en todas las enfermedades de causa alérgica: la imposibilidad de presentar síntomas en una primera exposición o contacto. Por ejemplo, un individuo que ingiere por primera vez una fruta tropical no podrá presentar síntomas alérgicos tras su ingesta esta primera vez. Es a partir de entonces que la evolución puede ser diferente: bien seguirá tolerando esta fruta sin problemas siempre o, por el contrario, a partir de esa primera vez, segunda, tercera o en ocasiones subsiguientes se habrá sensibilizado y manifestará síntomas de alergia en futuras ingestas. Ya en una exposición posterior, los pólenes que vuelven a ponerse en contacto con el sistema inmunitario son dirigidos directamente hacia los anticuerpos IgE específicos que ya habían sido secretados y que se encuentran unidos a la superficie de los mastocitos y basófilos y es entonces, al contactar el alérgeno –polen- y el anticuerpo -IgE específico frente al polen- cuando se produce una pequeña explosión que hace que el mastocito o basófilo libere el contenido de sus gránulos, llenos de histamina, y otras sustancias con potente actividad inflamatoria (véase tabla 1). Esto

ocurre posterior a los quince a veinte minutos luego de inhalar el polen al cual el individuo está sensibilizado y empezará a notar los síntomas típicos de la alergia naso ocular y respiratoria -picor de nariz y ojos, estornudos, lagrimeo, obstrucción nasal, destilación de secreciones acuosas por la nariz, tos, opresión torácica, dificultad respiratoria- producidos por la acción de la histamina y demás sustancias liberadas. Esta fase se conoce como reacción alérgica aguda. De cuatro a seis horas después de esta reacción inflamatoria (véase figura 5), se produce otra reagudización sin la participación de nuevos pólenes. Esta ocurre debido a unos productos que se liberaron junto con la histamina y que tienen como misión atraer al lugar donde se produce la inflamación unas células, los eosinófilos principalmente, que liberan su contenido interior formado por sustancias muy eficaces para destruir a los parásitos sin haberlos en esta ocasión. Es entonces cuando se empieza a dañar e inflamar, de una forma más crónica, la conjuntiva de los ojos, la mucosa de la nariz y/o de las vías respiratorias perpetuándose los síntomas de la conjuntivitis, rinitis y/o el asma bronquial. A esta fase se le denomina reacción alérgica tardía.

En contraposición a las reacciones alérgicas mediadas por la IgE que se desencadenan rápidamente tras exponerse a un alérgeno -reacciones de hipersensibilidad inmediata- existe otro tipo de reacción del sistema inmunitario denominada reacción de hipersensibilidad retardada. Este tipo de reacciones difiere su desarrollo en más de doce horas tras la exposición al antígeno.

Están implicados en ellas mecanismos de inmunidad celular -linfocitos T- a diferencia de las reacciones de hipersensibilidad inmediata que se encuentran fundamentalmente mediadas por los anticuerpos IgE. La sensibilización se produce tras la penetración del antígeno, generalmente a través de un contacto con la piel, que es capturado por las células presentadoras de antígeno y presentado a los linfocitos T en los ganglios regionales. Los antígenos presentados activan estos linfocitos locales y se inicia la secreción de citocinas que serán liberadas localmente y causantes de un daño celular y de manifestaciones clínicas típicas de este tipo de reacción, como los eccemas en la piel por alergia a los materiales de bisutería. En este caso se trata también de una desviación de la respuesta inmunitaria ordinaria, de carácter defensivo, contra bacterias y hongos. Al unirse a sustancias inocuas como el señalado caso del níquel a las proteínas de la piel se originan unos complejos extraños al organismo contra los cuales se desencadena una reacción alérgica y con la consecuencia de un daño local: el eczema alérgico.

Revista Puertorriqueña de Medicina y Salúd Pública

103

NOW APPROVED

Initiate. Advance. Protect.

Help protect against resistance with the barrier to rely on from the start

INDICATION SYMTUZA™ is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults: • who have no prior antiretroviral treatment history or • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

IMPORTANT SAFETY INFORMATION BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

• Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of SYMTUZA™. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA™. If appropriate, anti-hepatitis B therapy may be warranted.

CONTRAINDICATIONS

• Do not coadminister SYMTUZA™ and the following drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect: alfuzosin, carbamazepine, cisapride, colchicine (in patients with renal and/or hepatic impairment), dronedarone, elbasvir/grazoprevir, ergot derivatives (such as: dihydroergotamine, ergotamine, methylergonovine), lovastatin, lurasidone, oral midazolam, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam.

WARNINGS AND PRECAUTIONS

• Severe Acute Exacerbation of Hepatitis B in Patients Coinfected With HIV-1 and HBV: Patients with HIV-1 should be tested for the presence of chronic HBV before initiating antiretroviral therapy. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA™.

Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA™ should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING, on the following pages.

Start With the Protective Barrier of Darunavir treatment-emergent darunavir, primary PI or TAF mutations across clinical trial populations1*†‡§

• Only 1 patient receiving SYMTUZA™ was found to have M184I/V 2¶

IMPORTANT SAFETY INFORMATION (cont) • Hepatotoxicity: Drug-induced hepatitis and cases of liver injury, including some fatalities, have been reported in patients receiving darunavir, a component of SYMTUZA™. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions.

Appropriate laboratory testing should be conducted prior to initiating and during therapy with SYMTUZA™. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA™.

• Severe Skin Reactions: In patients receiving darunavir, a component of SYMTUZA™, severe skin reactions may occur. StevensJohnson syndrome was reported with darunavir coadministered with cobicistat in clinical trials at a rate of 0.1%. During darunavir postmarketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported.

Discontinue SYMTUZA™ immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING, on the following pages. *AMBER was a Phase 3, randomized, double-blind, active-controlled, international, multicenter, noninferiority study assessing the efficacy and safety of once-daily SYMTUZA™ (DRV 800 mg/ COBI 150 mg/FTC 200 mg/TAF 10 mg) vs DRV/COBI + FTC/TDF in treatment-naïve adults (N=725). Primary endpoint was the proportion of patients with VL <50 copies/mL at 48 weeks (noninferiority margin 10% by FDA Snapshot).1,2 EMERALD was a Phase 3, randomized, open-label, international, multicenter, noninferiority study of switching to SYMTUZA™ (DRV 800 mg/COBI 150 mg/FTC 200 mg/TAF 10 mg) vs continuing on bPI + FTC/TDF therapy in treatment-experienced adults who had been on therapy for ≥6 months with no history of virologic failure on darunavir-based regimens, and who were virologically suppressed prior to and at screening (N=1141). Primary endpoint was the proportion of patients with virologic rebound at Week 48 (noninferiority margin 4%), and a key secondary endpoint was the proportion of subjects who have VL <50 copies/mL at 48 weeks.1,3

†

‡

In the AMBER trial, of 362 treatment-naïve patients taking SYMTUZA™, 8 met the criteria for virologic failure and 7 patients experiencing virologic failure were analyzed for resistance.1,2

In the EMERALD trial, of 763 virologically suppressed patients taking SYMTUZA™, 6 met the criteria for virologic failure and 1 patient experiencing virologic failure was analyzed for resistance.1,3

§

This patient also had a transmitted K103N mutation at screening. M184V was detected pretreatment by deep sequencing (Illumina MiSeq) as a minority variant (9.4%).2

¶

bPI=boosted protease inhibitor; COBI=cobicistat; DRV=darunavir; FTC=emtricitabine; PI=protease inhibitor; TAF=tenofovir alafenamide; TDF=tenofovir disoproxil fumarate; VL=viral load.

Formulated for Improved Tolerability SYMTUZA™ demonstrated a favorable tolerability profile vs control arm in treatment-naïve patients1

of treatment-naïve subjects discontinued due to adverse events in the SYMTUZA™ arm vs 4% in the control arm1

• The most common adverse reactions occurring in ≥2% of treatmentnaïve patients were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence1 • This is not a complete list of adverse reactions. Please refer to the full Prescribing Information for more information

IMPORTANT SAFETY INFORMATION (cont) • Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant

use of SYMTUZA™ and other drugs may result in known or potentially significant drug interactions, some of which may lead to the loss of therapeutic effect of SYMTUZA™ and possible development of resistance or possible clinically significant adverse reactions from greater exposures of concomitant drugs.

Consult the full Prescribing Information for potential drug interactions prior to and during SYMTUZA™ therapy, review concomitant medications during SYMTUZA™ therapy, and monitor for the adverse reactions associated with concomitant medications.

• Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, had been reported in patients treated with combination antiretroviral therapy.

• New Onset or Worsening Renal Impairment: Renal impairment, including cases of acute renal failure and Fanconi

syndrome, has been reported with the use of tenofovir prodrugs. SYMTUZA™ is not recommended in patients with creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including nonsteroidal anti-infl ammatory drugs are at increased risk of developing renal-related adverse reactions.

In all patients, monitor serum creatinine, creatinine clearance, urine glucose, and urine protein prior to or when initiating SYMTUZA™ and during therapy. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue SYMTUZA™ in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

• Sulfa Allergy: Monitor patients with a known sulfonamide allergy after initiating SYMTUZA™.

• Lactic Acidosis/Severe Hepatomegaly With Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA™, and tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, alone or in combination with other antiretrovirals. Discontinue SYMTUZA™ in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING, on the following pages.

91% Virologic Response Achieved in Treatment-Naïve Patients 1

% of Patients Achieving Virologic Response (VL <50 copies/mL)

100

Control=DRV/c + FTC/TDF.

‡

Included subjects who had ≥50 copies/mL in the Week 48 window (days 295-378); subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL. CD4+=cluster of differentiation 4; DRV/c=darunavir/cobicistat; FTC/TDF=emtricitabine/tenofovir disoproxil fumarate; MH=Mantel-Haenszel; VL=viral load.

60

91

%

40

of patients treated with SYMTUZA™ had

20

at Week 48 (<50 copies/mL)*

undetectable VLs (n=362)

(n=363)

SYMTUZA™

Control†

• 4% virologic failure rate in the SYMTUZA™ arm vs 3% in the control arm1‡ 100

91%

91% 88% • 4% of patients in the SYMTUZA™ arm had no 80 virologic data vs 8% in the control arm1

% of Patients Achieving Virologic Response (VL <50 copies/mL)

IMPORTANT SAFETY INFORMATION (cont) 60 have been • Diabetes Mellitus/Hyperglycemia: New-onset or exacerbations of pre-existing diabetes mellitus andofhyperglycemia patients treated reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required.

40

with SYMTUZA™ had

• Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral undetectable VLs therapy. (<50 copies/mL) • Hemophilia: Increased bleeding in hemophiliacs has been reported in patients receiving protease inhibitors.

20 at Week 48 ADVERSE REACTIONS [95% CI (2.7%, -1.6 to 7.1)]* (n=362) (n=363)

• The most common clinical adverse reactions (all grades) occurring 0in at least 2% of treatment-naïve patients were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence. This is not a completeSYMTUZA™ list of all adverse drug reactions reported with the use of Control SYMTUZA™. Please refer to the full Prescribing Information for a complete list of adverse drug reactions.

DRUG INTERACTIONS

• Consult the full Prescribing Information for SYMTUZA™ for information on significant drug interactions, including clinical comments.

USE IN SPECIFIC POPULATIONS • Pregnancy: SYMTUZA™ is not recommended for use during pregnancy because of substantially lower exposures of darunavir and

cobicistat during pregnancy.

SYMTUZA™ should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with SYMTUZA™.

• Renal Impairment: SYMTUZA™ is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL per minute).

• Hepatic Impairment: SYMTUZA™ is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).

• Consult the full Prescribing Information for SYMTUZA™ for additional information on the Uses in Specific Populations.

Please see accompanying Brief Summary, including Boxed WARNING, for SYMTUZA™.

References: 1. SYMTUZA™ [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP. 2. Eron JJ, Orkin C, Gallant J, et al. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naïve HIV-1 patients. AIDS. 2018;32:1431-1442. 3. Orkin C, Molina JM, Negredo E, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3 randomised, non-inferiority trial. Lancet HIV. 2018;5(1):e23-e34.

Distributed by: Janssen Therapeutics, Division of Janssen Products, LP, Titusville, NJ 08560 © Janssen Therapeutics, Division of Janssen Products, LP 2018 07/18 cp-60915v1

cp-62076v2

B:11.75”

T:11.5”

S:10.3667”

†

88%

80

0

*Based on stratum adjusted MH test where stratification factors are HIV-1 RNA level (≤100,000 or >100,000 copies/mL) and CD4+ cell count (<200 or ≥200 cells/µL).

91%

SYMTUZA™

(darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use Brief Summary of Prescribing Information. For complete prescribing information, please consult official package insert.

WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of SYMTUZA. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions].

INDICATIONS AND USAGE SYMTUZA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults: • who have no prior antiretroviral treatment history or • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

DOSAGE AND ADMINISTRATION Testing Prior to Initiation of SYMTUZA Prior to or when initiating SYMTUZA, test patients for hepatitis B (HBV) virus infection [see Warnings and Precautions].

Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions].

Recommended Dosage SYMTUZA is a four-drug fixed dose combination product containing 800 mg of darunavir (DRV), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of SYMTUZA is one tablet taken orally once daily with food in adults. For patients who are unable to swallow the whole tablet, SYMTUZA may be split into two pieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Not Recommended in Patients with Severe Renal Impairment SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute [see Use in Specific Populations].

Not Recommended in Patients with Severe Hepatic Impairment SYMTUZA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations].

Not Recommended During Pregnancy SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy [see Use in Specific Populations and Clinical Pharmacology (12.3) in Full Prescribing Information].

SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with SYMTUZA. DOSAGE FORMS AND STRENGTHS Each SYMTUZA tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine (FTC), and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide (TAF). The yellow to yellowish-brown, capsule-shaped, film-coated tablet is debossed with “8121” on one side and “JG” on the other side.

CONTRAINDICATIONS SYMTUZA is contraindicated with the following co-administered drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions].

• Alpha 1-adrenoreceptor antagonist: alfuzosin • Antianginal: ranolazine • Antiarrhythmic: dronedarone • Anticonvulsants: carbamazepine, phenobarbital, phenytoin • Anti-gout: colchicine, in patients with renal and/or hepatic impairment • Antimycobacterial: rifampin • Antipsychotics: lurasidone, pimozide • Ergot derivatives, e.g., dihydroergotamine, ergotamine, methylergonovine • GI motility agent: cisapride • Herbal product: St. John’s wort (Hypericum perforatum) • Hepatitis C direct acting antiviral: elbasvir/grazoprevir • HMG-CoA reductase inhibitors: lovastatin, simvastatin • PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension • Sedatives/hypnotics: orally administered midazolam, triazolam

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets WARNINGS AND PRECAUTIONS Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy [see Dosage and Administration].

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA. Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir, a component of SYMTUZA. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse reactions.

Post-marketing cases of liver injury, including some fatalities, have been reported with darunavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with SYMTUZA and patients should be monitored during treatment as clinically appropriate. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of SYMTUZA treatment.

Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA. Severe Skin Reactions In patients receiving darunavir, a component of SYMTUZA, severe skin reactions may occur. These include conditions accompanied by fever and/or elevations of transaminases. Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%. During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported.

Discontinue SYMTUZA immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with SYMTUZA in the AMBER trial [see Adverse Reactions]. Rash events were mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using SYMTUZA was 2%.

Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of SYMTUZA and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications and Drug Interactions]: • Loss of therapeutic effect of SYMTUZA and possible development of resistance.

• Possible clinically significant adverse reactions from greater exposures of concomitant drugs.

See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during SYMTUZA therapy; review concomitant medications during SYMTUZA therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications and Drug Interactions].

When used with concomitant medications, SYMTUZA, which contains darunavir boosted with cobicistat, may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain SYMTUZA interactions [see Drug Interactions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and GuillainBarré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.

New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of SYMTUZA, there were no cases of proximal renal tubulopathy (PRT), including Fanconi syndrome, reported in the SYMTUZA group through Week 48. SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute.

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Prior to or when initiating SYMTUZA and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Discontinue SYMTUZA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Cobicistat, a component of SYMTUZA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating SYMTUZA, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation.

Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

Sulfa Allergy Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating SYMTUZA. In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with SYMTUZA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established.

Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors (PIs). In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued.

A causal relationship between PI therapy and these episodes has not been established.

ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Severe acute exacerbations of hepatitis B [see Warnings and Precautions] • Hepatotoxicity [see Warnings and Precautions] • Severe skin reactions [see Warnings and Precautions]

• Immune reconstitution syndrome [see Warnings and Precautions] • New onset or worsening renal impairment [see Warnings and Precautions] • Lactic acidosis/severe hepatomegaly with steatosis [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Adults with No Prior Antiretroviral Treatment History The safety profile of SYMTUZA in HIV-1 infected adults with no prior antiretroviral treatment history is based on Week 48 data from the AMBER trial, a randomized, double-blind, active-controlled trial where a total of 362 subjects received SYMTUZA once daily and 363 subjects received a combination of PREZCOBIX® (fixed-dose combination of darunavir and cobicistat) and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF).

The proportion of subjects who discontinued treatment with SYMTUZA or PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4% respectively.

An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX and F/TDF are presented in Table 3.

Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade 3 reaction was reported and no grade 4 adverse reactions were reported during treatment with SYMTUZA. Table 1: Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA PREZCOBIX+FTC/TDF (N=362) (N=363) All At least All At least Grades Grade 2 Grades Grade 2 Diarrhea 9% 2% 11% 2% Rasha 8% 4% 7% 5% Nausea 6% 1% 10% 3% Fatigue 4% 1% 4% 1% Headache 3% 1% 2% 1% Abdominal discomfort 2% 4% <1% Flatulence 2% <1% 1% a Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria Adverse Reactions in Virologically-Suppressed Adults The safety profile of SYMTUZA in virologically-suppressed HIV-1 infected adults is based on Week 48 data from 1,141 subjects in the EMERALD trial, a randomized, open-label, active-controlled trial where 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with FTC and TDF switched to SYMTUZA, and 378 subjects who continued their treatment regimen of a boosted protease inhibitor with FTC and TDF. Overall, the safety profile of SYMTUZA in subjects in this study was similar to that in subjects with no prior antiretroviral treatment history. The proportion of subjects who discontinued treatment with SYMTUZA due to adverse events, regardless of severity, was 1%.

Less Frequent Adverse Reactions The following adverse reactions occurred in less than 2% of adults with no antiretroviral treatment history or virologically suppressed subjects receiving SYMTUZA, or are from studies described in the prescribing information of the individual component PREZISTA (darunavir).

Gastrointestinal Disorders: dyspepsia, pancreatitis (acute), vomiting Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, StevensJohnson syndrome Metabolism and Nutrition Disorders: anorexia, diabetes mellitus, lipodystrophy Reproductive system and Breast disorders: gynecomastia Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis Psychiatric Disorders: abnormal dreams Immune System Disorders: (drug) hypersensitivity, immune reconstitution inflammatory syndrome Hepatobiliary Disorders: acute hepatitis

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Laboratory Abnormalities

In the EMERALD trial which had 1,141 virologically-suppressed adults treated with an HIV protease inhibitor and TDF containing regimen with a median baseline eGFR of 104 mL/min (SYMTUZA) and 103 mL/min (bPI+FTC/ TDF) who were randomized to continue their treatment regimen or switch to SYMTUZA, at Week 48, mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to SYMTUZA. Mean (SD) serum creatinine was 0.98 (0.18) mg/dL (SYMTUZA) and 0.98 (0.19) mg/dL (bPI+FTC/TDF) at baseline and 0.99 (0.18) mg/dL (SYMTUZA) and 0.99 (0.21) mg/dL (bPI+FTC/TDF) at Week 48. Median serum creatinine was 0.97 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at baseline and 1.0 mg/dL (SYMTUZA) and 0.97 mg/dL (bPI+FTC/TDF) at Week 48. Median UPCR was 62 mg per gram (SYMTUZA) and 63 mg/g (bPI+FTC/TDF) at baseline and 37 mg per gram (SYMTUZA) and 53 mg/g (bPI+FTC/TDF) at Week 48.

Bone Mineral Density AMBER The effects of SYMTUZA compared to PREZCOBIX + FTC/TDF on bone mineral density (BMD) change from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 48 was −0.7% with SYMTUZA compared to −2.4% with DRV/COBI + FTC/TDF at the lumbar spine and 0.2% compared to −2.7% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 16% of SYMTUZA subjects and 22% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 2% of SYMTUZA subjects and 15% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.

EMERALD In EMERALD, boosted Protease Inhibitor (bPI) and TDF-treated subjects were randomized to continue their TDF-based regimen or switch to SYMTUZA; changes in BMD from baseline to Week 48 were assessed by DXA. The mean percentage change in BMD from baseline to Week 48 was 1.5% with SYMTUZA compared to −0.6% with PREZCOBIX + FTC/TDF at the lumbar spine and 1.4% compared to -0.3% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of SYMTUZA subjects and 9% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by no SYMTUZA subjects and 2% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.

Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving a darunavir-containing regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Metabolism and Nutrition Disorders Redistribution of body fat Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors) Skin and Subcutaneous Tissue Disorders Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions].

DRUG INTERACTIONS Not Recommended With Other Antiretroviral Medications SYMTUZA is a complete regimen for HIV-1 infection and coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. For this reason, information regarding potential drugdrug interactions with other antiretroviral medications is not provided.

Potential for SYMTUZA to Affect Other Drugs Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of SYMTUZA with drugs that are primarily metabolized by CYP3A and/or CYP2D6, or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events (see Table 4).

Potential for Other Drugs to Affect SYMTUZA Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Co-administration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 4).

Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF, which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit P-gp may increase the absorption and plasma concentrations of TAF (see Table 4).

Table 2: Laboratory Abnormalities (Grade 2-4) Reported in ≥2% of Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) Laboratory Parameter SYMTUZA Grade Limit N=362 Creatinine Grade 2 >1.3 to 1.8 x ULN 4% Grade 4 ≥3.5x ULN <1% Triglycerides Grade 2 301-500 mg/dL 7% Grade 3 501-1,000 mg/dL 1% Grade 4 > 1,000 mg/dL <1%% Total Cholesterol Grade 2 240-<300 mg/dL 17% Grade 3 >= 300 mg/dL 2% Low-Density Lipoprotein Cholesterol Grade 2 160-189 mg/dL 9% Grade 3 ≥ 190 mg/dL 5% Elevated Glucose Levels Grade 2 126-250 mg/dL 6% Grade 3 251-500 mg/dL <1%

PREZCOBIX+ FTC/TDF N=363 14% 0 4% 1% <1% 4% 1%

4% 1%

6% 0

ALT and/or AST elevations (Grade 2-4 combined) occurred in 2% of adult subjects receiving SYMTUZA with no antiretroviral treatment history in AMBER (Week 48 Analysis). Results were consistent in subjects receiving PREZCOBIX+FTC/TDF. Table 3: Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis)a SYMTUZA PREZCOBIX+FTC/TDF N=356 N=355 Baseline Week 48 Baseline Week 48 Meanb mg/dL Change mg/dL Change N=304c N=290 Total cholesterol 168 +30 164 +11 HDL cholesterol 45 +6 44 +2 LDL cholesterol 199 +19 98 +5 Triglycerides 117 +34 112 +21 Total cholesterol to 4.1 0.2 4.0 0.1 HDL ratio a Subjects on lipid-lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on PREZCOBIX+FTC/TDF). Subjects initiating a lipid-lowering agent postbaseline had their last fasted on-treatment value (prior to starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF). b The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the last value carried forward prior to initiating lipid-lowering agent post-baseline. c One subject did not have a Week 48 result for LDL cholesterol (n=303).

The percentage of subjects starting any lipid lowering drug during treatment in the SYMTUZA and PREZCOBIX + FTC/TDF arm were 1.7% (n=6) and 0.6% (n=2), respectively.

Renal Laboratory Tests In the AMBER trial, which had 670 adults with no prior antiretroviral treatment history with a median baseline eGFR of 119 mL/min (SYMTUZA) and 118 mL/min (PREZCOBIX + FTC/TDF), mean (SD) serum creatinine increased by 0.05 (0.10) mg/dL in the SYMTUZA group and by 0.09 (0.11) mg/dL in the PREZCOBIX + FTC/TDF group from baseline to Week 48. Median serum creatinine was 0.90 mg/dL (SYMTUZA) and 0.89 mg/ dL (PREZCOBIX + FTC/TDF) at baseline and 0.95 mg/dL (SYMTUZA) and 0.97 mg/dL (PREZCOBIX +FTC/TDF) at Week 48. Increases in serum creatinine occurred by Week 2 of treatment and remained stable. Median urine protein-to-creatinine ratio (UPCR) was 47 mg per gram (SYMTUZA) and 51 mg/g (PREZCOBIX + FTC/TDF) at baseline and 30 mg per gram (SYMTUZA) and 34 mg/g (PREZCOBIX + FTC/TDF) at Week 48.

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily excreted by the kidneys through glomerular filtration and active tubular secretion, co-administration of SYMTUZA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions].

Significant Drug Interactions Table 4 provides a listing of established or potentially clinically significant drug interactions with SYMTUZA and recommended steps to prevent or manage these interactions. These recommendations are based on drug interaction trials conducted with the components of SYMTUZA, as individual agents or in combination, or are predicted interactions. No drug interaction trials have been performed with SYMTUZA or with all the components administered together. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs.

Table 4: Significant Drug Interactions: Concomitant Drug Class: Drug Name, Clinical Comment Alpha 1-adrenoreceptor antagonist: alfuzosin. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.

Antianginal: ranolazine. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions.

Antiarrhythmics: dronedarone. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. other antiarrhythmics, e.g., amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine. Clinical monitoring is recommended upon co-administration with antiarrhythmics. digoxin. When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations.

Antibacterials: clarithromycin, erythromycin, telithromycin. Consider alternative antibiotics with concomitant use of SYMTUZA. Anticancer agents: dasatinib, nilotinib. A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary when co-administered with SYMTUZA. Consult the dasatinib and nilotinib prescribing information for dosing instructions. vinblastine, vincristine. For vincristine and vinblastine, consider temporarily withholding the cobicistat-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when SYMTUZA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consider initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

Anticoagulants: Direct Oral Anticoagulants (DOACs). apixaban. Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with SYMTUZA depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. rivaroxaban. Coadministration of rivaroxaban with SYMTUZA is not recommended because it may lead to an increased bleeding risk. betrixaban, dabigatran, edoxaban. No dose adjustment is needed when betrixaban, dabigatran, or edoxaban is co-administered with SYMTUZA. warfarin. Monitor international normalized ratio (INR) upon co-administration of SYMTUZA with warfarin.

Anticonvulsants: carbamazepine, phenobarbital, phenytoin. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance.

Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g., eslicarbazepine, oxcarbazepine. Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If co-administration is necessary, monitor for lack or loss of virologic response.

Anticonvulsants that are metabolized by CYP3A: e.g., clonazepam. Clinical monitoring of anticonvulsants is recommended.

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

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

Other antidepressants: trazodone. When co-administering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.

Antifungals: itraconazole, ketoconazole, posaconazole. Monitor for increased darunavir or cobicistat adverse reactions. Specific dosing recommendations are not available for co-administration with itraconazole or ketoconazole.

Monitor for increased itraconazole or ketoconazole adverse reactions. voriconazole. Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole.

Anti-gout: colchicine. Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or lifethreatening reactions. For patients without renal or hepatic impairment: • Treatment of gout flares – co-administration of colchicine: 0.6 mg (1 tablet) ×1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.

• Prophylaxis of gout flares – co-administration of colchicine: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

• Treatment of familial Mediterranean fever – co-administration of colchicine: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Antimalarial: artemether/lumefantrine. Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation.

Antimycobacterials: rifampin. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. rifabutin. Co-administration of SYMTUZA with rifabutin is not recommended.

If the combination is needed, the recommended dose of rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis. rifapentine. Co-administration with rifapentine is not recommended.

Antipsychotics: lurasidone. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. pimozide. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. other antipsychotics, e.g., perphenazine, risperidone, thioridazine. A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with SYMTUZA. quetiapine. Initiation of SYMTUZA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions.

Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking SYMTUZA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. β-Blockers: e.g., carvedilol, metoprolol, timolol. Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized

by CYP2D6.

Calcium channel blockers: e.g., amlodipine, diltiazem, felodipine, nifedipine, verapamil. Clinical monitoring is recommended for co-administration with calcium channel blockers metabolized by CYP3A. Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone methylprednisolone, mometasone, triamcinolone. Co-administration with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to SYMTUZA. Consider alternative corticosteroids.

Co-administration with corticosteroids of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use.

Endothelin receptor antagonists: bosentan. Initiation of bosentan in patients taking SYMTUZA: In patients who have been receiving SYMTUZA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

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

Switching from darunavir co-administered with ritonavir to SYMTUZA in patients on bosentan: Maintain bosentan dose.

Ergot derivatives: e.g., dihydroergotamine, ergotamine, methylergonovine.

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

GI motility agent: cisapride. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir.

Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations. simeprevir. Co-administration with simeprevir is not recommended.

Herbal product: St. John’s wort (Hypericum perforatum). Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance.

HMG-CoA reductase inhibitors: lovastatin, simvastatin. Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

other HMG-CoA reductase inhibitors, e.g., atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin. For atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin, start with the lowest recommended dose and titrate while monitoring for safety.

Dosage recommendations with atorvastatin or rosuvastatin are as follows: • atorvastatin dosage should not exceed 20 mg/day • rosuvastatin dosage should not exceed 20 mg/day Hormonal contraceptives: Additional or alternative (non-hormonal) forms of contraception should be considered when estrogen based contraceptives are coadministered with SYMTUZA. drosperinone/ethinylestradiol. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. other progestin/estrogen, contraceptives. No data are available to make recommendations on co-administration with oral or other hormonal contraceptives.

Immunosuppressants: cyclosporine, sirolimus, tacrolimus. These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended with concomitant use.

Immunosuppressant/neoplastic: everolimus. Co-administration of everolimus and SYMTUZA is not recommended.

Inhaled beta agonist: salmeterol. Co-administration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

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

Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. tramadol. A dose decrease may be needed for tramadol with concomitant use.

Narcotic analgesic for treatment of opioid dependence: buprenorphine, buprenorphine/naloxone, methadone. Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking SYMTUZA: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose.

Initiation of SYMTUZA in patients taking buprenorphine, buprenorphine/ naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms.

Phosphodiesterase PDE-5 inhibitors: e.g., avanafil, sildenafil, tadalafil, vardenafil. Co-administration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established.

Co-administration with PDE-5 inhibitors may result in an increase in PDE-5 inhibitor-associated adverse reactions including hypotension, syncope, visual disturbances and priapism.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). The following dose adjustments are recommended for use of tadalafil with SYMTUZA: • Initiation of tadalafil in patients taking SYMTUZA: In patients receiving SYMTUZA for at least one week, start tadalafil at 20 mg once daily.

Increase to 40 mg once daily based upon individual tolerability.

• Initiation of SYMTUZA in patients taking tadalafil: Avoid use of tadalafil during the initiation of SYMTUZA. Stop tadalafil at least 24 hours prior to starting SYMTUZA. After at least one week following the initiation of SYMTUZA, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

• Patients switching from darunavir co-administered with ritonavir to SYMTUZA: Maintain tadalafil dose.

Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitorassociated adverse reactions.

Platelet aggregation inhibitor: ticagrelor. Co-administration of SYMTUZA and ticagrelor is not recommended.

Sedatives/hypnotics: orally administered midazolam, triazolam.

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. metabolized by CYP3A: e.g., buspirone, diazepam, estazolam, zolpidem.

With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions. parenterally administered midazolam. Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered.

This table is not all inclusive

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SYMTUZA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary There are insufficient human data on the use of SYMTUZA in pregnant individuals from the APR to inform on a potential drug-associated risk of birth defects and miscarriage. Available data from the APR show no difference in rate of overall birth defects for darunavir and emtricitabine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates pregnant individuals and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation.

In animal reproduction studies, no adverse developmental effects were observed when the components of SYMTUZA were administered separately at darunavir exposures less than 1- (mice and rabbits) and 2.6-times (rats) higher, at cobicistat exposures 1.7- and 4.1-times higher (rats and rabbits respectively) at emtricitabine exposures 88- and 7.3- times higher (mice and rabbits, respectively), and tenofovir alafenamide exposures equal to or 85- times higher (rats and rabbits, respectively) than human exposures at the recommended daily dose of these components in SYMTUZA (see Data). No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.1 times the human exposure at the recommended therapeutic dose.

Clinical Considerations Not Recommended During Pregnancy SYMTUZA is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy (see Data) and [see Clinical Pharmacology (12.3) in Full Prescribing Information].

SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with SYMTUZA. Data Human Data Darunavir/Cobicistat: Darunavir and cobicistat in combination with a background regimen was evaluated in a clinical trial of 7 pregnant individuals taking darunavir and cobicistat prior to enrollment and who were willing to remain on darunavir and cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum.

Six pregnant individuals completed the trial.

Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum [see Clinical Pharmacology (12.3) in Full Prescribing Information].

One out of 6 pregnant individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five pregnant individuals had sustained virologic response (HIV RNA <50 copies/mL) throughout the study period.

There are no clinical data on the virologic response when darunavir and cobicistat are initiated during pregnancy.

Darunavir: Based on prospective reports to the APR of 679 live births following exposure to darunavir-containing regimens during pregnancy (including 425 exposed in the first trimester and 254 exposed in the second/ third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.1% (95% CI: 1.0% to 4.0%) with first trimester exposure to darunavir containing-regimens and 2.4% (95% CI: 0.9% to 5.1%) with second/third trimester exposure to darunavircontaining regimens.

Cobicistat: Insufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects.

Emtricitabine: Based on prospective reports to the APR of 3749 exposures to emtricitabine-containing regimens during pregnancy (including 2614 exposed in the first trimester and 1135 exposed in the second/third trimester), there was no difference between emtricitabine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to emtricitabine-containing regimens and 2.1% (95% CI: 1.4% to 3.1%) with the second/third trimester exposure to emtricitabine-containing regimens.

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Tenofovir alafenamide: Insufficient numbers of pregnancies with exposure to tenofovir alafenamide have been reported to the APR to estimate the rate of birth defects.

Animal Data Darunavir: Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (2.6-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended daily dose of darunavir in SYMTUZA. Cobicistat: Cobicistat was administered orally to pregnant rats at doses up to 125 mg/kg/day on GD 6-17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.7 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. In pregnant rabbits, cobicistat was administered orally at doses up to 100 mg/kg/day during GD 7-20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 4.1 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses up to 75 mg/kg from GD 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.1 times the human exposures at the recommended daily dose of cobicistat in SYMTUZA. Emtricitabine: Emtricitabine was administered orally to pregnant mice and rabbits (up to 1000 mg/kg/day) through organogenesis (on GD 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 88 times higher and in rabbits approximately 7.3 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA. In a pre/postnatal development study, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures of approximately 88 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA. Tenofovir Alafenamide (TAF): TAF was administered orally to pregnant rats (up to 250 mg/kg/day) and rabbits (up to 100 mg/kg/day) through organogenesis (on GD 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures approximately similar to (rats) and 85 times higher (rabbits) than the exposure in humans at the recommended daily dose. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 51 (rats) and 80 (rabbits) times higher than human tenofovir exposures at the recommended daily dose of TAF in SYMTUZA. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF (another prodrug of tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on GD 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposure in humans at the recommended daily dose of TDF. Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIVinfected mothers in the United States not to breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Based on published data, emtricitabine has been shown to be present in human breast milk. There are no data on the presence of darunavir, cobicistat, or TAF in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir and cobicistat are present in the milk of lactating rats. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF (see Data).

Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infants, instruct mothers not to breastfeed if they are receiving SYMTUZA. Data Animal Data Darunavir: Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is excreted in milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 66% of those obtained in humans at the recommended clinical dose of darunavir with ritonavir.

Cobicistat: During the pre/postnatal developmental toxicology study, at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10.

Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is excreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating rhesus monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.

Pediatric Use The safety and effectiveness of SYMTUZA in pediatric patients less than 18 years of age have not been established. Darunavir, a component of SYMTUZA is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.

Juvenile Animal Toxicity Data Darunavir: In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on postnatal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.

Geriatric Use Clinical trials of SYMTUZA included 35 subjects aged above 65 years of which 26 received SYMTUZA. No differences in safety or efficacy have been observed between elderly subjects and those aged 65 years or less. In general, caution should be exercised in the administration and monitoring of SYMTUZA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Renal Impairment SYMTUZA is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL per minute). No dosage adjustment of SYMTUZA is required in patients with creatinine clearance greater than or equal to 30 mL per minute [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Cobicistat has been shown to decrease creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosage adjustment for renal impairment when used in combination with SYMTUZA [see Warnings and Precautions].

Hepatic Impairment No dosage adjustment of SYMTUZA is required in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment.

SYMTUZA has not been studied in patients with severe hepatic impairment (Child Pugh Class C) and there are only limited data regarding the use of SYMTUZA components in this population. Therefore, SYMTUZA is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information].

OVERDOSAGE Human experience of acute overdose with SYMTUZA is limited. There is no specific antidote for overdose with SYMTUZA. Treatment of overdose with SYMTUZA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

Since darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

Product of Canada Manufactured by: Patheon Inc, 2100 Syntex Ct Mississauga ON L5N 7K9, Canada Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560 © 2018 Janssen Pharmaceutical Companies cp-62058v1

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NOW AVAILABLE INDICATION Olumiant is a Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies.

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

IMPORTANT SAFETY INFORMATION FOR OLUMIANT (baricitinib) tablets WARNING: SERIOUS INFECTIONS, MALIGNANCY, AND THROMBOSIS SERIOUS INFECTIONS: Patients treated with Olumiant are at risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt Olumiant until the infection is controlled. Reported infections include: • Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Test patients for latent TB before initiating Olumiant and during therapy. Treatment for latent infection should be considered prior to Olumiant use.

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

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

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

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Olumiant including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

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

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

Please see the following pages for additional Important Safety Information and Brief Summary of Prescribing Information, including Boxed Warning about Serious Infections, Malignancies, and Thrombosis.

Visit olumiant.com/hcp to learn if Olumiant is appropriate for your patients

Olumiant reduced signs and symptoms of RA in TNFi-IR patients1-3 Patients receiving Olumiant + cDMARDs demonstrated higher ACR response rates vs placebo + cDMARDs at weeks 12 and 24 100

ACR Response Rates

90

PERCENTAGE OF PATIENTS (NRI�

80

70

60

***

50

***

49

45

40

30 27

20

0

***

13

ACR20

ACR50

3

2

ACR70

13

13

ACR20

WEEK 12

Placebo + cDMARDs (n=176)

23

***

10 8

*

27

**

20

ACR50

ACR70

WEEK 24

Olumiant 2 mg/day + cDMARDs (n=174)

*p≤0.05; **p≤0.01; ***p≤0.001.

The primary endpoint was the proportion of patients achieving ACR20 response at week 12.

From week 16, non-responding patients could be rescued to receive baricitinib 4 mg/day.† Patients who were rescued or discontinued treatments were considered non-responders in the analysis.

Study IV (BEACON) was a 24-week, randomized, double-blind trial in 527 patients with moderately to severely active RA who had an inadequate response or intolerance to at least 1 TNF inhibitor. Patients received Olumiant 2 mg (n=174) or baricitinib 4 mg (n=177) once-daily or placebo (n=176), added to background cDMARD treatment. The primary endpoint was the proportion of patients achieving ACR20 response at week 12.

†Baricitinib 4mg is not an approved dose TNFi-IR=tumor necrosis factor-inadequate response; NRI=non-responder imputation; ACR20/50/70=American College of Rheumatology 20%/50%/70% improvement criteria.

IMPORTANT SAFETY INFORMATION FOR OLUMIANT tablets (cont’d) WARNINGS AND PRECAUTIONS SERIOUS INFECTIONS: The most common serious infections reported with Olumiant included pneumonia, herpes zoster, and urinary tract infection. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus, and BK virus were reported with Olumiant. Some patients have presented with disseminated rather than local disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid Olumiant in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating Olumiant in patients: • with chronic or recurrent infection • who have been exposed to TB • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection.

Closely monitor patients for infections during and after Olumiant treatment. Interrupt Olumiant if a patient develops a serious infection, an opportunistic infection, or sepsis. Do not resume Olumiant until the infection is controlled.

Tuberculosis – Before initiating Olumiant evaluate and test patients for latent or active infection and treat patients with latent TB with standard antimycobacterial therapy. Olumiant should not be given to patients with active TB. Consider anti-TB therapy prior to initiating Olumiant in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Monitor patients for TB during Olumiant treatment.

Viral Reactivation – Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies with Olumiant. If a patient develops herpes

zoster, interrupt Olumiant treatment until the episode resolves.

The impact of Olumiant on chronic viral hepatitis reactivation is unknown. Screen for viral hepatitis in accordance with clinical guidelines before initiating Olumiant.

MALIGNANCY AND LYMPHOPROLIFERATIVE DISORDERS: Malignancies were observed in Olumiant clinical studies.

Consider the risks and benefits of Olumiant prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing Olumiant in patients who develop a malignancy. NMSCs were reported in patients treated with Olumiant. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

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

GASTROINTESTINAL PERFORATIONS: Gastrointestinal perforations have been reported in Olumiant clinical studies, although the role of JAK inhibition in these events is not known.

Use Olumiant with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Promptly evaluate patients who present with new onset abdominal symptoms for early identification of gastrointestinal perforation.

LABORATORY ABNORMALITIES: Neutropenia – Olumiant treatment was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm3) compared to placebo. Avoid initiation

Visit olumiant.com/hcp to learn if Olumiant is appropriate for your patients

or interrupt Olumiant treatment in patients with an ANC <1000 cells/mm3. Evaluate at baseline and thereafter according to routine patient management.

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

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

Anemia – Decreases in hemoglobin levels to <8 g/dL were reported in Olumiant clinical trials.

Avoid initiation or interrupt Olumiant treatment in patients with hemoglobin <8 g/dL. Evaluate at baseline and thereafter according to routine patient management.

Liver Enzyme Elevations – Olumiant treatment was associated with increased incidence of liver enzyme elevation compared to placebo.

Increases to ≥5x and ≥10x upper limit of normal were observed for both ALT and AST in patients in Olumiant clinical trials.

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

approximately 12 weeks following Olumiant initiation. Manage patients according to clinical guidelines for the management of hyperlipidemia.

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

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

USE IN SPECIFIC POPULATIONS PREGNANCY AND LACTATION: No information is available to support the use of Olumiant in pregnancy or lactation. Advise women not to breastfeed during treatment with Olumiant.

HEPATIC AND RENAL IMPAIRMENT: Olumiant is not recommended in patients with severe hepatic impairment or in patients with moderate or severe renal impairment.

Please see the following pages for Brief Summary of Prescribing Information, including Boxed Warning about Serious Infections, Malignancies, and Thrombosis.

BA HCP ISI 01JUN2018

Lipid Elevations – Treatment with Olumiant was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Assess lipid parameters

References: 1. Olumiant [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC. 2. Genovese MC, Kremer J, Zamani O, et al.

Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374:1243-1252. 3. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016; 374(suppl):1-30.

Olumiant® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries or affiliates.

PP-BA-US-0507 07/2018 ©Lilly USA, LLC 2018. All rights reserved.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

OLUMIANT® (baricitinib)

BA HCP BS 01JUN2018

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

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

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

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

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

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

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

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

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

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

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

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

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

Cases of disseminated tuberculosis were also reported.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

• The mean LDL/HDL ratio remained stable.

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

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

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

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

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

Events Upper respiratory tract infectionsa Nausea Herpes simplexb Herpes zoster a

b

Placebo n=1070 (%) 11.7 1.6 0.7 0.4

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

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

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

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

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

OLUMIANT® (baricitinib)

BA HCP BS 01JUN2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients who develop adverse reactions should receive appropriate treatment.

Additional information can be found at www.Olumiant.com

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

BA HCP BS 01JUN2018 OLUMIANT® (baricitinib)

BA HCP BS 01JUN2018

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 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.

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

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

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

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

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

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

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

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

Adhere to administration instructions.

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

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

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

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

• 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.

• Hypersensitivity and Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Humulin R U-500. If hypersensitivity reactions occur, discontinue Humulin R U-500; treat per standard of care and monitor until symptoms and signs resolve.

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

PP-HM-US-0518

05/2017

©Lilly USA, LLC 2017. All rights reserved.

Important Safety Information for Humulin R U-500, continued Warnings and Precautions, continued • Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Thiazolidinediones (TZDs), which are PPAR-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Observe patients for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

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

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

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

• 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.

Storage • Protect from heat and light. Do not freeze. Do not use Humulin R 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 of Humulin R U-500 should be kept in the refrigerator or at room temperature and used within 40 days of opening. Throw away any opened vial after 40 days of use, even if there is insulin left in the vial.

• Humulin R U-500 KwikPen: Unopened Humulin R U-500 KwikPens should be kept in a refrigerator. Opened (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, even if there is insulin left in the pen.

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

HM U500 HCP ISI 27SEP2016

Humulin® and KwikPen® are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Particularly close monitoring may be required.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

NDC 0002‑8824‑27 NDC 0002‑8501‑01

PATIENT COUNSELING INFORMATION: See FDA‑approved patient labeling.

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

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

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

HI U500 HCP BS 27SEP2016

Humulin R U-500 (insulin human injection)

Humulin R U-500 (insulin human injection)

HI U500 HCP BS 27SEP2016

HI U500 HCP BS 27SEP2016

2018

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

MSP ARTÍCULO DE REVISIÓN

Puerto Rico

Fecha

Título

Lugar

31 de agosto al 2 de septiembre

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

San Juan Marriot Resort San Juan, PR

Sociedad de Médicos Graduados de la Escuela de Medicina UPR

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

CONVENCIÓN

La Concha Hotel San Juan, PR

AMEC

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

CONVENCIÓN

1 de septiembre 2018

Convención Anual Academia de Neurología de PR

Coordinador o Contacto

Comentarios

1 al 3 de septiembre 2018

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

Mayagüez Resort & Casino Mayagüez, PR

Mignaliz Vega

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

CONVENCIÓN

8 de septiembre 2018

Update in liver diseases 2018 - Asociación Puertoriqueña de Gastroenterología

La Concha Renaissace Resort 1077 Ashford Avenue, San Juan PR

RiVS Marketing

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

CONFERENCIA

8 de septiembre 2018

35ta Conferencia Epilepsia del CaribeSociedad Puertorriqueña de Epilepsia

Intercontinental Hotel Isla Verde

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

13 al 16 de Septiembre 2018

Convención Anual Sociedad Radiológica de PR

Condado Plaza Hotel San Juan, PR

Serra & Serra Group

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

CONVENCIÓN

14 al 16 de septiembre 2018

Cursos obligatorios para médicos

Club de Leones Mayagüez, PR

High Education Health Inc.

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

CURSOS

15 de septiembre 2018

Convención Anual Sociedad de Nefrología de PR

Hotel Marriot San Juan, PR

AMEC

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

CONVENCIÓN

22 de septiembre de 2018

Simposio Negligencia, Imprudencia o Impericia Médica

Club Rotario Río Piedras, PR

High Education Health

787-964-6394 heh@hehpr.com

SIMPOSIO

22 de septiembre de 2018

Excellence In GI Nursing - Sociedad Puertoriqueña de asistentes de Gastroenterología

La Concha Renaissace Resort 1077 Ashford Avenue, San Juan PR

RiVS Marketing

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

28 al 30 de septiembre de 2018

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

Wyndham Rio Mar Río Grande, PR

AHOMPR Germaine Quiñones

6 de octubre 2018

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

Ponce Hilton Hotel Ponce, PR

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

6 de octubre 2018

Quinta Cumbre de Cáncer de Seno

Centro de convenciones de PR San Juan, PR

SDMS Group

787-731-3325 787-294-6119

CONGRESO

13 al 14 de octubre 2018

Acupuntura, más que una medicina alternativa

Club Rotario Río Piedras

High Education Health

787-964-6394 heh@hehpr.com

CURSOS

18 al 20 de octubre 2018

68 Annual Meeting - Puerto Rico Urological Association

Sheraton Puerto Rico Hotel and Casino 200 Convention Boulevard, San Juan PR 00907

Puerto Rico Urological 787-277-0674 Association Aixa Vélez

21 al 22 de octubre de 2018

Cursos Obligatorios- Asociación Puertorriqueña de Gastroenterología

Intercontinental Hotel San Juan, PR

RiVS Marketing

787-548-0047 info@rivsmarketing.com

CURSO

27 al 28 de octubre de 2018

Annual Convention Puerto Rico HIV Treaters Medical Association

Embassy Suites Hotel Dorado, PR

Educational Partners & Coaching, Inc. Vilma Pérez

787-646-0780

CONVENCIÓN

27 de octubre de 2018

2018 Annual Allergy and Immunology Congress

Intercontinental Hotel San Juan

IC Planners Ivette Colón

787-504-3655 ivettecolon@icplannerspr.com

CONGRESO

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

8 al 9 de Noviembre 2018

Congreso Internacional de Salud y Tecnología 2018

Sheraton Puerto Rico Hotel Convention Center San Juan, PR

AC Advertising

Sandra Berríos 787-236-6344 787-630-5740

787-608-1477 ahomprgq@gmail.com

CONFERENCIA

CURSO

CONVENCIÓN

SIMPOSIO

CONVENCIÓN

Revista Puertorriqueña de Medicina y Salúd Pública

CONGRESO

135

octubre Seno 2018 28 al 30 de Convención anual Asociación de septiembre Hematología y Oncologìa Médica 13 14 de de al 2018 Acupuntura, más que una de PR (AHOMPR) octubre medicina alternativa 2018 3rd Electrophysiology 6 de SymposiumAmerican College 18 al 20 de octubre 68 Annual Meeting - Puerto Ricoof Cardiology, PR Chapter octubre 2018 Urological Association 2018 6www.medicinaysaludpublica.com de Quinta Cumbre de Cáncer de octubre Seno Obligatorios- Asociación 21 al 22 de Cursos 2018 octubre de Puertorriqueña de Gastroenterología 2018 13 al 14 de Acupuntura, más que una octubre 27 al 28 de medicina alternativa Annual Convention Puerto Rico HIV 2018 octubre de Treaters Medical Association 2018 18 al 20 de 68 Annual Meeting - Puerto Rico octubre Urological Association 27 de 2018 2018 Annual Allergy and Immunology octubre Fecha Título Congress de 2018 21 al 22 de Cursos Obligatorios- Asociación octubre de Puertorriqueña de Gastroenterología 2 al 4 de 2018 Convención Anual Asociación de Médicos Noviembre Pediatras Región Este (AMPRE) 2018 27 al 28 de Annual Convention Puerto Rico HIV octubre de Treaters Medical Association 82018 al 9 de Congreso Internacional de Salud y Noviembre Tecnología 2018 27 de 2018 2018 Annual Allergy and Immunology octubre Congress Current Concept s in Breast Pathology dede 2018 10 Seminar- Academia de Patología y Noviembre Medicina de Laboratorio 2018 2 al 4 de Convención Anual Asociación de Médicos Noviembre Pediatras RegiónSociedad Este (AMPRE) 17 de Mini Convención 2018 Puertorriqueña de Neumología Noviembre 82018 al 9 de Congreso de Salud y Noviembre 17 de 2018 ACPInternacional Clinical Vignettes & Research Tecnología 2018 2018 Noviembre Competition Program- American College 2018 of Physicians Current Concept s in Breast Pathology 10 de Seminar- Academia de Patología y Noviembre 5 de Cumbre sobre VIH/SIDA Medicina de Laboratorio 2018 Diciembre 2018 17 de Mini Convención Sociedad Puertorriqueña de Neumología 7Noviembre al 9 de Convención Anual Colegio de Médicos 2018 Diciembre Cirujanos de PR 17 de 2018 ACP Clinical Vignettes & Research 2018 Noviembre Competition Program- American College of Physicians 72018 al 9 de Convención Semi Anual de SPED Diciembre 5 de 2018 Cumbre sobre VIH/SIDA Diciembre 25 al 27 de 2018 Compulsory Courses for Physicians Enero 2019

2018

SDMS Group AHOMPR Germaine Quiñones High Education Health

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

American College of 787-706-7495 Puerto Rico Urological 787-277-0674 Cardiology-PR Chapter accprchapter@gmail.com Association Aixa Vélez

Centro de convenciones de PR Intercontinental San Juan, PR Hotel San Juan, PR

SDMS Group RiVS Marketing

Agenda Médica

MSP Somos Ciencia

136

Centro de convenciones de PR San Juan, PR Wyndham Rio Mar Río Grande, PR Club Rotario Río Piedras

Puerto Rico

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

Lugar

Intercontinental Hotel San Juan, PR Intercontinental Hotel San Juan, PR Embassy Suites Hotel Dorado, PR Sheraton Puerto Rico Hotel Convention Center San Juan, PR Intercontinental Hotel San Juan Hyatt place San Juan, PR Intercontinental Hotel San Juan,Puerto PR Rico Hotel Sheraton Convention Center San Juan, PR Sheraton Puerto Rico Hotel Convention Center La Concha Renaissance San Juan, PR San Juan, PR

787-294-6119 787-608-1477 ahomprgq@gmail.com 787-964-6394 heh@hehpr.com

787-731-3325 787-294-6119 787-548-0047 info@rivsmarketing.com

787-964-6394 High Education Educational Partners heh@hehpr.com Health & Coaching, Inc. 787-646-0780 Vilma Pérez Puerto Rico Urological 787-277-0674 Association Aixa Vélez 787-504-3655 IC Planners ivettecolon@icplannersCoordinador o Contacto Ivette Colón pr.com 787-548-0047 RiVS Marketing info@rivsmarketing.com 787-706-0442 BPlanner Merna Morales Educational Partners bplanner21@gmail.com & Coaching, Inc. 787-646-0780 Vilma Pérez Sandra Berríos AC Advertising 787-236-6344 787-630-5740 787-504-3655 IC Planners ivettecolon@icplannersIvette Colón 787-406-4571 pr.com Serra & Serra 787-640-5776 Group info@serrayserra.com 787-706-0442 BPlanner bplanner21@gmail.com Merna Morales 787-706-0442 BPlanner bplanner21@gmail.com Merna Morales Sandra Berríos AC Advertising 787-236-6344 787-548-0047 RiVS Marketing 787-630-5740 info@rivsmarketing.com

Hyatt place San Juan, PR Ponce Hilton Ponce, PR

Serra & Serra AETC-RCM Group

Sheraton Puerto Rico Hotel Convention Center Centro dePR Convenciones de Puerto San Juan, RicoSan Juan, PR La Concha Renaissance San Juan, PR Hotel San Juan San Juan, PR Ponce Hilton Ponce, Club dePR Leones Mayagüez, PR

BPlanner ColegioMorales de Merna Médicos Cirujanos de PR RiVS Marketing Educational Partners & Coaching, Inc. AETC-RCM High Education Health Colegio de RiVS Marketing Médicos Cirujanos de PR

2019 Agenda Médica

787-406-4571 Sra. Norma Cartagena 787-640-5776 787-764-4951 info@serrayserra.com Sra Mildred González 787-768-2929 787-706-0442 bplanner21@gmail.com 787-751-5979 www.colegiomedicopr.org 787-548-0047 info@rivsmarketing.com Vilma Pérez 787-646-0780 Sra. Norma Cartagena 787-764-4951 Sra Mildred González 787-964-6394 787-768-2929 heh@hehpr.com

CONGRESO CONVENCIÓN CURSOS SIMPOSIO CONVENCIÓN CONGRESO CURSO CURSOS CONVENCIÓN CONVENCIÓN CONGRESO Comentarios CURSO CONVENCIÓN CONVENCIÓN CONGRESO CONGRESO SEMINARIO CONVENCIÓN CONFERENCIA CONGRESO CONFERENCIA SEMINARIO SEMINARIO CONFERENCIA CONVENCIÓN CONFERENCIA CONVENCIÓN SEMINARIO CURSOS

77 al al 910dede Diciembre febrero de 2018 2019

Convención Anual Colegio de Médicos Digestive Diseases of the Caribbean 2019 Cirujanos de PR

Sheraton Center Centro deConvention Convenciones de Puerto San Juan,Juan, PR PR RicoSan

714alal917 dede Fecha Diciembre Febrero 2018 2019

Convención Puertorriqueña Convención Anual Semi Anual de SPED de Título Pediatría

Hotel SanConvention Juan Sheraton Center Lugar San Juan, PR PR

Educational 787-548-0047 Vilma Pérez RiVS Marketing Partners & Coordinador o Contacto info@rivsmarketing.com 787-646-0780 Coaching, Inc.

25 al 27 de 9 de febrero Enero 2019 2019

Compulsory Courses for Physicians Customer Service Focused on Medical Practice

Club Leones Club de Rotario Río Piedras Mayagüez, PR San Juan, PR

High High Education Education Health Health

787-964-6394 heh@hehpr.com

CURSOS

7 al 10 de 2febrero de de 2019 2019 Marzo 14 al 17 de Febrero 72019 al 9 de Marzo 2019 9 de febrero 2019 23 de Marzo 2019 2 de Marzo 2019 29 al 31 de Marzo 2019 7 al 9 de 5Marzo al 6 de2019 abril de 2019

Digestive Diseases of the Caribbean 2019 Simposio Ortopédico de Columna-SPOT

Sheraton Convention Center San Juan, PR El San Juan Hotel San Juan, PR Sheraton Convention Center San Juan, PR Ponce Hilton Ponce, PR Club Rotario Río Piedras San Juan, PR Hotel Intercontinental Isla Verde El San Juan Hotel San Juan, PR Club Rotario, Río Piedras San Juan, PR

RiVS Marketing Sociedad Puertorriqueña de Ortopedia y Traumatología RiVS Marketing

787-548-0047 info@rivsmarketing.com 787-723-6751 asis.spot@gmail.co

CONVENCIÓN SIMPOSIO

Ponce Hilton Ponce,Hilton PR Ponce Ponce, PR

787-843-0610 Merna morales academiamedicadelsur@g787-706-0442 mail.com bplanner21@gmail.com High Education Health 787-964-6394 heh@hehpr.com 787-640-5776 Serra & Serra patologospr@serrayseGroup rra.com High Education Health 787-964-6394 heh@hehpr.com Sociedad 787-723-6751 Puertorriqueña de asis.spot@gmail.com Ortopedia y Merna morales Business Planners Traumatología 787-706-0442 bplanner21@gmail.com High Education Health 787-964-6394 heh@hehpr.com 787-640-5776 Serra & Serra patologospr@serrayseGroup Educational 787-646-0780 rra.com partners vperez@epcpr.com Sociedad 787-723-6751

Convención Anual Puertorriqueña de Pediatría Convención Anual Academia Médica del Sur Customer Service Focused on Medical Practice Congreso Control de Infecciones en Diferentes Escenarios de Salud Simposio Ortopédico de Columna-SPOT Cursos Obligatorios para Médicos San Juan

Convención Anual Academia Médica del Pulmonary and Critical Care Congress Sur 2019-Sociedad Puertorriqueña de Neumología 23 de Marzo Congreso Control de Infecciones en Diferentes Escenarios de Salud 62019 al 7 de abril Convención Anual Academia de Patología de 2019 y Medicina de Laboratorio de PR 29 al 31 de Cursos Obligatorios para Médicos Marzo 2019 San Juan 27 de abril de Simposio Ortopédico de Medicina 2019 Deportiva-SPOT 5 al 6 de abril Pulmonary and Critical Care Congress de 2019 2019-Sociedad Puertorriqueña de Neumología 27 de abril de Workshop Acupuncture in Shoulders and 2019 Low Back 6 al 7 de abril Convención Anual Academia de Patología de Revista de Medicina y Salúd Pública 3 al2019 5 de Puertorriqueña y2da Medicina Laboratorio de PR CumbredeAsociaciones Psiquiátricas de Mayo 2019 Puerto Rico 27 de abril de

Hotel Intercontinental Isla VerdeConvention Center Sheraton San Juan, PR Club Rotario, Río Piedras San Juan, PR El San Juan Hotel San Juan, PR Ponce Hilton Ponce, PR Hotel Intercontinental Isla Verde Sheraton Convention Center San MeliáJuan, CocoPRBeach Resort Río Grande, PR El San Juan Hotel

787-751-5979 787-548-0047 www.colegiomedicopr.org info@rivsmarketing.com

787-548-0047 info@rivsmarketing.com 787-843-0610 Acadeia Médica academiamedicadelsur@gdel Sur mail.com High Education Health 787-964-6394 heh@hehpr.com High Education Health 787-964-6394 heh@hehpr.com Sociedad 787-723-6751 Puertorriqueña de asis.spot@gmail.co Ortopedia y High Education Health 787-964-6394 Traumatología heh@hehpr.com Acadeia Médica del Sur Planners Business

CONVENCIÓN

Comentarios CONVENCIÓN

CONVENCIÓN CONVENCIÓN CURSOS CONGRESO SIMPOSIO CURSOS CONVENCIÓN CONVENCIÓN CONGRESO CONVENCIÓN CURSOS SIMPOSIO CONVENCIÓN CURSO CONVENCIÓN CONVENCIÓN

2019

Diferentes Escenarios de Salud

Hotel Intercontinental Isla Verde

29 al 31 de Marzo 2019

Cursos Obligatorios para Médicos San Juan

Club Rotario, Río Piedras San Juan, PR

High Education Health 787-964-6394 MSP ARTÍCULO DE REVISIÓN CURSOS heh@hehpr.com

5 al 6 de abril Pulmonary and Critical Care Congress deFecha 2019 2019-Sociedad Puertorriqueña de Título Neumología

Ponce Hilton LugarPR Ponce,

Business Planners

6 al 7 de abril Convención Anual Academia de Patología de 2019 y Medicina de Laboratorio de PR

Sheraton Convention Center San Juan, PR

Serra & Serra Group

787-640-5776 patologospr@serrayserra.com

CONVENCIÓN

27 de abril de Simposio Ortopédico de Medicina 2019 Deportiva-SPOT

El San Juan Hotel San Juan, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología

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

SIMPOSIO

27 de abril de Workshop Acupuncture in Shoulders and 2019 Low Back

Hotel Intercontinental Isla Verde

High Education Health 787-964-6394 heh@hehpr.com

CURSO

3 al 5 de Mayo 2019

2da Cumbre Asociaciones Psiquiátricas de Puerto Rico

Meliá Coco Beach Resort Río Grande, PR

Educational partners

787-646-0780 vperez@epcpr.com

CONVENCIÓN

4 al 5 de Mayo 2019

Convención Anual Radiológica (SOCRAD)

Wyndham Rio Mar Rio Grande, PR

Serra & Serra Group

787-640-5776 info@socrad.com

CONVENCIÓN

17 al 19 de Mayo 2019

Convención Anual Asociación de Reumatólogos de PR

Wyndham Rio Mar Rio Grande, PR

Serra & Serra Group

787-640-5776 reumalogospr@serrayserra.com

CONVENCIÓN

24 al 27 de Mayo 2019

SPED Annual Convention

Meliá Coco Beach Resort Río Grande, PR

Educational partners

787-646-0780 vperez@epcpr.com

CONVENCIÓN

Junio 2019 (fecha por anunciar)

Convención anual Academia de Medicina General de PR

Lugar por confirmar* Wyndham Rio Mar Rio Grande, PR

SR Consultants

939-292-4115 srconsultantsandevents @gmail.com

CONVENCIÓN

Convención anual Sociedad Puertorriqueña de Oftalmología

St. Regis Hotel Río Grande, PR

Sociedad Puertorriqueña de Oftalmología

Sociedad Puertorriqueña de Oftalmología

CONVENCIÓN

21 al 23 de junio 2019

Convención anual Asociación Puertorriqueña de Medicina Física y Rehabiitación

Meliá Coco Beach Resort Río Grande, PR

Serra & Serra Group

787-640-5776 asocfisiatraspr@serrayserra.com

CONVENCIÓN

22 de junio 2019

Simposio Ortopédico de Trauma- SPOT

El San Juan Hotel San Juan, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología

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

SIMPOSIO

12 al 14 Julio 2019

Convención Anual Sociedad Puertorriqueña de Cardiología

Falta Confirmar lugar

Sociedad Puertorriqueña de Cardiología

787-620-2228 socprcardio@gmail.com

CONVENCIÓN

Agosto (Fecha por anunciar)

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

Wyndham Rio Mar Rio Grande, PR

AHOMPR

Germaine Quiñones 787-608-1477 ahomprgq@gmail.com

CONVENCIÓN

24 de agosto de 2019

Asociación de Gastroenterología y Hepatología Pediátrica de PR

IC PLANNERS

Ivette Colón 787-504-3655 ivettecolon@icplannerspr.com

SIMPOSIO

Sociedad Puertorriqueña de Ortopedia y Traumatología

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

CONVENCIÓN

6 al 9 de junio 2019)

heh@hehpr.com

30 de Agosto Convención Anual Sociedad al 2 de Puertorriqueña de Ortopedia y septiembre Traumatología de 2019

Wyndham Rio Mar Rio Grande, PR

31 de Agosto Convención Anual Asociación de Médicos al 2 de Pediatras Región Oeste (AMPRO) septiembre de 2019

Mayagüez Resort & Casino Mayagüez,PR

Octubre (Fecha por anunciar)

Convención Caribe Gyn

Hotel Ponce Hilton Ponce, PR

26 de Octubre de 2019

Asociación de Médicos Alergistas de PR

IC PLANNERS

8 al 10 de noviembre 2019

Convención Anual Asociación Médica de Pediatras Región Este (AMPRE)

Business Planners

22 al 24 de noviembre 2019

Convención Sociedad Puertorriqueña de Neumología

Diciembre 2019 (fecha por anunciar)

Convención anual Colegio de Médicos Cirujanos de PR

12 al 15 de diciembre 2019

SPED AACE Congress

Wyndham Rio Mar Rio Grande, PR

Caribe Hilton Hotel San Juan, PR

Merna morales

787-706-0442 Coordinador o Contacto bplanner21@gmail.com

CONGRESO

Comentarios CONVENCIÓN

Mignaliz Vega 302-893-2136 CONVENCIÓN amprodirectiva@gmail.com ampropediatras@gmail.com Germaine Quiñones 787-608-1477 CONVENCIÓN germaine.quinonez@gmail.com Ivette Colón 787-504-3655 CONVENCIÓN ivettecolon@icplannerspr.com Merna Morales CONVENCIÓN 787-706-0442 bplanner21@gmail.com

Business Planners

Merna Morales 787-706-0442 bplanner21@gmail.com

CONVENCIÓN

Colegio de Médicos Cirujanos de PR

787-751-5979 info@colegiomedicopr.org

CONVENCIÓN

Educational partners

787-646-0780 vperez@epcpr.com

CONNGRESO

Revista Puertorriqueña de Medicina y Salúd Pública

137

www.medicinaysaludpublica.com Servicio de Noticias Científicas de Medicina y Salud Pública de Puerto Rico Periodistas: Mayra Acevedo, Susana María Rico, César Fuquen, Solangy Lozano, LauraMojica.

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Radiólogos celebran su convención anual sobre cáncer de mama La Sociedad Radiológica de Puerto Rico llevó a cabo a finales del mes de octubre su convención anual. Este año, el evento -en el que participaron 250 profesionales de la salud, entre los que se destacaron mamografistas y radiólogos- se orientó al cáncer de seno, su prevención y diagnóstico a través de imágenes radiológicas y el tratamiento objetivo y subjetivo a las pacientes.

La enfermedad cardíaca, líder entre las causas de muerte en Puerto Rico Más información:

Francisco Lefebre, Cardiólogo

De acuerdo con datos del Instituto de Estadística de Puerto Rico, cada año mueren alrededor de 5.000 boricuas como consecuencia de enfermedades del corazón. De acuerdo con el cardiólogo Francisco Lefebre, las condiciones más comunes en la población: infartos, los fallos cardíacos y las arritmias podrían prevenirse con un mejor estilo de vida, aumentando los buenos hábitos alimenticios y la reducción del consumo de cigarrillo, un factor que influye en la aparición de enfermedad cardíaca en personas menores de 40 años.

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Dra. Mayra Maldonado, radióloga especialista en seno

La FDA amplía la vacuna contra el HPV hasta los 45 años Más información:

La vacuna tiene el potencial de prevenir el desarrollo de más del 90 por ciento de estos cánceres producidos por cepas de VPH.

La vacuna Gardasil 9 que cubre 9 cepas del Virus del Papiloma Humano (VPH) además de prevenir la aparición de ciertos tipos de cáncer y enfermedades recibió la aprobación para ser usada en mujeres y hombres entre 27 y 45 años de edad. La vacuna, si se aplica antes de contraer el virus, evita la aparición de tumores malignos asociados hasta en un 90% según los Centros para el Control y la Prevención de Enfermedades de EE. UU.

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#Díseloatufamilia, la nueva campaña que conciencia sobre la donación de órganos Por quinto año consecutivo, pacientes trasplantados o en lista de espera, familiares donantes, empleados del Hospital Auxilio Mutuo y público general participaron de la creación de un arcoíris humano con la frase “Díselo a tu familia”. Una actividad llevada a cabo por la organización sin fines de lucro LifeLink Puerto Rico, organización dedicada a la recuperación de órganos y tejidos para trasplantes. La entidad busca con este tipo de actividades, fomentar la cultura de donación de órganos y tejidos en la población puertorriqueña.

Pacientes, familiares donantes, empleados del Hospital Auxilio Mutuo y público general participaron de la creación de un arcoíris humano con la frase “Díselo a tu familia”

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Con patente un nuevo fármaco “pionero” en Crohn

Alta tasa de supervivencia en pacientes con cáncer urotelial en Puerto Rico

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Presentación de Alofisel, un medicamento pionero para tratar complicaciones de la enfermedad de Crohn.

Un fármaco conocido como Alofisel es un medicamento pionero en el tratamiento de las fisuras anales, una de las complicaciones más serias asociadas a la enfermedad de Crohn y que hasta el momento solo podía tratarse de forma quirúrgica.

La característica principal del Alofisel es que es un medicamento alogénico, es decir, que tiene como principio activo el uso de células madres de tejido adiposo de donantes no relacionados con los futuros pacientes.

Más información:

Doctor Ricardo Sánchez, urólogo oncólogo

Un 70% de pacientes diagnosticados con cáncer urotelial, el más común en la vejiga, sobreviven a la fase más letal que se produce cuando la enfermedad penetra el tejido muscular de este órgano. La alta supervivencia se debe a la intervención oportuna de los oncólogos con los tratamientos más recientes -como inmunoterapia o laparoscopia- para tratar esta condición que se desarrollan en Puerto Rico.

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Salud firma acuerdo con ASES para ampliar beneficios a pacientes que viven con VIH Más información:

Nace el primer bebé tras un polémico trasplante de útero de un cadáver

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Secretario de Salud de República Dominicana, Dr. Rafael Rodríguez Mercado

La niña nacida en Brasil tras un trasplante de útero de una mujer fallecida en una imagen facilitada por el Hospital das Clínicas de Sao Paulo. HOSPITAL DAS CLINICAS

El Secretario de Salud, Dr. Rafael Rodríguez Mercado, firmó un Acuerdo de Colaboración y Reembolso de Costos de Medicamentos junto a la Administradora de Seguros de la Salud (ASES) con el fin de garantizar que todos los pacientes portadores de VIH en Puerto Rico tengan acceso permanente al tratamiento del virus y puedan obtener más medicamentos.

Una mujer de 32 años se convirtió en madre luego de recibir un útero trasplantado de un cadáver.

Aunque la receptora del órgano producía óvulos y no presentaba anormalidad en sus ovarios, nació sin útero a causa de con una enfermedad congénita que afecta a 1 de 4.500 mujeres. El hecho que ocurrió en Brasil se considera un gran hito médico -al ser el primer caso exitoso- y plantea nuevos dilemas en el ejercicio de la profesión.

Investigan un probable caso de rabia humana en niño de seis años Más información:

Acreditado hasta el 2022 el Programa de Maestría de la Escuela de Enfermería con especialidad en anestesia Más información:

Dr. Rafael Sánchez Cárdenas, Ministro de Salud Pública de República Dominicana

El Ministerio de Salud investiga el caso de un menor de 6 años ingresado al Hospital Robert Reid Cabral con fiebre, espasmos musculares, dolor en el pecho y otros síntomas asociados a un posible caso de rabia. Los médicos sospechan de la enfermedad luego que se mencionara que el niño fue mordido por un perro desconocido y altamente agresivo, meses antes de ser llevado al servicio de emergencias.

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La Escuela de Enfermería del Recinto de Ciencias Médicas (RCM) de la Universidad de Puerto Rico

La Escuela de Enfermería del Recinto de Ciencias Médicas (RCM) de la Universidad de Puerto Rico recibió la acreditación del Council on Accreditation of Nurse Anesthesia Educational Programs (COA) a su programa de Maestría en Ciencias en Enfermería con Especialidad en Anestesia hasta el 2022, hecho que enorgullece y reconoce la labor educativa de alta calidad en ciencias de la salud en Puerto Rico.

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Nace fundación para fomentar investigación científica en el campo dermatológico en Puerto Rico

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Entrenan médicos primarios en dermatología con el fin de emitir diagnósticos tempranos Más información:

Dr. Luis Espinoza, dermatólogo y expresidente de la Sociedad Dermatológica de Puerto Rico.

Fundación Puertorriqueña para el Mejoramiento de la Dermatología

Con el objetivo de hacer frente a las condiciones dermatológicas que se presentan en la isla, se ha creado la Fundación Puertorriqueña de Dermatología. Un espacio diseñado por el Dr. y dermopatólogo Jorge Sánchez para avanzar en la investigación científica en esta rama de la medicina y así ofrecer nuevos tratamientos para la población afectada por melanoma, psoriasis, hidradenitis supurativa, entre otras enfermedades cutáneas.

Ante el bajo número de dermatólogos en la isla, la Fundación Puertorriqueña para el Mejoramiento de la Dermatología (FPDERMA) en el marco del simposio “Diagnosis of Skin Conditions” llevó a cabo una serie de conferencias diseñadas para que los profesionales de la salud logren detectar tempranamente los síntomas de algunas condiciones dermatológicas para que los pacientes afectados reciban el tratamiento adecuado, en el momento oportuno.

Puerto Rico solo cuenta con un dermatólogo pediátrico certificado

Posicionada labor de los dermatólogos por los pacientes de psoriasis en la isla

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Más información:

Doctor Francisco Colón, único dermatólogo pediátrico "board certified" en Puerto Rico.

Dr. Amílcar Rodríguez y Dra. Aileen Santos, ambos dermatólogos.

El Dr. Francisco Colón es el único especialista en dermatología de la isla que está capacitado para atender las afecciones cutáneas en pacientes pediátricos. La certificación obtenida en la Universidad de San Diego (California) permite que los niños y jóvenes de la isla reciban atención adecuada ante condiciones como dermatitis atópica, infecciones producidas por hongos o acné.

Los pacientes afectados por psoriasis en Puerto Rico y los dermatólogos que pertenecen a la Asociación Puertorriqueña de Ayuda al Paciente con Psoriasis (APAPP) destacan que las actividades de información y promoción sobre los tratamientos ya rinden frutos, pues la población afectada por la enfermedad presenta una mayor adherencia al tratamiento y comparte sus experiencias con la población puertorriqueña.

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Luis Ortiz Espinosa, dermatólogo y expresidente de la Sociedad Dermatológica de Puerto Rico.

Sobresaliente labor del Dr. Luis Ortiz Espinosa en el fortalecimiento de la dermatología en Puerto Rico

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Aunque la dermatología es una de las ramas de la medicina con menos especialistas en la isla, la labor del Dr. Luis Ortiz Espinosa se ha convertido en un referente para colegas y pacientes durante su extensa trayectoria. Como uno de los escasos dermatólogos de Puerto Rico, su trabajo como médico no solo se ha orientado al diagnóstico y tratamiento de las condiciones cutáneas que afectan a la población sino también a darle mayor visibilidad a su especialidad.

Su compromiso por la comunidad afectada por enfermedades cutáneas no se detiene. Hoy en día, al Dr. Ortiz Espinosa se le conoce por ser el presidente de la reciente Fundación Puertorriqueña de Dermatología, una institución que hace énfasis en la investigación científica, la búsqueda de nuevos tratamientos, la difusión de información a médicos y pacientes para que esta rama de la medicina se fortalezca en Puerto Rico y la población acceda a la atención que merece.

En varios oportunidades, el Dr. Ortiz ha tenido la oportunidad de presidir la Sociedad Dermatológica de Puerto Rico, una institución dedicada a la capacitación constante de los dermatólogos boricuas y la difusión de los avances médicos en esta área, la Sociedad Americana contra el Cáncer, entre otros reconocidos espacios. Además, es el fundador de las clínicas dermoestéticas Nova Derm, un centro pionero en la isla que brinda tratamientos dermatológicos y estéticos a través de las más recientes tecnologías.

Por ello, los especialistas en dermatología y otros profesionales de la salud reconocen en el Dr. Ortiz Espinosa a una de las más importantes referencias y a un destacado estudioso de las enfermedades de la dermis que atacan a los puertorriqueños, para garantizar los mejores servicios de salud a la población. Su trayectoria lo convierte en una de las máximas autoridades en el campo y la dermatología puertorriqueña siente el orgullo de ver cómo uno de los suyos, se destaca como un líder de primer orden en todos los aspectos de nuestra vida en comunidad.

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