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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

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¡Dile SÍ a la donación! Familia de Gerald, J. Otero donante de órganos.

¡Únete a LifeLink de Puerto Rico! Habla con tus seres queridos y comparte con ellos tu deseo de ser donante de órganos y tejidos para trasplantes. Regístrate e invita a otros a registrarse. Ayúdanos a salvar las vidas de aquellos en espera de una segunda oportunidad.

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CONTENIDO 66

Síndrome de Jarcho Levin: a 80 años de su descripción clínica

El albinismo y la fibrosis pulmonar

Genética del albinismo desde una perspectiva oculocutánea

Nuevo consenso global para el tratamiento farmacológico del paciente adulto con Diabetes Tipo 2: Poniendo el Corazón Adelante

Cuando las alucinaciones y el delirio te cambian la vida

Red del síndrome Hermansky-Pudlak y los servicios que ofrece a pacientes y familiares

El síndrome de Hermansky Pudlak (HPS) y la salud mental

El trasplante de pulmón: una decisión complicada para los pacientes de HPS en Puerto Rico

105 122 127

VIH y el paciente mayor de edad

Puntos de vista

Agenda médica

130

Noticias de medicinaysaludpublica.com

Historia natural del síndrome Morquio

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

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IMPERICIA MÉDICA

– PROTEGE EL FUTURO DE TU PRÁCTICA

Triple-S Propiedad ofrece a los profesionales de la salud la tranquilidad de estar bien asegurados con pólizas de responsabilidad profesional. — • Impericia médica • Responsabilidad profesional hospitalaria • Laboratorios • Misceláneos Contamos con alternativas de seguros que se ajustan a las necesidades de los profesionales de las distintas ramas de la medicina. Llama o consulta con tu representante o productor de seguros.

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PROPIEDAD

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

comienzos de los años 70, se mudó a la casa del lado de la de mis padres una nueva familia. Sin saberlo, una de sus hijas se convertiría en mi gran amiga de toda la vida. Para entonces, ella sencillamente era Nancy, una chica muy blanca de pelo rubio y yo, Juan. En Puerto Rico ella vivió menos de dos años, pues regresó a Nueva York, ciudad de donde originalmente provenía. Nancy no sabía entonces que su blancura en realidad se llama albinismo oculocutáneo y que padecía el síndrome de Hermansky-Pudlack, ni yo tenía idea que me convertiría en el genetista que diagnostica y trata esas enfermedades. Hoy, 47 años más tarde, nuestra amistad perdura. A través de la vida nos hemos acompañado en la distancia con el cariño y constancia de la amistad verdadera, la que no depende de verse frecuentemente. Esta edición de Medicina y Salud Pública la dedicamos completamente a las llamadas ‘enfermedades raras’, esas condiciones que casi no existen alrededor del mundo pero que en Puerto Rico tienen una prevalencia mucho más alta, más que en ninguna otra parte. Esas enfermedades que son difíciles de pronunciar para los médicos, y ,más aún, para la población en general. Esas condiciones en las que los galenos pronuncian arbitrariamente fecha de defunción prematura a los pacientes. Sí, sas enfermedades que -aún cuando son prevalentes en la isla- no sabemos diagnosticarlas y mucho menos que hacer con ellas.

En Puerto Rico tenemos varias enfermedades “raras” con una alta incidencia. Entre estas se encuentran el albinismo, el síndrome de Hermansky - Pudlack, el síndrome de Bardet Biedl, el síndrome de Jarcho Levin, el síndrome de Morquio y la encefalopatía por mutaciones al gen TBCK. Podemos también mencionar las hemoglobinopatías como la anemia falciforme y otros desórdenes metabólicos como la hiperglicinemia no-cetótica. Tenemos el gran honor de contar con la colaboración de grandes médicos puertorriqueños, considerados expertos en estas enfermedades, aportando sus conocimientos sobre el tema con artículos de gran valor médico y científico. A todos, gracias mil por inmediatamente responder afirmativamente a nuestro llamado para recibir sus colaboraciones. Finalmente deseo retomar a mi amiga Nancy Lee Suárez y dedicarle esta edición de la revista. Hace 7 años recibió un trasplante de pulmón y con su ejemplo de vida, no solo como paciente, sino como promovedora, activista y educadora del síndrome de Hermansky - Pudlack a nivel mundial, me ha enseñado mucho y privilegiado con su cariño y amistad. A la comunidad de profesionales de la salud les dejo con una de las mejores ediciones de nuestra revista. Disfrútenla y háganse partícipes del conocimiento, diagnóstico y tratamiento de éstas porque ,histórica y genéticamente, nos pertenecen. Nancy, Love always!. Revista Puertorriqueña de Medicina y Salúd Pública

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.

‡

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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

IX HCP BS 01DEC2017

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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. Lactation Risk Summary—There are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health beneits of breastfeeding should be considered along with the mother’s clinical need for Taltz and any potential adverse effects on the breastfed infant from Taltz or from the underlying maternal condition. Pediatric Use—The safety and effectiveness of Taltz in pediatric patients (<18 years of age) have not been evaluated. Geriatric Use—Of the 4204 psoriasis subjects exposed to Taltz, a total of 301 were 65 years or older, and 36 subjects were 75 years or older. Although no differences in safety or eficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not suficient to determine whether they respond differently from younger subjects. OVERDOSAGE—In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately. PATIENT COUNSELING INFORMATION—Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Taltz and each time the prescription is renewed, as there may be new information they need to know. Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or preilled syringe correctly (Instructions for Use). Infection: Inform patients that Taltz may lower the ability of their immune system to ight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection (Warnings and Precautions). Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions (Warnings and Precautions). Additional information can be found at www.Taltz.com.

IX HCP BS 01DEC2017

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El albinismo y la fibrosis pulmonar Por: Jesse Román, MD Jane & Leonard Korman Respiratory Institute and Division of Pulmonary, Allergy and Critical Care Medicine Thomas Jefferson University Philadelphia, PA

Resumen: En Puerto Rico, muchas personas con albinismo sufren el síndrome de Hermansky Pudlak, un síndrome genético raro asociado con albinismo oculocutáneo, disfunción plaquetaria y sangrado, colitis y, en muchos casos, fibrosis pulmonar. La fibrosis pulmonar en ciertas formas de HPS presenta con proliferación de fibroblastos y acumulación excesiva de colágeno y de otras matrices de tejido conectivo que conducen a la destrucción de la arquitectura pulmonar original y a la pérdida de función pulmonar. La condición es progresiva y no hay disponibles intervenciones capaces de prevenir, detener o revertir la enfermedad. Se realizan esfuerzos a nivel mundial cuyo objetivo es la fibrosis pulmonar y se están evaluando varios fármacos de investigación. Es crucial la inclusión de pacientes de Puerto Rico con fibrosis pulmonar en estos estudios para asegurar que las intervenciones evaluadas son pertinentes a nuestra población. 14

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Abstract: In Puerto Rico, many persons with albinism suffer from the Hermansky Pudlak Syndrome, a rare genetic disorder associated with oculocutaneous albinism, platelet dysfunction and predisposition to bleeding, colitis, and, in many cases, pulmonary fibrosis. Pulmonary fibrosis in certain forms of HPS is characterized by the proliferation of fibroblasts and the excessive deposition of collagen and other connective tissue matrices resulting in the destruction of the original lung architecture and leading to loss of lung function. The condition is progressive and there are no interventions capable of preventing, halting, or reverting the disease. Worldwide efforts focusing on pulmonary fibrosis are evaluating new drugs and other interventions. It is crucial that patients from Puerto Rico be included in such studies in order to ensure that effective interventions are relevant to our population.

MSP ARTÍCULO ORIGINAL

Palabras claves: Albinismo, fibrosis pulmonar, Hermasky-Pudlak Syndrome. Keywords: Albinism, pulmonary fibrosis, Hermansky-Pudlak Syndrome.

Revista Puertorriqueña de Medicina y Salúd Pública

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Hay información emergente que refuerza la relación entre el albinismo y la fibrosis pulmonar, lo cual tiene implicaciones significativas para nuestros lectores en Puerto Rico, país en donde el albinismo oculocutáneo es relativamente común. Aunque en muchos casos esto representa una ocur rencia esporád ica con consecuencias asociadas limitadas, un buen número de los puertorriqueños con esta enfermedad poseen una mutación en uno de varios genes responsables del Síndrome Hermansky Pudlak (HPS, por sus siglas en inglés). El HPS es un trastorno genético raro que se caracteriza por albinismo, disfunción plaquetaria y predisposición a sangramiento, colitis y, en algunos casos, fibrosis pulmonar además de otras manifestaciones, dependiendo de los genes involucrados (1). De los 10 genes relacionados actualmente con el HPS, 2 son más prominentes en los puertorriqueños. El HPS-1 predomina en el norte de la región oeste de la isla y el HPS-3 es más común en la región montañosa central. El HPS-1 es una de las formas más graves de la condición y está asociada, casi invariablemente, con la fibrosis pulmonar. Esta última es responsable de mucha de

Early/Recycling Endosome

Endosome Lysosome Lysosme

LRO

Golgi

Phagosome

Endoplasmic Reticulum

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la morbilidad y la mortalidad de la condición (2). La f ibrosis pulmonar ocurre cuando hay proliferación de fibroblastos y acumulación excesiva de colágeno y otras matrices de tejido conectivo que destruyen la arquitectura pulmonar original y derivan en pérdida de función pulmonar. (3). En la mayoría de los casos, la condición es crónica, progresiva y no reversible. En general, la fibrosis pulmonar es la manifestación patológica de un número de enfermedades pulmonares intersticiales (también conocidas como enfermedades pulmonares difusas del parénquima), que comprenden cerca de 300 trastornos distintos (sarcoidosis y fibrosis pulmonar idiopática -trastornos pulmonares intersticiales relativamente comunes -- hasta la neumonitis por hipersensibilidad y la linfangioleiomiomatosis). Muchas de estas condiciones son raras, pese a que algunas tienen una etiología definida (por ejemplo, por exposición al asbesto o inducida por fármacos) o están ligadas a otros trastornos sistémicos (por ejemplo, condiciones reumatológicas como la artritis reumatoide) (4). Sin embargo, la f ibrosis pulmonar es -con frecuencia- de causa desconocida o idiopática. Por lo tanto, no debe

considerarse como un diagnóstico definitivo sino la manifestación de una enfermedad que requiere mayor exploración hasta llegar a un diagnóstico formal, pues ello tiene importantes implicaciones para el pronóstico y el tratamiento. Se estima que tanto factores ambientales (por ejemplo, fumar) como factores genéticos contribuyen al desarrollo de la fibrosis pulmonar. Más recientemente se han relacionado ciertos genes a la entidad prototipo de la fibrosis pulmonar: la fibrosis pulmonar idiopática, una una condición observada en más de 150. 000 personas en los EE.UU., especialmente en pacientes mayores de 50 años de edad, fumadores o exfumadores y que presentaban frecuentemente un patrón específico en las imágenes tomográficas del pecho e histología, denominado patrón UIP (siglas en inglés de la Pulmonía Intersticial Usual) (5). Estos genes incluyen el MUC5B, el SPC y los genes relacionados con el control de la longitud del telómero, que se han implicado en el envejecimiento y en trastornos como el síndrome mielodisplásico y la insuficiencia hepática (6). No todo el que tiene estas variaciones genéticas desarrolla fibrosis pulmonar y, por lo tanto, las formas en las que estos factores genéticos, exposiciones

Diagrama de endosomas en una célula pulmonary. Los lisosomas son organelos o vesículas que contienen enzimas hidrolíticas capaces de digerir biomoléculas dentro de la celula. Organelos relacionados a lisosomas (LRO, por sus siglas en inglés) (fleche) son un grupo especializó de lisosoma. En HPS, se postula que la función de los LROs se interrumpe y hay acumulación intracelular de ciertos metabolitos, lo que puede provocar una reacción en cadena que promueve la inflamación de los tejidos, aumento de factores profibróticos, la proliferación de fibroblastos y pobre function de células epiteliales del pulmón (adaptado de referencia 2).

MSP ARTÍCULO ORIGINAL

Higher incidence of Associated diseases in both patient and carriers of the BBS1 gene mutations.

Puerto Rican population

W y demás factores contribuyentes interactúan para desarrollar la enfermedad en ciertos individuos continúan siendo el foco de mucha investigación. Si bien la identificación de los factores genéticos y su papel en el desarrollo y el progreso de los trastornos pulmonares fibrosantes son, en la mayoría de los casos, incierta, hay condiciones en las cuales mutaciones genéticas específicas están asociadas claramente con el desarrollo de la enfermedad. Ése es el caso del HPS. El HPS afecta a aproximadamente 1 de cada 750,000 personas en el mundo, concentradas frecuentemente en áreas geográficas específicas como India, Japón, Reino Unido y Europa Occidental. Aunque esta es una enfermedad rara a nivel mundial, en Puerto Rico es de importancia pues la isla tiene la prevalencia más alta de HPS -- responsable de cerca del 50% de todos los casos

mundialmente-- y afecta a más de 1 de cada 1,800 (sobre 1,900 personas) (7). Las manifestaciones clínicas del HPS incluyen el albinismo ocu locut á neo, d iátesi s del sangrado debido a disfunción plaquetaria, a veces acompañada de inmunodef iciencia, colitis g ranu lomatosa y/o f ibrosis pulmonar (1,8). Se han descrito 10 mutaciones en esta condición, que se han denominado HPS-1, HPS-2, …, hasta HPS-10. Se ha informado fibrosis pulmonar en HPS-1, HPS4 y, más recientemente, en HPS2. Los pacientes con HPS-1 y HPS-4 típicamente desarrollan fibrosis pulmonar en su tercera a quinta década de vida (2,9). Aunque la patogénesis de la fibrosis pulmonar en el HPS no está clara, la función de organelos del lineage de los lisosomas (LRO, por sus siglas en inglés) se interrumpe y hay acumulación intracelular de ciertos metabolitos, lo que puede provocar una reacción en cadena que promueve la inf lamación de los tejidos, aumento de factores pro-fibroticos, la proliferación de fibroblastos y pobre función de células epiteliales del pulmón (2,10). La fibrosis pulmonar o enfermedad pulmonar intersticial asociada con el HPS representa la principal causa de morbilidad y mortalidad en estos pacientes (2). Al igual que otras formas de fibrosis pulmonar, esta condición en HPS es progresiva y, actualmente, no es reversible. En general, la fibrosis pulmonar no responde a los tratamientos médicos convencionales. El trasplante pulmonar, la única opción para muchos de estos pacientes, se ha realizado con éxito en un pequeño número de pacientes de HPS con fibrosis pulmonar avanzada (11). La

reciente aprobación de dos fármacos antifibróticos levantó el entusiasmo sobre la posibilidad de tratamiento de la fibrosis pulmonar en HPS. No obstante, hay disponible muy poca información sobre su efectividad en este escenario. Uno de estos medicamentos, la pirfenidona, se ha probado en dos estudios. Gahl y sus colegas informaron sus observaciones cuando investigaron la seguridad y ef icacia de la pirfenidona al tratar a 21 adultos con HPS, principalmente con la HPS1 (12). Hallaron que 11 pacientes tratados con pirfenidona perdieron un capacidad vital forzada (FVC, por sus siglas en inglés) (predicción anual) a razón de un 5% más lentamente que los 10 pacientes tratados con placebo; esto fue estadísticamente significativo. Un modelo de coeficientes aleatorios, sin embargo, no mostró una diferencia signif icativa. En contraste, utilizando datos restringidos sólo a pacientes con un FVC inicial de sobre un 50% de la predicción, ambos modelos mostraron que el grupo de la pirfenidona perdió función pulmonar a una razón de aproximadamente un 8%/año más lentamente que el grupo del placebo. Los efectos secundarios fueron similares en ambos grupos. Este estudio sugiere que la pirfenidona pudiera ser beneficiosa en el HPS. O’Brien et al. realizó un estudio prospectivo, aleatorio, doble ciego, controlado con placebo, para examinar la seguridad y eficacia de la pirfenidona para el tratamiento de la fibrosis pulmonar de leve a moderada relacionada con HPS1 y HPS-4 (13). El estudio reclutó a 35 sujetos durante un período de 4 años; 23 sujetos recibieron pirfenidona, mientras que 12 recibieron el placebo. Cuatro sujetos Revista Puertorriqueña de Medicina y Salúd Pública

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se retiraron del estudio, 3 murieron y se registraron 10 eventos adversos graves. Sin embargo, ambos grupos experimentaron efectos secundarios similares. Un análisis interino realizado 12 meses después de reclutar a 30 pacientes no mostró diferencia estadística entre los grupos del placebo y la pirfenidona. El estudio se detuvo por futilidad. En pocas palabras, ambos estudios mostraron que la pirfenidona es segura en esta población, pero no probaron ser efectiva. Un reto principal que afecta la capacidad para evaluar adecuadamente la utilidad de intervenciones noveles en el tratamiento de la fibrosis pulmonar en HPS es el número limitado de pacientes disponibles en cualquiera de los estados en los Estados Unidos continentales. Esto puede superarse mediante el reclutamiento y el seguimiento de sujetos en la isla de Puerto Rico, en donde vive la concentración mundial más alta de pacientes de HPS. Para comenzar a enfrentar este reto, y en colaboración con la Red HPS (HPS Network en inglés), en el año 2016, se estableció el Centro De Fibrosis Pulmonar en el Centro Médico de Mayagüez, Puerto Rico, en donde los pacientes con fibrosis pulmonar (incluidos los pacientes con HPS) son evaluados para asegurar un diagnóstico, t rat a m iento y seg u i m iento adecuados. Actualmente, se recopila información para entender mejor la epidemiología de la fibrosis pulmonar en Puerto Rico, así como el impacto de esta manifestación en el HPS. Se espera que esto pronto conduzca a pruebas clínicas prospectivas en la isla diseñadas para evaluar intervenciones noveles capaces de poner un alto al progreso de la fibrosis pulmonar. En resumen, el albinismo 18

Revista Puertorriqueña de Medicina y Salúd Pública

y la f ibrosis pulmonar están estrechamente relacionados en Puerto Rico pues muchas personas con albinismo en la isla tienen HPS, un síndrome genético raro asociado con albinismo oculocutáneo, disfunción plaquetaria y sangrado, colitis y, en muchos casos, fibrosis pulmonar. La fibrosis pulmonar en ciertas formas de HPS es progresiva y no hay disponibles intervenciones capaces de prevenir, detener o revertir la enfermedad. Por eso es importante la detección temprana y la evaluación para trasplante del pulmón en casos avanzados. Se realizan esfuerzo a nivel mundial cuyo objetivo es la fibrosis pulmonar y se están evaluando varios fármacos de investigación. Es crucial la inclusión de pacientes de Puerto Rico con fibrosis pulmonar en estos estudios para asegurar que las intervenciones evaluadas son pertinentes a nuestra población. Referencias

Huizing M, Malicdan MCVm Gochuico BR, Gahl WA. Hermansky-Pudlak Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2018. 2000 Jul 24, updated 2017 Oct 26]. https://www.ncbi.nlm.nih.gov/books/ NBK1287/ Vicary GW, Vergne Y, Santiago-Cornier A, Young LR, Roman J. Pulmonary fibrosis in Hermansky-Pudlak Syndrome. Ann Thor Soc. 2016; 13:1839-1846. Upagupta C Shimbori C, Alsilmi R, Kolb M. Matrix abnormalities in pulmonary fibrosis. Eur Respir Rev 2018;27(148). pii. 180033. doi: 10.1183/16000617.0033-2018 Mathai SC, Danoff SK. Management of interstitial lung disease associated with connective tissue disease. BMJ. 2016 Feb 24;352:h6819. doi: 10.1136/bmj.h6819. Lederer DJ and Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med.

2018;378:1811-1823. Mathai SK, Newton CA, Schwartz DA, Garcia CK. Pulmonary fibrosis in the era of stratified medicine. Thorax. 2016;71:11541160 Santiago Borrero PJ, Rodriguez-Perez Y, Renta JY, Izquierdo NJ, Del Fierro L, Munoz D, Molina NL, Ramirez S, PaganMercado G, Ortiz I, et al. Genetic testing for oculocutaneous albinism type 1 and 2 and Hermansky-Pudlak syndrome type 1 and 3 mutations in Puerto Rico. J Invest Dermatol. 2006;126:85-90. Huizing M, Gahl WA. Disorders of vesicles of lysosomal lineage: the HermanskyPudlak Syndrome. Curr Mol Med. 2002;2:451-467. Rouhani FN, Brantly ML, Markello TC, Helip-Wooley A, O’Brien K, Hess R, Huizing M, Gahl WA, Gochuico BR. Alveolar macrophage dysregulation in HermanskyPudlak syndrome type 1. Am J Respir Crit Care Med. 2009; 180:1114-1121. Huizing M, Boissy RE, Gahl WA. Hermansky-Pudlak syndrome: vesicle formation from yeast to man. Pigment Cell Res. 2002; 15:405-419. El-Chemaly S, O’Brien KJ, Nathan SD, Weinhouse GL, Goldberg HJ, Connors JM, Cui Y, Astor TL, Camp PC Jr, Rosas IO, Lemma M, Speransky V, Merideth MA, Gahl WA, Gochuico BR. Clinical management and outcomes of patients with HermanskyPudlak syndrome pulmonary fibrosis evaluated for lung transplantation. PLoS One 2018;13(3):e0194193. Gahl WA, Brantly M, Troendle J, Avila NA, Padua A, Montalvo C, Cardona H, Calis KA, Gochuico B. Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Mol Genet Metab 2002; 76:234-242. O’Brien K, Troendle J, Gochuico BR, Markello TC, Salas J, Cardona H, Yao J, Bernardini I, Hess R, Gahl WA. Pirfenidone for the treatment of Hermansky-Pudlak syndrome pulmonary fibrosis. Mol Genet Metab. 2011;103:128-134.

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Genética del albinismo desde una perspectiva oculocutánea

Simón Carlo, MD IRB Chair Assistant Professor

Biochemistry, Pediatrics & Psychiatry

Palabras claves: Albinismo Oculocutáneo, Desorden Genético, Manifestaciones Clínicas, Gen, Mutaciones.

Keywords: Oculocutaneous Albinism, Genetic Disorder, Clinical Manifestations, Gene, Mutations.

Resumen: El albinismo es un grupo de desórdenes genéticos, en los cuales la producción del pigmento ‘melanina’ está ausente o disminuido. Como consecuencia, se afecta la coloración de la piel, el cabello y los ojos. Respecto a estos últimos, el albinismo -asociado a problemas de visión- también reduce la pigmentación del iris y la retina provocando disminución de la visión, nistagmo y fotofobia. La incidencia es de aproximadamente 1 en 20,000 personas en los Estados Unidos. Hay diferentes tipos de albinismo los cuales van a variar en sus manifestaciones clínicas y el gen afectado que está causando el desorden.

Abstract: Albinism is a group of genetic disorders in which the production of melanin pigment is absent or diminished which affects the coloration of the skin, hair and eyes. In the eyes reduces the pigmentation of the iris and retina, causing decreased vision, nystagmus and photophobia. Albinism is also associated with vision problems. The incidence is approximately 1 in 20,000 people in the United States. There are different types of albinism which will vary in their clinical manifestations and the affected gene that is causing the disorder.

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l albinismo es un grupo de desórdenes genéticos, en los cuales la producción del pigmento ‘melanina’ está ausente o disminuido. Como consecuencia, se afecta la coloración de la piel, el cabello y los ojos. Respecto a estos últimos, el albinismo -asociado a problemas de visión- también reduce la pigmentación del iris y la retina provocando disminución de la visión, nistagmo y fotofobia. La incidencia es de aproximadamente 1 en 20,000 personas en los Estados Unidos. Hay diferentes tipos de albinismo los cuales van a variar en sus manifestaciones clínicas y el gen afectado que está causando el desorden. La mayoría de los tipos de albinismo se heredan de forma autosómica recesiva, en casos donde ambos padres son portadores para la condición. De hecho, con cada embarazo hay un 25% de posibilidades de que el bebé herede ambas mutaciones y padezca la condición. Clasificación de las manifestaciones de albinismo: Albinismo oculocutáneo (OCA) 1 a. Las personas con OCA1a tienen una ausencia total de melanina. Quienes padecen la condición, tienen cabello blanco, piel muy pálida y ojos claros. En otra manifestación conocida como OCA1b, las personas producen algo de melanina. Tienen piel, pelo y ojos de color claro pero su coloración puede aumentar a medida que envejecen. Mutaciones en el gen TYR causan el tipo 1. El diagnóstico de OCA1 es mayormente clínico al observar las características típicas de la hipopigmentación. El diagnóstico molecular se hace buscando las mutaciones o secuenciando el gen TYR. Como tratamientos preventivos se deben llevar a cabo exámenes oftalmológicos y dermatológicos, además de utilizar bloqueador solar a diario, ropa larga y protección para los ojos. Estos pacientes no deben exponerse al sol. La segunda variante, nombrada OCA2 tiene menos severidad que OCA1. En este desorden las mutaciones ocurren en el gen OCA 2 (conocido anteriormente como p gene), causando disminución en la producción de melatonina y 20

Revista Puertorriqueña de Medicina y Salúd Pública

por ende hipopigmentación. Suele presentarse con más frecuencia en personas africanas o indios americanos. La pigmentación en estos individuos va desde variaciones mínimas hasta normal en algunos casos, cuando son comparados con los familiares o la misma población. El desorden conocido por Brown OCA y más común en africanos es parte de OCA2. OCA3 es otra variedad de OCA. En este tipo, el albinismo ocurre por mutaciones en el gen TYRP1 y se presenta, generalmente, en personas de raza negra. Los pacientes presentan un tono rojizo en la piel y cabello, además de tener los ojos clares. A comparación de los anteriores, los cambios visuales tienden a ser menos severos en OCA3. También se conoce como albinismo oculocutáneo rufo (rufous). El albinismo oculocutáneo tipo 4 (OCA4) tiene las mismas características de OCA 1 y OCA 2 con disminución del pigmento cutáneo y del pelo. Las manifestaciones oftalmológicas son las mismas que se presentan en los demás tipos de albinismo: nistagmo, reducción del pigmento del iris, disminución del pigmento retiniano, hipoplasia de la fóvea con pérdida de visión y afectación en la derivación de los nervios ópticos a nivel del quiasma, hecho que causa estrabismo, reducción de la visión estereoscópica y alteración en los potenciales evocados visuales (PEV). Las variaciones en la pigmentación del pelo y piel por lo general son mínimas a través de la vida del individuo. Para obtener el diagnóstico definitivo de OCA4, se utilizan pruebas moleculares que identifiquen mutaciones en el gen SLC45A2. Debido a que los diferentes tipos de albinismo comparten muchas de las manifestaciones clínicas se recomienda que se haga un panel que incluya todos los genes causantes de albinismo (todos estos genes están asociados a la producción de melanina, sustancia que da color a la piel, el cabello y los ojos) o directamente pruebas del genoma. Hay individuos con albinismo que no tienen mutaciones en ninguno de los genes conocidos. En estas personas, la causa genética de la condición es desconocida, pero se están investigando nuevos genes relacionados a la producción de pigmentos.

MSP ARTÍCULO ORIGINAL

"EL ALBINISMO ES UN GRUPO DE DESÓRDENES GENÉTICOS, EN LOS CUALES LA PRODUCCIÓN DEL PIGMENTO ‘MELANINA’ ESTÁ AUSENTE O DISMINUIDO. COMO CONSECUENCIA, SE AFECTA LA COLORACIÓN DE LA PIEL, EL CABELLO Y LOS OJOS" El albinismo ocular (AOLX) es un trastorno que ocurre como una mutación en el gen GPR143 (previamente conocido como OA1). Debido a ello, causa problemas con el funcionamiento del melanosoma y conduce a manifestaciones cutáneas menores y deterioro visual congénito y persistente en los hombres afectados, esto como resultado de una mutación genética en el cromosoma X. Aunque las mujeres son portadoras de la mutación sin saberlo, en ocasiones pueden presentar manifestaciones clínicas atenuadas. Incluso, hasta el 90% de los afectados tiene mutaciones en el gen mencionado. EL AOLX se caracteriza por nistagmo infantil, disminución de la agudeza visual, hipopigmentación del pigmento del iris, se mantiene estable la agudeza visual durante la vida y generalmente no es progresivo. Se conocen casos en los que esto puede mejorar durante la adolescencia. Otra de las manifestaciones de albinismo es el síndrome de Hermansky-Pudlak (SHP). Éste se caracteriza por albinismo oculocutáneo, problemas hemorrágicos, fibrosis pulmonar, colitis granulomatosa e inmunodeficiencia en algunos de los pacientes. Aunque los hallazgos oftalmológicos son iguales al resto de los desórdenes de albinismo, el color del cabello varía de blanco a marrón, el color de la piel suele ser de un tono más claro que el de otros miembros de la familia. Sin embargo, se pueden presentar problemas hemorrágicos como hematomas, sangrado nasal (epistaxis), sangrado gingival, hemorragias posparto, hemorragias rectales o menstruaciones prolongadas y profusas. Estos episodios pueden ocurrir después de una cirugía como circuncisión o extracciones dentales. En este caso, a demostración de la

ausencia de cuerpos densos en las plaquetas a través de la microscopía electrónica nos asiste en el diagnóstico. En pacientes con este síndrome, la fibrosis pulmonar aparece generalmente después de la tercera década y si se desarrolla colitis granulomatosa, es grave en un 15% de los afectados. Además, pueden ocurrir también defectos inmunológicos y neutropenia. El diagnóstico principal se hace por las manifestaciones clínicas y el historial familiar, pero en Puerto Rico el HPS1 y el HPS3 son relativamente comunes. La identificación de mutaciones patógenas en los siguientes genes: AP3B1, AP3D1, BLOC1S3, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5 o HPS6, nos ayuda a confirmar el diagnóstico. Los pacientes con SHP requieren de un equipo de especialistas que los asistan de forma coordinada y comprensiva para minimizar las complicaciones, debe incluir genetista, neumólogo, gastroenterólogo, hematólogo y las mujeres un ginecobstetra que conozca la condición además del oftalmólogo y el dermatólogo. El síndrome de Chediak-Higashi (CHS) se caracteriza por un albinismo oculocutáneo que se considera parcial y que causa problemas de inmunodeficiencia y tendencia al sangrado. La mayoría de los afectados, casi el 85%, desarrollan linfohistiocitosis hemofagocítica, una reaccion hiperinflamatoria que puede llevar a la muerte. El diagnóstico se confirma identificando inclusiones gigantes dentro de leucocitos en sangre periférica y / o mediante la identificación de mutaciones en el gen LYST. El piebaldismo es un desorden genético autosómico dominante. Su incidencia se estima Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

"LA MAYORÍA DE LOS TIPOS DE ALBINISMO SE HEREDAN DE FORMA AUTOSÓMICA RECESIVA, EN CASOS DONDE AMBOS PADRES SON PORTADORES PARA LA CONDICIÓN"

Willi y A ngelman, vitíligo, hipomelanosis de Ito y síndrome de Waardenburg, donde se puede ver la coloración mas clara de la piel, pero no pertenecen al grupo del albinismo oculocutáneo. También se siguen identificando genes y mutaciones nuevas que causan estos problemas de hipopigmentación, ya que en ocasiones necesitan ser reclasificados. Al igual que en el resto de los desórdenes genéticos y metabólicos lo más importante es sospecharlo a través del examen físico y contar con las herramientas en menos de 1/20000 recién moleculares disponibles en nuestra nacidos. Se caracteriza por la era para así dar un diagnóstico final ausencia congénita de melanocitos y una consejería genética adecuada. en las áreas afectadas por una mutación del gen c-kit y por Referencias su presencia de áreas sin color Oculocutaneous and ocular albinism (acrómicas) simétricas al nacer. Kubasch AS, Meurer M. Hautarzt. 2017 En el 80% de los casos se puede Nov;68(11):867-875. ver un mechón de pelo blanco. https://www.healthline.com/health/ El diagnóstico diferencial incluye albinism#types vitíligo, albinismo y síndrome de ht tps://ghr.nlm.nih.gov/condition/ Waardenburg. Se han descrito oculocutaneous-albinism#inheritance asociaciones con neurofibromatosis Oculocutaneous albinism type 3 Conditions - GTR - NCBI tipo I. Hay otros problemas genéticos www.ncbi.nlm.nih.gov que pueden tener hipopigmentación Genereviews Oculocutaneous Albinism como los síndromes de Prader Type 1 Richard Alan Lewis, MD, MS

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Oculocutaneous Albinism Type 2 Richard Alan Lewis, MD, MS. Ocular Albinism, X-Linked Richard Alan Lewis, MD, MS. Chediak-Higashi Syndrome Toro C, Nicoli ER, Malicdan MC, et al. 2009 Mar 3 [Updated 2018 Jul 5] Chediak Higashi Syndrome. Ajitkumar A1, Ramphul K2. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jun 10. Identification of TYR mutations in patients with oculocutaneous albinism. Sun W, Shen Y, Shan S, Han L, Li Y, Zhou Z, Zhong Z, Chen J.Mol Med Rep. 2018 Jun;17(6):8409-8413. doi: 10.3892/mmr.2018.8881. Epub 2018 Apr 13. Hermansky-Pudlak Syndrome. Huizing M, Malicdan MCV, Gochuico BR, Gahl WA. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2000 Jul 24 [updated 2017 Oct 26]. Oculocutaneous Albinism Type 4. Hayashi M, Suzuki T. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 19932018. 2005 Nov 17 [updated 2017 Sep 7].

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

•

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.

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)

INDICATIONS AND USAGE Trulicity® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: Not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans. Prescribe Trulicity only to patients for whom the potential benefits outweigh the potential risk. Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. It is not a substitute for insulin. Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. Not recommended in patients with pre-existing severe gastrointestinal disease. CONTRAINDICATIONS Do not use in patients with a personal or family history of MTC or in patients with MEN 2. Do not use in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components. WARNINGS AND PRECAUTIONS

DG HCP BS 10FEB2017 7 x 9.5

Trulicity, DG HCP BS 10FEB2017 7 x 9.75

DG HCP BS 10FEB2017 7 x 9.5

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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)

DG HCP BS 10FEB2017 7 x 9.5

Trulicity, DG HCP BS 10FEB2017 7 x 9.75

varying degrees of hepatic impairment, no clinically relevant change in dulaglutide pharmacokinetics (PK) was observed. Renal Impairment: In the four Phase 2 and five Phase 3 randomized clinical studies, at baseline, 50 (1.2%) Trulicity-treated patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73 m2), 171 (4.3%) Trulicity-treated patients had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73 m2) and no Trulicity-treated patients had severe renal impairment (eGFR <30 mL/min/1.73 m2). No overall differences in safety or effectiveness were observed relative to patients with normal renal function, though conclusions are limited due to small numbers. In a clinical pharmacology study in subjects with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in dulaglutide PK was observed. There is limited clinical experience in patients with severe renal impairment or ESRD. Trulicity should be used with caution, and if these patients experience adverse gastrointestinal side effects, renal function should be closely monitored. Gastroparesis: Dulaglutide slows gastric emptying. Trulicity has not been studied in patients with pre-existing gastroparesis. OVERDOSAGE Overdoses have been reported in clinical studies. Effects associated with these overdoses were primarily mild or moderate gastrointestinal events (eg, nausea, vomiting) and non-severe hypoglycemia. In the event of overdose, appropriate supportive care (including frequent plasma glucose monitoring) should be initiated according to the patient’s clinical signs and symptoms. PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide • Inform patients that Trulicity causes benign and malignant thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (eg, a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their physician. • Inform patients that persistent severe abdominal pain, that may radiate to the back and which may (or may not) be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue Trulicity promptly, and to contact their physician, if persistent severe abdominal pain occurs. • The risk of hypoglycemia may be increased when Trulicity is used in combination with a medicine that can cause hypoglycemia, such as a sulfonylurea or insulin. Review and reinforce instructions for hypoglycemia management when initiating Trulicity therapy, particularly when concomitantly administered with a sulfonylurea or insulin. • Patients treated with Trulicity should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients treated with Trulicity of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs. • Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of Trulicity and other GLP-1 receptor agonists. If symptoms of hypersensitivity reactions occur, patients must stop taking Trulicity and seek medical advice promptly. • Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant. • Prior to initiation of Trulicity, train patients on proper injection technique to ensure a full dose is delivered. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. • Inform patients of the potential risks and benefits of Trulicity and of alternative modes of therapy. Inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and advise patients to seek medical advice promptly. • Each weekly dose of Trulicity can be administered at any time of day, with or without food. The day of once-weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before. If a dose is missed and there are at least 3 days (72 hours) until the next scheduled dose, it should be administered as soon as possible. Thereafter, patients can resume their usual once-weekly dosing schedule. If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, the patient should not administer the missed dose and instead resume Trulicity with the next regularly scheduled dose. • Advise patients treated with Trulicity of the potential risk of gastrointestinal side effects. • Instruct patients to read the Medication Guide and the Instructions for Use before starting Trulicity therapy and review them each time the prescription is refilled. • Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. • Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels towards the normal range. HbA1c is especially useful for evaluating long-term glycemic control.

Eli Lilly and Company, Indianapolis, IN 46285, USA US License Number 1891 Copyright © 2014, 2015, Eli Lilly and Company. All rights reserved. Additional information can be found at www.trulicity.com DG HCP BS 10FEB2017 Trulicity® (dulaglutide)

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MSP ARTÍCULO ORIGINAL

Red del Síndrome Hermansky-Pudlak

y los servicios que ofrece a pacientes y familiares

Donna Appell, RN Executive Director/Founder Hermansky-Pudlak Syndrome Network Inc.

Palabras claves: Síndrome de Hermansky-Pudlak, Condiciones genéticas, Mutaciones, Albinismo Resumen: El síndrome de Hermansky-Pudlak es una condición genética rara que se caracteriza por la presencia de albinismo, de un trastorno hemorrágico y de ceguera legal. En ocasiones, los individuos pueden desarrollar una enfermedad renal. El HPS ocurre en todas las nacionalidades, pero es muy común entre las personas de descendencia puertorriqueña con una prevalencia en el HPS1 de 1: 1800 en el noroeste de la isla. Aproximadamente el 75 por ciento de nuestra membresía son de descendencia puertorriqueña.

La Red del Síndrome de Hermansky-Pudlak (HPS) fue incorporada en 1995 por Donna Appell RN. Su hija, sufrió una hemorragia por la colitis de HPS a la edad de dos años, la cual causó una lesión cerebral traumática. Durante 26 años, la Red HPS se ha esforzado por servir a nuestra gente. Continuaremos en esta búsqueda hasta que nuestro sueño de una cura se haga realidad. El síndrome de HermanskyPudlak es una condición genética rara que se caracteriza por la

Keywords: Hermansky-Pudlak syndrome, Genetic conditions, Mutations, Albinism Summary: AHermansky-Pudlak syndrome is a rare genetic condition characterized by the presence of albinism, a bleeding disorder and legal blindness. On occasions, individuals may develop kidney disease. HPS occurs in all nationalities, but it is very common among people of Puerto Rican descent with a prevalence in HPS1 of 1: 1800 in the northwest of the island. Approximately 75 percent of our membership is of Puerto Rican descent.

presencia de albinismo, de un trastorno hemorrágico y de ceguera legal. La condición puede progresar y desarrollar una enfermedad intestinal inf lamatoria similar a la enfermedad de Crohn. La fibrosis pulmonar, una enfermedad pulmonar fatal, ocurre en la adultez (el 100% de las veces, en 3 de los 10 tipos de genes HPS 1,2 y 4). En ocasiones, los individuos pueden desarrollar una enfermedad renal. Se debe tener en cuenta que el HPS ocurre en todas las nacionalidades, siendo muy común en personas

de descendencia puertorriqueña con una prevalencia en el HPS1 de 1:1800 en el noroeste de la isla. Actualmente, el 75% de nuestra membresía es población con esta descendencia. Por ende, nuestra misión es brindar apoyo, educación y esperanza a las personas y familias afectadas por el HPS. Dentro de nuestras labores, f inanciamos y facilitamos la investigación clínica y proveemos recursos para que los profesionales de la salud logren alcanzar nuestro sueño común: obtener

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

"El síndrome de Hermansky-Pudlak es una condición genética rara que se caracteriza por la presencia de albinismo, de un trastorno hemorrágico y de ceguera legal" una cura. También organizamos conferencias y asistimos en obtener acceso a expertos en diagnóstico. Por ejemplo, mensualmente, uno de nuestros trabajadores sociales modera llamadas de apoyo y entrega información a adultos y padres de personas con HPS, tanto en inglés como en español. De igual forma, mantenemos una red de comunicación y apoyo social que es vital para nuestros miembros, también tenemos dos enfermeras registradas en la oficina para ayudar a nuestra membresía. Además, Hilda Cardona, RN quien es parte de nuestra Junta Directiva, viaja a la isla y visita a las familias en sus hogares. También contamos con un trabajador social bilingüe, Carmen Camacho, MA, LSW quien ayuda a nuestros miembros durante el proceso de trasplante de pulmón mediante un programa llamado TIPS (Transplant Information and Peer Support). Carmen es también miembro de nuestra mesa directiva. Cuando una familia llega a la red con una persona recién diagnosticada, se le envía materiales educativos para que los compartan con sus médicos, maestros y profesionales de la salud. Incluso, los miembros están inscritos en un banco de datos que nos permite enviar boletines y noticias sobre conferencias, investigaciones clínicas y eventos de recaudación de fondos. Durante este año y el pasado año, la red ha organizado y/o

Revista Puertorriqueña de Medicina y Salúd Pública

patrocinado varios proyectos para nuestros miembros en Puerto Rico: • Enviamos fondos, guantes y mascarillas para protección respiratoria después del huracán María. • Remitimos fondos para comprar un espirómetro pediátrico y suministros para una nueva clínica pulmonar pediátrica de HPS. • 3) Organizamos una conferencia en abril en San Juan para médicos y familias en colaboración con la Asociación Torácica Americana y estamos planeando otra conferencia para celebrarse en abril de 2019. • Asistimos con el costo de transporte al aeropuerto para permitir que algunos miembros participen en la investigación de HPS en el Instituto Nacional de Salud en Bethesda, Maryland. • Patrocinamos a médicos locales con becas de viaje para asistir a la Conferencia Internacional de la asociación Torácica Americana en San Diego, mayo de 2018 La red HPS ya ha recibido varios premios por nuestro trabajo de organizaciones como: American Thoracic Society for Health Equality, reconocimientos de la Legislatura de Puerto Rico y también fuimos elegidos por la FDA y NORD como uno de los 30 héroes en la celebración

de 30 aniversario de la Ley de Medicamentos Huérfanos. En 2013, la Red HPS se unió al Consorcio de Enfermedades Pulmonares Raras, de la Red de Investigación Clínica de Enfermedades Raras (RDCRN). El RDCRN es una iniciativa de la Oficina de Investigación de Enfermedades Raras, NCATS, NIH, que consta de 21 grupos de investigación (consorcios) y un Centro de Coordinación y Recolección de Datos que trabajan juntos para mejorar la disponibilidad de información, tratamiento y estudios clínicos sobre enfermedades raras. Estas instituciones también se enfocan en crear conciencia sobre condiciones raras y sus necesidades tanto en los pacientes como en la comunidad médica. Además, se abrieron cuatro centros de investigación clínica y hay planes para incluir a PR. La Red HPS colaboró en el establecimiento de un centro de atención clínica para personas con fibrosis pulmonar en Mayagüez, PR, la cual recientemente tuvo una clínica multidisciplinaria muy exitosa en la que se atendieron pacientes con HPS. Para más información sobre la Red del Síndrome Hermansy-Pudlak y los servicios que ofrece a pacientes y familiares, puede comunicarse al 1.800.789.9477 / fax 516.624.0640 y en la web www.hpsnetwork.org.

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

Nasopharyngitis

Diarrhea

Headache

Hypertension

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

Pregnancy

Elevated cholesterol levels**

Headache

Upper respiratory tract infection

Increased blood creatine phosphokinase

Rash

Diarrhea

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

Gastroenteritis

Anemia

Nausea

* 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

El síndrome de Hermansky-Pudlak (HPS) y la salud mental Coralys N. Santiago, M.S. Programa doctoral en Psicología Clínica (Psy.D.) de la Universidad Carlos Albizu Miembro del HPS Network

Palabras clave: Ansiedad, autoestima, autoconcepto, condición, depresión, desarrollo psicosocial, emociones, estabilidad emocional, limitaciones, HPS, pensamientos, personalidad, salud mental, Síndrome de Hermansky-Pudlak

Keywords: Anxiety, self-esteem, self-concept, condition, depression, psychosocial development, emotions, emotional stability, limitations, HPS, thoughts, personality, mental health, Hermansky-Pudlak syndrome Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Introducción: Coralys Nicole Santiago González, es una joven de 24 años, natural de Arecibo, estudiante del Programa doctoral en Psicología Clínica (Psy.D.) de la Universidad Albizu de San Juan. Cuenta con un grado de Maestría en Psicología Clínica, de dicha universidad, y se encuentra por culminar su grado doctoral. Coralys fue diagnosticada con el Síndrome de Hermansky-Pudlak tipo 1 y es miembro del HPS Network. Se ha mantenido participando, junto a sus padres y hermano, quien también es HPS tipo 1, de charlas, convenciones, clínicas de salud y demás actividades dirigidas a informar y educar sobre la condición. Actualmente se halla realizando intervenciones grupales para proveer apoyo psicosocial a pacientes y cuidadores de pacientes con HPS, un miércoles al mes, en las Clínicas de Continuidad del Hospital Pediátrico Universitario en Rio Piedras. Resumen: El hecho de nacer con una condición de salud específica es un factor que impacta en los pensamientos y las emociones de la persona que la padece y de las personas significativas que le rodean. Autoestima y autoconcepto son factores que ayudarán a las personas con HPS a mantenerse emocionalmente estables a lo largo de toda su vida. La personalidad y la autoestima se comienzan a desarrollar desde el nacimiento y a lo largo de la vida. En estos casos, para lograr que los pacientes con HPS mantengan una buena autoestima y un equilibrio emocional, es necesario en primer lugar, que sus padres se encuentren saludables a nivel de salud mental. En el presente artículo se presenta: 1) una mirada general a las etapas del desarrollo psicosocial de Erik Erikson, 2) las experiencias que viven particularmente los pacientes con HPS en cada una de estas etapas y 3) la forma en que tanto los padres, como los profesionales de la salud y hasta los maestros pueden contribuir, de forma positiva o negativa, a su estabilidad psicológica.

omo estudiante de psicología y paciente con HPS tipo 1, he podido conocer y comprender la influencia que puede tener la condición, y experiencias relacionadas a ésta en la salud mental y emocional de una persona. El nacer con una condición de salud, por sí mismo, es un factor que impacta los pensamientos y las emociones, tanto de la persona que la padece, como de las personas significativas que le rodean. Para lograr un

Revista Puertorriqueña de Medicina y Salúd Pública

Abstract: Being born with a health condition is a factor that impacts greatly in the thoughts and emotions of the person who has it and the significant people around him or her. Self-esteem and self-concept are factors that will help people with HPS to stay emotionally stable throughout their lives. Personality and selfesteem begin to develop since birth and throughout their whole life and, to ensure that patients with HPS maintain a good self-esteem and an emotional balance, it is necessary, in the first place, that their parents be healthy regarding their mental health. In the present article I present 1) a brief overview of the stages of Erik Erikson's psychosocial development theory, 2) the experiences that patients with HPS go through in each of these stages, and 3) the way in which parents, health professionals and even teachers can contribute, positively or negatively, to their psychological stability.

buen manejo de los efectos de la condición a nivel psicológico, es necesario iniciar por los padres. El que ellos logren una aceptación incondicional de la condición HPS de sus hijos es el primer paso y, a mi parecer, el más importante. Igualmente existen varias formas en que los profesionales de la salud pueden contribuir a estos fines. Esa primera impresión al ver a un hijo y darse cuenta de que es diferente, puede causar gran impresión. Para

MSP ARTÍCULO ORIGINAL

"El nacer con una condición de salud, por sí mismo, es un factor que impacta los pensamientos y las emociones, tanto de la persona que la padece, como de las personas significativas que le rodean"

unos puede ser motivo de alegría y para otros, de tristeza. Ciertamente, el descubrimiento de un hijo con una enfermedad posiblemente cause preocupación y muchas preguntas. Los profesionales de la salud pueden aumentar dicha preocupación, al realizar comentarios negativos sobre la condición o sobre el futuro del recién nacido. Pero por otro lado, pueden ayudar a disminuirla, al proveerle a los nuevos padres la orientación adecuada sobre la condición y datos de profesionales a los cuales acudir; pero para ello es necesario tener conocimiento sobre HPS. El que los padres se nieguen a conocer sobre HPS y se resistan a asistir a los seguimientos médicos de sus hijos, como forma de “negar” o “evitar” la condición, causa frustración en los padres y, posteriormente, la causará en los hijos. Para que los niños se mantengan estables a nivel psicológico, es crucial que los padres velen por su propia salud mental y trabajen con sus emociones y esquemas de pensamientos, ya que serán quienes les provean a los menores las herramientas y destrezas para desarrollarse adecuadamente y manejar cualquier reto al que se enfrenten.

Un factor importante para que los niños con HPS se mantengan resilientes y emocionalmente estables, es poseer buena autoestima y autoconcepto, ambos se desarrollan desde la infancia. De acuerdo con la teoría del desarrollo psicosocial de Erick Erikson, los seres humanos atravesamos 8 etapas a lo largo de nuestra vida, mediante las cuales vamos desarrollando nuestra personalidad según somos impactados por factores sociales y culturales [2]. La primera etapa, Confianza Básica vs. Desconfianza Básica (nacimiento a 18 meses), es donde el infante desarrolla conf ianza en las personas y objetos a su alrededor; a fin de desarrollar “la creencia de que pueden satisfacer sus necesidades y cumplir sus deseos” [2]. El primer paso para ayudar a establecer el autoestima y autoconcepto de niños con HPS es aceptarlos y amarlos incondicionalmente; ello ayudará a que se acepten y amen tal cual son. Gestos y acciones básicos, como mantener contacto físico (abrazar y besar), estar presente en momentos importantes y tener contacto visual profundo, contribuyen a que se sientan seguros, apoyados y amados. En la segunda etapa, Autonomía vs. Vergüenza y Duda (18 meses

a 3 años), los niños buscan lograr un equilibrio entre la autodeterminación y el control que ejercen sus padres sobre ellos [2]. Según van creciendo y tornándose más conscientes de sí, es importante respetar sus opiniones y deseos. Por ello, es útil brindarle un espacio adecuado para expresarse y tomar decisiones, al permitirles escoger su merienda, por ejemplo [1]. El escucharle, negociar y permitirles tomar decisiones simples, ayuda a fortalecer su autoestima y a definir su identidad, haciéndoles sentir que pueden lograr las cosas que se proponen. En las etapas de Iniciativa vs. Culpa (3 a 6 años), y Laboriosidad vs. Inferioridad (6 a 12 años) los niños buscan un equilibrio entre el deseo de perseguir metas y las reservas sobre hacerlo, por culpa o temor al castigo, y buscan sentirse capaces de dominar actividades y realizar tareas efectivamente [2]. El que padres, maestros o médicos respondan de forma negativa ante las preguntas e iniciativas de los menores pudiese llevarlos a experimentar culpa y temor por intentar cosas nuevas [1]. El desalentar o sobre limitar a los niños con HPS por sus dificultades visuales, falta de pigmentación

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MSP ARTÍCULO ORIGINAL

"EL AUTOESTIMA Y AUTOCONCEPTO AYUDARÁN A PERSONAS CON HPS A MANTENERSE EMOCIONALMENTE ESTABLES A LO LARGO DE SU VIDA Y SON LOS PADRES O CUIDADORES QUIENES DEBEN AYUDAR A CONSTRUIRLOS"

Revista Puertorriqueña de Medicina y Salúd Pública

o disfunción plaquetaria, para protegerlos, puede hacer que duden de sí mismos, se tornen ansiosos o dependientes, desarrollen síntomas de depresión y teman intentar cosas que, probablemente, puedan realizar adecuadamente, con las ayudas o medidas necesarias que se ajusten a su condición. Muchas personas pueden desa lentar a los niños con comentarios negativos o burlas, principalmente maestros y compañeros. Sería útil alentarlos a intentar cosas nuevas o a continuar intentando cuando algo no le salga bien y ayudarles a trazar metas alcanzables, con expectativas realistas de lo que pueden lograr, considerando su condición. Además, es importante resaltar principalmente sus talentos y aquellos aspectos positivos de sus esfuerzos. Durante la adolescencia se atraviesa la etapa de Identidad vs. Confusión de identidad (12 a 18 años), en la que las personas comienzan a buscar su identidad

al explorar sus valores, creencias y metas para futuro (estudios, trabajo, casa, relaciones etc.) [2, 1]. Comienzan a buscar su lugar en la sociedad, empiezan a compararse con otras personas e intentan seguir ciertos estándares sociales. El considerarse distintos a los demás, el sentirse incómodos al no poder hacer ciertas cosas como el resto de las personas (p.ej. ir a la playa sin usar protección contra rayos UV o practicar cierto deporte con riesgo de sufrir una lesión y sangrar), el valorarse negativamente y el no poder encajar en las expectativas sociales puede llevarlos a experimentar sentimientos de inadecuacidad, tristeza y, en ocasiones, ira. Es importante que, en esta etapa, las personas no se vean limitadas en oportunidades para descubrir su lugar en la sociedad, desarrollar su propia identidad y pasar de la adolescencia a la adultez. En adolescentes y adultos jóvenes con HPS esto es un verdadero

MSP ARTÍCULO ORIGINAL

reto, ya que muchas veces se ven limitados de oportunidades para independizarse, desarrollarse en algún ámbito y/o lograr metas. Las dificultades para obtener licencia de conducir (para aquellos cuya capacidad visual no les limita demasiado), los limitados recursos de transportación en el país, la poca empatía, el desconocimiento de numerosos profesionales sobre el HPS y hasta el mero hecho de tener que leer o llenar documentos que no pueden leer, debido al tamaño de letra tan reducido, son solo unos pocos de los retos que les limitan en el diario vivir. Éstos, ciertamente, amenazan su autoestima, su independencia e incluso su salud física, al impedirles asistir a sus seguimientos o recibir la ayuda idónea; todo ello puede conducir a frustración, tristeza y coraje ante su impotencia frente a estas situaciones. En la 6ta etapa, Intimidad vs. Aislamiento (18 a 40 años), ocurre la transición de adolescente a joven adulto, la independización, se comienzan a cumplir metas y se busca establecer relaciones sig n i f icat ivas y duraderas, particularmente relaciones de pareja [2]. Para las personas con HPS, hallar un/a compañero/a que vea más allá de la condición, dispuesto a aceptar todo lo que esta conlleva, y/o lidiar con la resistencia de la familia de la pareja, quienes pueden hacer comentarios negativos como “no puede hacer las cosas como todo mundo” o “vas a ser como su lazarillo”, constituye otro reto que, aunque desafían su

autoestima, se puede lograr vencer. En esta etapa también surge el cuestionamiento sobre si tener hijos o no, principalmente en las mujeres, dadas las complicaciones que un parto o cesárea pueden acarrear con sus deficiencias plaquetarias. A estas edades usualmente comienzan a desarrollarse dificultades de salud, como la colitis granulomatosa y la f ibrosis pulmonar, cuyos tratamientos y gastos monetarios pueden causar gran angustia emocional, principalmente si se requiere un trasplante de pulmón, lo cual conlleva una extensa preparación que incluye reubicarse en los EE. UU. y someterse a numerosos procedimientos médicos. Para ayudar a aminorar dicha angustia por los procedimientos y los altos costos de estos, sería beneficioso que el plan de salud del gobierno extienda la Cubierta Especial/Catastrófica de Salud a pacientes HPS de todas las edades y, para lograrlo, se requiere del apoyo de pacientes y profesionales de la salud que estén informados sobre la condición. En las etapas de Generatividad vs. Estancamiento (40 a 65 años) e Integridad vs. Desesperación (65 años hasta la muerte), las personas se cuestionan sobre cuán productiva ha sido su vida, contemplan sus logros y evalúan si han aprovechado sus años. Una persona se siente productiva cuando devuelve algo a la sociedad al sentir que dejó una huella (p.ej. buen desempeño laboral o contribuir en la crianza de niños) [2, 1]. Al realizar dicha evaluación y

sentir que no han contribuido como desearían, quizás por las numerosas l i m it aciones mencionadas previamente, pueden sentirse poco productivos, insatisfechos con sus vidas y desarrollar desesperanza y síntomas de depresión [1]. El autoestima y autoconcepto ayudarán a personas con HPS a mantenerse emocionalmente estables a lo largo de su vida y son los padres o cuidadores quienes deben ayudar a construirlos. Los profesionales de la salud pueden contribuir al darse a la tarea de conocer, a fin de desarrollar mayor empatía ante la condición y proporcionar los mejores servicios posibles. Igualmente pueden contribuir al recomendar buscar ayuda psicológica si observan o escuchan que un paciente manifiesta dif icultades emocionales. Por último, los propios pacientes tienen la responsabilidad de reconocer sus dificultades y buscar las ayudas de salud mental que les sean más adecuadas.

Referencias:

[1] McLeod, S. A. (mayo 3, 2018). Erik Erikson's stages of psychosocial development. Retrieved from https://www. simplypsychology.org/Erik-Erikson.html [2] Papalia, D. E., Feldman, R. D. (2012). Desarrollo Humano (12ma ed.). México, D. F.: McGraw-Hill Interamericana.

Revista Puertorriqueña de Medicina y Salúd Pública

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)

B:11.75”

T:11.5”

S:10.3667”

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

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

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)

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)

Bleeding into a critical organ

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)

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)

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

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

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

Síndrome de Tipo 1, Puerto Rico

Quebradillas

Aguadilla

30 casos o más

Revista Puertorriqueña de Medicina y Salúd Pública

10-19 casos

20-29 casos

Hermansky-Pudlak San Juan

Ponce 04

2-9 casos

10-19 casos

0 casos Diseño: Julián David Herrera Fuente: Facultad de Medicina de la Ponce

Health Sciences University

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

El trasplante de pulmón Una decisión complicada para los pacientes de HPS en Puerto Rico

Por: Carmen Lizzette Camacho, MA, LSW Clinical Counselor at Advocates Community Counseling

Miembro Junta de Directores de HPS Network Coordinadora de HPS Network en New England

Abstract: Hermansky-Pudlak syndrome (HPS) is an autosomal recessive genetic condition that occurs in the form of albinism, nystagmus (abnormal movement of the eyes), poor vision, bleeding and in some of its subtypes, colitis. granulomatous and pulmonary fibrosis (FP). PF occurs in 100% of patients with HPS 1, 2 and 4 and these patients usually die between 30 to 50 years. The lack of a transplant center in Puerto Rico means that the management of this condition presents different challenges than those faced by patients with FP in the United States. The HPS Network has developed a program to educate and support HPS patients who wish to be evaluated for lung transplantation.

Resumen: El Síndrome de Hermansky-Pudlak (HPS, por sus siglas en inglés) es una condición genética autosomal recesiva que se presenta en forma de albinismo, nistagmo (movimiento anormal de los ojos), pobre visión, sangrado y en alguno de sus subtipos, colitis granulomatosa y fibrosis pulmonar (FP). La FP ocurre en el 100% de los pacientes con HPS 1, 2 y 4 y por lo general estos pacientes fallecen entre los 30 a 50 años. La falta de centro de trasplante en PR hace que el manejo de esta condición presente retos diferentes a los que confrontan los pacientes con FP en los Estados Unidos. La Red de HPS ha desarrollado un programa para educar y apoyar a los pacientes de HPS que desean ser evaluados para trasplante de pulmón.

Palabras clave: albinismo; Síndrome Hermansky-Pudlak; fibrosis pulmonar; Puerto Rico; PR; HPS, trasplante de pulmón

Keywords: albinism, Hermansky-Pudlak Syndrome; pulmonary fibrosis; Puerto Rico; PR; HPS, lung transplant.

ermansky Pudlak Syndrome (HPS) is a genetic autosomal condition that presents with albinism, nystagmus (abnormal movement of the eye), low vision, bleeding and in some of its subtypes, pulmonary fibrosis (PF) and granulomatous colitis. The PF of HPS occurs 100% on HPS 1,2 and 4 and generally these patients passes away between their 30 and 50. The lack of a transplant center in PR means that the management of this condition presents different challenges to those faced by PF patients in the United States. The HPS Network has developed a program to educate and support HPS patients who wish to be evaluated for lung transplantation. El Síndrome de Hermansky-Pudlak (HPS, por sus siglas en inglés) es una condición genética autosomal recesiva que se presenta en forma de albinismo, nistagmo (movimiento anormal de los ojos), pobre visión, sangrado y en alguno de sus subtipos, colitis granulomatosa y fibrosis pulmonar (FP). El sangrado que puede ser de leve a grave es causado por un defecto en las plaquetas las cuales carecen de cuerpos densos. 54

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De acuerdo con estudios realizados por el Instituto Nacional de Salud (NIH), la prevalencia mundial de HPS es de 1 a 9 casos por 1,000,000 de la población. (Expert Reviewers: Dr. William Gahl, 2010). Sin embargo, en Puerto Rico la prevalencia es mucho mayor, debido al efecto del fundador. La prevalencia de HPS 1 en la región noroeste de Puerto Rico, es 1 de cada 1,800 personas (Marjan Huizing, 2000); ocurre en 5 de cada 6 personas con albinismo nacidas en esta área de la isla. (Witkop CJ, 1990). La complicación pulmonar causada por el HPS es catastrófica. La FP ocurre en el 100% de los pacientes con HPS 1, 2 y 4, por lo general fallecen entre los 30 a 50 años. (Glenn W. Vicary, 2016). Actualmente el único tratamiento para la FP de HPS es un trasplante de pulmón. El hecho de la alta incidencia de HPS 1 en PR y el hecho de no haber un centro de trasplante de pulmón en la isla, complica el cuido y tratamiento de estos pacientes, debido a que las necesidades del paciente con HPS en PR son diferentes a las de los pacientes de EE.UU. Por ejemplo, en PR no se ofrece rehabilitación pulmonar. Además por la falta de conocimiento de los pacientes, los afectados no buscan el uso de oxígeno; hecho que los hace más susceptibles a hipertensión pulmonar. Es por esto por lo que la Red de HPS desarrolló un programa para educar a pacientes y proveedores de la salud sobre cómo ayudar y apoyar a estos ndividuos durante el proceso de trasplante. Transplant Information and Peer Support (TIPS) es un programa dedicado a aconsejar y apoyar a aquellos interesados en un trasplante. Como parte del programa, se desarrolló un manual que le explica a el paciente y su familia el proceso de trasplante. (Preparándome para mi trasplante de pulmón). Los retos del sangrado en trasplante se han contenido. Si se maneja el sangrado con plaquetas y/o DDAVP, la posibilidad de sangrado es muy baja y los riesgos que enfrenta un paciente con HPS son los mismos que enfrentaría cualquier individuo que necesite un trasplante. Por este motivo, los centros de trasplantes están considerando tratar al paciente de HPS más frecuentemente que en años anteriores. Se han registrado con la red de HPS 24 casos de trasplantes de pulmón, todos efectuados satisfactoriamente. Debemos considerar que el paciente puertorriqueño con HPS tiene unos retos y situaciones muy diferentes a los pacientes con FP en los Estados Unidos. El paciente

con HPS tiene que relocalizarse a los Estados Unidos. No solo es un cambio económico, pero social. Gracias a la colaboración de la Red de HPS, TIPS y NIH, hemos aprendido que el individuo con HPS que está considerando un trasplante, debe comenzar el proceso de relocalización a los Estados Unidos y comenzar el proceso de evaluación cuando su FVC está alrededor del 60%. Recordemos que el proceso de evaluación no es lo mismo que el proceso de ser listado para trasplante. El proceso de evaluación es lo que te lleva a ser listado y toma meses en completar todas las pruebas médicas. Además, hay que considerar que la persona tiene que estar apta para viajar con el nivel de oxígeno permitido por las líneas aéreas. Los pacientes y los médicos deben considerar ciertos factores al hacer el referido al centro de trasplante: Seguro Médico El proceso de trasplante es muy costoso. La evaluación y el trasplante de pulmón sin incluir gastos de cuido y mantenimiento, puede sobrepasar 1 millón de dólares. El paciente tiene que considerar que cobertura médica tiene y qué cambios debe efectuar para que sus gastos estén cubiertos, especialmente porque la cobertura en Puerto Rico no incluye trasplante. Se les ofrece a las familias una suma de 350,000 dólares para gastos de trasplante, pero el individuo es responsable por el balance. Este fondo usualmente cubre los gastos de evaluación. Sin embargo, el individuo debe considerar relocalizarse para así poder aplicar por las ayudas médicas estatales y verificar elegibilidad antes de comenzar el proceso de evaluación. Si el individuo tiene la cobertura de Medicare, debe también procesar un seguro médico que cubra el 20% que no se cubre en el plan Medicare. Los individuos con planes privados deberán asegurarse de que su plan cubre el trasplante y los gastos de hospital en los Estados Unidos. Finanzas Las personas que tienen FP llegan a un punto donde no pueden trabajar o cuidar de ellas mismas. Es importante que los proveedores de salud estén dispuestos a completar formularios de discapacidad tanto para el seguro social como para seguros privados. El tener que dejar de trabajar, más los gastos de relocalización y de cuidado es estresante tanto para el paciente, como para Revista Puertorriqueña de Medicina y Salúd Pública

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Gastos Misceláneos Los costos del trasplante son solamente una parte de los gastos a considerar con este proceso. Las visitas al hospital conllevan gastos de estacionamiento, gasolina y comidas. Después del trasplante las visitas al hospital son frecuentes. Además, hay que considerar los medicamentos para evitar rechazo y otros gastos Grupos de apoyo y familia médicos no cubiertos por el seguro como, por ejemplo, Aunque el primer impulso es relocalizarse en un área el equipo de espirometría para monitorear la función en donde ya se han hecho trasplantes exitosamente, la pulmonar después del trasplante. recomendación es que se deben relocalizar a un centro de trasplante en la ciudad donde el paciente tenga Ajuste a una nueva comunidad familiares o un grupo de apoyo dispuesto a ayudar Las familias y los pacientes se deben dar tiempo para durante el proceso de evaluación y de recuperación. Los adaptarse a su nueva comunidad, conocer el área, hacer centros de trasplante requieren que haya por lo menos contacto con grupos comunitarios o iglesias y acoplarse dos personas disponibles para cuidar de la persona a una cultura diferente a la que están acostumbrados. trasplantada, inclusive, después del trasplante, ya que Es importante también el poder dar tiempo a acoplarse hay un tiempo en el cual el paciente no puede estar solo al cambio de lenguaje o puedan tener acceso a alguna y tiene que estar acompañado las 24 horas del día. persona u organización que les ayude con traducción. Al parecer, estos factores se pueden alcanzar. Sin Alojamiento embargo, imagine a una persona tratando de acoplarse Cada estado es muy diferente en cuanto a el costo de e investigar servicios, alojamiento y transporte cuando renta y alojamiento. Es importante que las personas su oxigenación es baja y no está física o mentalmente consideren cuánto pueden costear en término de rentas fuerte para poder llevar a cabo todas estas diligencias. Es o si tiene la oportunidad de alojarse con familiares por esto por lo que se enfatiza al paciente que comience durante el proceso de evaluación y recuperación. el proceso cuando aún no esté utilizando oxígeno. No Después del trasplante, el paciente tiene que asistir solo pueden manejar los cambios en sus vidas y los de a citas médicas frecuentes especialmente durante el su familia, sino que también podrán asistir durante primer año, así que el centro prefiere que el paciente ese tiempo a rehabilitación pulmonar y preparar su esté a una distancia razonable para poder asistir a las cuerpo para este procedimiento. Tanto el paciente, citas de seguimiento. los familiares como los profesionales de la salud deben considerar estos puntos cuando se está discutiendo la Servicios Comunitarios y Transportación posibilidad del trasplante y así disminuir el elemento de Debido a los problemas visuales del HPS, el individuo sorpresa que muchos pacientes y sus familias confrontan confronta situaciones muy diferentes a las de cualquier cuando se lleva a cabo. persona con FP. Se aconseja que durante el proceso de decidir que centro de trasplante desea, también evalúe Referencias: qué servicios adicionales se ofrecen en esa comunidad 1.Expert Reviewers: Dr. William Gahl, D. M. (2010, March). ORPHA: Por ejemplo, hay servicios de transportación pública 79430. Retrieved from Orphanet. y servicios de paratránsito (transportación de puerta 2.Marjan Huizing, P. M. (2000, July 24). Hermansky-Pudlak a puerta, ADA), cuáles son los servicios para personas Syndrome. GeneReviews® [Internet]. (A. H. Adam MP, Ed.) Seattle no videntes (clases de movilidad, pases de acceso a (WA). Retrieved October 26, 2017, from https://www.ncbi.nlm.nih. transportación pública). Además, en algunos estados gov/books/NBK1287/ las personas con una placa de impedidos no tienen 3.Witkop CJ, N. B. (1990, August). (1990, August). Albinism que pagar por estacionamiento en áreas con metro, lo and Hermasky-Pudlak syndrome in Puerto Rico. Boletin de la que puede ayudar económicamente en el proceso de Asociación Medica de Puerto Rico, 82(8), 333-9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/2261023 trasplante y las visitas múltiples al hospital. los familiares que cuidan de él/ella. Si la persona tiene los recursos, se aconseja que la persona consulte con un abogado para crear un fideicomiso por discapacitación. Si la persona no consta con ahorros o ingresos, se aconseja que solicite las ayudas estatales del área donde se relocalicen.

4.Hermansky Pudlak Syndrome Network

Revista Puertorriqueña de Medicina y Salúd Pública

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Foto tomada de: Natural history of Morquio A patient with tracheal obstruction from birth to death.

Historia Natural del Síndrome de Morquio Por: Heriberto Román, MD Clinical Cordinator Supervisor Clinical Research Center San Jorge Children’s Hospital

Resumen El Síndrome de Morquio se ubica dentro de los trastornos de almacenamiento de mucopolisacáridos. Afecta a cerca de 1 de cada 200,000 personas. Originalmente, existían dos subtipos distintivos que se cree eran causados por dos deficiencias enzimáticas diferentes. Se comienza a sospechar de problemas cuando los niños tienen entre 1-3 años de edad. Los primeros signos que se observan por lo general son anomalías al caminar, posición anormal de las piernas, deformidad de la caja torácica y/o crecimiento más lento. Las características físicas que pueden guiar a un fenotipo reconocible incluyen: baja estatura desproporcionada con tronco marcadamente corto, cuello corto, pectus carinatum, brazos y piernas delgados, contracturas en la flexión de la cadera, engrosamiento facial (a medida que avanza el trastorno y más leve que en muchas otras mucopolisacaridosis).

Abstract Morquio Syndrome is located within storage disorders of mucopolysaccharides. It affects about 1 in 200,000 people. Originally, there were two distinctive subtypes that were believed to be caused by two different enzyme deficiencies. You begin to suspect problems when children are between 1-3 years of age. The first signs that are observed are usually anomalies when walking, abnormal position of the legs, deformity of the thoracic cage and / or slower growth. The physical characteristics that can guide a recognizable phenotype include: disproportionate short stature with markedly short trunk, short neck, pectus carinatum, thin arms and legs, contractures in hip flexion, facial thickening (as the disorder progresses and more mild than in many other mucopolysaccharidoses).

Palabras clave: Síndrome de Morquio, Trastorno genético, Mutación genética, Enfermedades raras.

Key words: Morquio syndrome, genetic disorder, genetic mutation, rare diseases. Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

l Síndrome de Morquio se ubica dentro médula espinal por la compresión cervical, enfermedad de los trastornos de almacenamiento de pulmonar restrictiva y enfermedad cardiaca así como mucopolisacáridos. Afecta a cerca de 1 de al manejo efectivo de las mismas. Incluso con un cada 200,000 personas. Originalmente, existían tratamiento óptimo, muchas personas afectadas morían dos subtipos distintivos que se cree eran causados a comienzos o durante la vida adulta, aunque no es por dos deficiencias enzimáticas diferentes. Como extraño ver casos de pacientes que alcanzan la quinta o en la mayoría de las mucopolisacaridosis, no se sexta década de vida. Generalmente, el tamaño del bebé al momento del observa sintomatología en el neonato. Se comienza a sospechar de problemas cuando los niños tienen nacimiento es normal y su crecimiento continúa sin entre 1-3 años de edad y la confirmación del alteraciones durante el primer y segundo año de vida, diagnóstico podría confirmar mediante panel momento en el que comienza un crecimiento más de mucopolisacarisosis por sangre. Los primeros lento. Respecto al crecimiento lineal, éste se detiene signos que se observan por lo general son anomalías tempranamente, más frecuentemente entre los 7 y 12 al caminar, posición anormal de las piernas, años de edad. Esto es muy importante para determinar el deformidad de la caja torácica y/o crecimiento más momento ideal para iniciar el tratamiento de reemplazo lento. Las características físicas que pueden guiar enzimático y realizar ciertas intervenciones quirúrgicas, a un fenotipo reconocible incluyen: baja estatura dada la recurrencia a la malformación secundaria al desproporcionada con tronco marcadamente corto, crecimiento. Por lo general, la estatura máxima está entre cuello corto, pectus carinatum, brazos y piernas 80 y 140 cm en pacientes con el diagnóstico de Morquio. delgados, contracturas en la flexión de la cadera, Sin embargo, tener una estatura baja significa que el paciente tendrá ciertas necesidades engrosamiento facial (a medida que afectara su dia a dia por el resto que avanza el trastorno y de vida. más leve que en muchas otras "Históricamente, Hoy día existe tratamiento mucopolisacaridosis). la mayoría de los conocido como elosulfase alfa El Síndrome de Morquio es un pacientes mueren que ayuda a reemplazar la proceso autosómico recesivo. Esto enzima afectada en pacientes con significa que una pareja que ha prematuramente (en mucopolisacaridosis. Éste contiene tenido un hijo con esta afección la adolescencia o en una enzima que naturalmente es tendrá un riesgo de 25% de tener los primeros años de producida en el cuerpo en personas otro hijo con este problema. saludables. Esto tiene cierta relevancia, ya la edad adulta)" La capacidad intelectual a que la fertilidad en las personas diferencia de los otros tipos de afectadas es normal. Las mujeres afectadas normalmente llevan sus embarazos a término, mucopolisacaridosis es normal, a menos que estén a pesar de que es probable que desarrollen compromiso presentes otras complicaciones. De hecho, se podría respiratorio posteriormente durante el embarazo y esperar encontrar variaciones en los patrones de se ven en la necesidad inevitable de someterse a una desarrollo y, particularmente, retrasos en el desarrollo cesárea. Esta condición surge como consecuencia de de las habilidades motoras gruesas debido a una una deficiencia de Nacetilgalactosamina-6-sulfatasa, estatura baja y anomalías de las articulaciones. Además, una enzima, un hecho que ocurre como resultado de las los afectados presentan frecuentemente opacidad de la mutaciones de pérdida de función en ambas copias del córnea, un signo que usualmente no es una condición gen GALNS. Se han detectado diferentes mutaciones en severa y que causa pocos problemas.La experiencia GALNS y existe cierta correlación genotípica-fenotípica sugiere que la intervención quirúrgica es una opción – lo que significa que, en cierta forma, las mutaciones en los casos más severos, aunque puede existir presentes predicen la severidad de las manifestaciones recurrencia. Muy rara vez podrían desarrollarse otras complicaciones oculares como glaucoma o cataratas. clínicas. Históricamente, la mayoría de los pacientes mueren En caso de presentarse, se tratan como se haría en prematuramente (en la adolescencia o en los primeros personas normales. La pérdida de la audición por lo general comienza a años de la edad adulta). Los riesgos están claramente relacionados a la severidad de la disfunción de la mediados de la infancia, una afección que también se 58

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presenta como una pérdida frecuentemente progresiva pero moderada. En los afectados con este síndrome, es común la disfunción del oído medio. Se debe realizar una evaluación audiológica por lo menos una vez al año, al comienzo del diagnóstico y continuamente a lo largo de la vida del paciente. Por otro lado, el esmalte dental es uniformemente anormal– delgado, rugoso e hipoplásico. Esta condición afecta tanto a los dientes de leche como a los permanentes. Existe una marcada y mayor frecuencia de fracturas dentales, desgaste dental y caries. Se ha utilizado con éxito la ortodoncia en los pacientes con Síndrome de Morquio, importante tomar en consideración las anomalías del esmalte dental. Pueden surgir problemas respiratorios de características restrictivas u obstructivas. La enfermedad pulmonar restrictiva puede ser secundaria al menor tamaño de la caja torácica, a la forma de la caja torácica con o sin problemas secundarios a cifoscoliosis. Los síntomas obstructivos son también multifactoriales – vías respiratorias intrínsecamente pequeñas, posiblemente la acumulación de material de almacenamiento en las vías respiratorias e hipertrofia adenoidea y tonsilar. Podrían existir dificultades respiratorias debido a complicaciones neurológicas aunque estas han disminuido por las correcciones cervicales profilácticas. Las visitas al neumólogo y al especialista en somnología ayudan a definir los tratamientos adecuados a seguir según la necesidad del paciente. Es decir que se debe tener evaluación de función pulmonar y polisomnologia anualmente. Por ello, resulta imprescindible cumplir con sus vacunas incluyendo la influenza anualmente. A nivel cardiológico se ve daño valvular afectando el lado izquierdo (válvulas aórtica y mitral). Esta manifestación es benigna en la mayoría de los niños pero podría convertirse en una condición severa durante la vida adulta. Es importante la evaluación cardiológica y ecocardiografía al momento de realizar el diagnóstico y anualmente. A nivel espinal, tenemos uno de los puntos más críticos en la atención de las personas con síndrome de Morquio. Si no se brinda una atención adecuada, podrían surgir cuadros de espondilosis cervical alta y/o muerte súbita por insuficiencia respiratoria. Los problemas de la columna cervical están presentes y por lo general son progresivos, entre ellos, la aparición frecuente de compresión de la columna cervical. Esta anomalía podría originar cualquiera de las siguientes condiciones: mielopatía lenta y progresiva, parálisis y muerte súbita (probablemente secundaria a una isquemia de los centros de control de la respiración del bulbo raquídeo). Los signos

tempranos de mielopatía incluyen menor resistencia, hiperreflexia y clonus, particularmente de las piernas, problemas con incontinencia intestinal o urinaria. Las imágenes radiológicas de la columna cervical son muy recomendables, pues son la primera sospecha de la presencia del síndrome en el paciente. Luego del diagnóstico las radiografías, resonancias magnéticas, tomografías computarizadas se recomiendan una vez al año. Referencias

1.Clinical and molecular characteristics of colombian patients with mucopolysaccharidosis IVA, and description of a new galns gene mutation. Moreno Giraldo, LJ; Escudero Rodríguez, ÁM; Sánchez Gómez, A; Satizabal Soto, JM /URL - https://www.ncbi.nlm.nih. gov/pubmed/30094185?dopt=Citation 2.Mol Genet Metab Rep, 2018 vol. 15 pp. 116-120. Elosulfase alfa for mucopolysaccharidosis type IVA: Real-world experience in 7 patients from the Spanish Morquio-A early access program. Pintos-Morell, G; Blasco-Alonso, J; Couce, ML; Gutiérrez-Solana, LG; Guillén-Navarro, E; O'Callaghan, M; Del Toro, M / URL https:// www.ncbi.nlm.nih.gov/pubmed/30023300?dopt=Citation 3.Mol. Genet. Metab., 2018 vol. 125(1-2) pp. 18-37. Molecular genetics and metabolism, special edition: Diagnosis, diagnosis and prognosis of Mucopolysaccharidosis IVA. Peracha, H; Sawamoto, K; Averill, L; Kecskemethy, H; Theroux, M; Thacker, M; Nagao, K; Pizarro, C; Mackenzie, W; Kobayashi, H; Yamaguchi, S; Suzuki, Y; Orii, K; Orii, T; Fukao, T; Tomatsu, S /URL - https:// www.ncbi.nlm.nih.gov/pubmed/29779902?dopt=Citation 4.J Pediatr (Rio J), 2018. Left ventricular assessment in patients with mucopolysaccharidosis using conventional echocardiography and myocardial deformation by two-dimensional speckle-tracking method. Andrade, MFA; Guimarães, ICB; Acosta, AX; Leão, EKEA; Moreira, MIG; Mendes, CMC U R L- h t t p s : // w w w . n c b i . n l m . n i h . g o v / pubmed/29957247?dopt=Citation 5.Mol Genet Metab Rep, 2018 vol. 14 pp. 59-67 Natural history of Morquio A patient with tracheal obstruction from birth to death. Doherty, C; Averill, LW; Theroux, M; Mackenzie, WG; Pizarro, C; Mason, RW; Tomatsu, S U R L- h t t p s : // w w w . n c b i . n l m . n i h . g o v / pubmed/29326877?dopt=Citation Ransford, A. O., Crockard, H. A., Stevens, J. M., & S. M. (1996). Occipito-atlanto-axial fusion in Morquio-Brailsford syndrome. The Journal of Bone and Joint Surgery., British, 2-7. Retrieved from https://www.semanticscholar.org/paper/Occipitoatlanto-axial-fusion-in-Morquio-Brailsford-Ransford-Crockard/ d777dc7e47ecb0aa7af7f0475f84669ab321f365. Revista Puertorriqueña de Medicina y Salúd Pública

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Síndrome de Jarcho Levin: a 80 años de su descripción clínica Por: Alberto Santiago Cornier, MD, PhD Jefe División de Genética del San Jorge Children’s Hospital Director Centro Investigaciones Clínicas del San Jorge Children’s Hospital Catedrátrico Asociado de la Universidad Central del Caribe, Departamento de Pediatría Catedrático Asociado de la Ponce Health & Sciences University, Departamento de Salud Pública Práctica Privada Torre Médica Hospital San Jorge y SER de Puerto Rico

Resumen: El síndrome de Jarcho Levin ha estado asociado a la población puertorriqueña desde que inicialmente fue descrito en 1938 por Saul Jarcho y Paul Levin del Johns Hopkins Hospital. Jarcho Levin es un epónimo que ha sido utilizado para describir varios fenotipos clínicos que presentan con anomalías vertebrales, costales y acortamiento de la espina dorsal causando enanismo de tronco corto. La disostosis espondilotorácica también conocida como Síndrome de Jarcho Levin es una condición genética autosómica recesiva, causada por mutaciones en el gen MESP2 (Cornier et al.). Las anomalías vertebrales y costales

Revista Puertorriqueña de Medicina y Salúd Pública

que caracterizan a STD puede llevar a restricción torácica importante en aproximadamente 60% de los nacidos requiriendo intervención médica. Debido al compromiso respiratorio la mortalidad reportada es de 50% [Cornier et al 2004]. El síndrome de Jarcho Levin es una de las enfermedades genéticas a la cual los puertorriqueños estamos asociados mundialmente. Tenemos que reconocer a estos pacientes lo más temprano en el embarazo; ser capaces de proveer el manejo clínico apropiado de manera consistente y basado en la literatura médica y no en la improvisación.

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Palabras Claves: Síndrome de Jarcho Levin; Disostosis espondilotoracica; población puertorriqueña Key words: Jarcho Levin syndrome; Spondylothoracic Dysostosis; Puerto Rican population Revista Puertorriqueña de Medicina y Salúd Pública

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Abstract: Jarcho Levin syndrome has been associated to the Puerto Rican population since its initial description by Saul Jarcho y Paul Levin from the Johns Hopkins Hospital in 1938. Jarcho Levin is an eponym used to described various clinical phenot y pes presenting with vertebral and ribs anomalies and shortening of the spine. Spondylothoracic Dysostosis is an autosomal recessive disorder cause by mutations in the MESP2 gene (Cornier et al.) The vertebral and ribs anomalies can cause severe thoracic restriction in approximately 60% of the cases requiring medical intervention. Due to respiratory compromise mortality can be as high as 50% (Cornier et al, 2004). Jarcho Levin syndrome is one of the genetic disorders that are worldwide associated to Puerto Ricans. We must be capable of recognizing the syndrome early in pregnancy, and provide the appropriate clinical management based on medical literature recommendations and not in improvisation.

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l síndrome de Jarcho Levin ha estado asociado a la población puertorriqueña desde que inicialmente fue descrito en 1938 por Saul Jarcho y Paul Levin del Johns Hopkins Hospital. Estos reportaron los primeros dos casos de insuficiencia torácica debido a anomalías vertebrales y costales. Se cumplen 80 años desde la primera exposición de este síndrome y todavía hay mucha confusión tanto de diagnóstico como de manejo médico. Jarcho Levin es un epónimo que ha sido utilizado para describir varios fenotipos clínicos

Puerto Rico tiene la incidencia y prevalencia mas alta del mundo en disostosis espondilotorácica. Según los datos del registro de anomalías congénitas del Departamento de Salud de Puerto Rico la incidencia es de 1.4% de cada 10,000 nacidos vivos, siendo el tipo de Displasia Espondilotorácica (STD) tres veces mayor que el tipo de Displasia Espondilocostal (SCD). Estos números podrían ser aún mayores debido a que si el paciente no presenta problemas respiratorios al nacer no se le hará placa de pecho y las anomalías pasaran por desapercibido hasta mucho más tarde en la vida del paciente. Este

"El síndrome de Jarcho Levin ha estado asociado a la población puertorriqueña desde que inicialmente fue descrito en 1938 por Saul Jarcho y Paul Levin del Johns Hopkins Hospital"

que presentan con anomalías vertebrales, costale y acortamiento de la espina dorsal causando enanismo de tronco corto “shorttrunk dwarfism” (Berdon et al.). A pesar de que un grupo de genetistas y ortopedas, mayormente miembros del Consorcio Internacional de Anomalías vertebrales y escoliosis (ICVAS por sus siglas en inglés), hemos tratado de establecer criterios claros para el diagnóstico clínico y radiológico (Offiah et al, Cornier et al.) aún no hay consenso sobre el mismo. Ciertamente el fenotipo del síndrome se ha expandido y subdividido en dos prevalentes presentaciones clínicas: la disostosis espondilotorácica (STD) y la disostosis espondilocostal (SCD).

fenotipo fue el que inicialmente Jarcho y Levin presentaron en su papel original en 1938. Las demás variantes clínicas se han ido añadiendo y a pesar de que la medicina molecular se ha encargado de identificar diferentes genes para los diferentes fenotipos, algunos autores insisten en llamar Jarcho Levin a otras variantes clínicas. La disostosis espondilotoracica también conocida como Síndrome de Jarcho Levin es una condición genética autosómica recesiva, causada por mutaciones en el gen MESP2 (Cornier et al.). El MESP2 es miembro de la familia de factores de transcripción conocidos como bHLH,que una función clave en definir la parte rostrocaudal de la

MSP ARTÍCULO ORIGINAL

"Aproximadamente el 90% de los individuos con STD desarrollan hernias inguinales, anomalías en la que hasta un 75% son de carácter bilateral" futura vértebra, y, por lo tanto el patrón de formación de los somitas interaccionando con otros genes dentro del “Notch signalnig pathways”. Clínicamente los pacientes presentan múltiples anomalías vertebrales a través de la espina dorsal incluyendo hemivertebras, vértebras fusionadas, ausencia de vértebras y cuerpos vertebrales con diámetro anteroposterior aumentado causando la fusión de las costillas en la parte posterior del tórax que abre en forma de abanico anteriormente causando la forma típica del pecho de estos pacientes, muy amplio anteriormente y estrecho posteriormente, al igual que los problemas respiratorios asociados a un tórax acortado y músculos intercostales no funcionales, debido a la fusión de las vértebras. Los problemas clínicos pueden variar desde serios problemas respiratorios al nacer comprometiendo la vida de los pacientes requiriendo de modalidades agresivas de asistencia respiratoria (mortalidad de %), hasta problemas respiratorios de leves a moderados que pueden ser manejados sin necesidad de intubación endotraqueal.

vida y luego en la pubertad [Dimeglio 1993, Dimeglio 2005]. El largo promedio de la espina de los pacientes con STD es 1.27% (entre 135 a 145 cm) del largo esperado de acuerdo a la edad y sexo representando un 3.1% del largo normal esperado (Ramírez, et al.). La escoliosis no es común en los pacientes con STD. Sin embargo, sí es muy frecuente en los pacientes con STD. La razón es que los pacientes con STD tienen anomalías costales bilaterales y simétricos. Los pacientes con SCD tiene anomalías congénitas asimétricas predisponiéndolos para escoliosis y cifosis de la espina dorsal. Solo el 20% de las personas con STD desarrollan rotaciones de la espina en el axis con escoliosis de mínima a leve. (Cornier et el, 2004) Aproximadamente el 90% de los individuos con STD desarrollan hernias inguinales, anomalías en la que hasta un 75% son de carácter bilateral. Estas hernias son el resultado del aumento de la presión intraabdominal debido al excesivo uso del diafragma para la respiración. Además, el 15% de afectados presentan hernias umbilicales también. Otras anomalías congénitas han sido descritas asociadas a STD y SCD incluyendo Historia Natural de la Disostosis anomalías cardíacas como defectos del septo atrial en Espondilotorácica 5% de los pacientes. Defectos como paladar hendido, Las anomalías vertebrales y costales que caracterizan talipe equino varus, agenesis del glenoide y doble a STD puede llevar a restricción torácica importante sistema colector urinario y defectos del tubo neural se en aproximadamente 60% de los nacidos requiriendo han reportado con prevalencia de aproximadamente intervención médica. Debido al compromiso respiratorio 1% o menos.El tratamiento de las manifestaciones la mortalidad reportada es de 50% [Cornier et al 2004]. clínicas varía por edad y severidad (Cornier A.S. Gene Sin embargo datos más recientes no publicados sugieren Reviews) una mortalidad en aproximadamente 45%, muy probablemente a los adelantos médicos de la medicina • Es de extrema importancia identificar neonatal, mejor conocimiento del manejo médico y del prenatalmente a los bebés con STD para alertar curso clínico de la enfermedad per se, las diferencias de y preparar un equipo de profesionales de la salud que incluyan obstetras, neonatologos, pediatras la circunferencia torácica y el desarrollo de los pulmones y genetistas e intensivistas pediátricos. El equipo entre los pacientes que sobreviven y los que no aún no se también debe incluir a enfermeras especializadas, conocen (Cornier et al 2008). nutricionistas y consejeros genéticos con El crecimiento de la espina está cercanamente experiencia en la condición. relacionado con el desarrollo de los pulmones con un crecimiento más acelerado en los primeros 5 años de Revista Puertorriqueña de Medicina y Salúd Pública

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"Los bebés y niños con STD deben ser inmunizados contra el RSV (Virus sincitial respiratorio) todo el año, no solo en la época de temporada de RSV. La inmunización debe ser por los primeros 5 a 7 años de vida 9"

• El

bebé debe ser puesto en aislamiento respiratorio con un manejo de enfermería de 1 a 2 como mucho con las debidas medidas preventivas de contaminación. Más del 90% de los pacientes que fallecen en el periodo neonatal se debe a infecciones pulmonares adquiridas en la unidad de cuidado neonatal (NICU)

• Factor

• Evitar

alimentación en bolo en pacientes neonatales con problemas respiratorios. Esto causa distensión de la burbuja gástrica interfiriendo con el diafragma que es la fuente principal muscular de la respiración de estos pacientes. Alimentación naso-gástrica lenta a razón de 0.75 a 1 onza por hora por 16 a 20 horas continuas debe ser administrada con Descanso de 4 a 6 horas. Para los bebés que pesan entre 2.72 a 3.18 kg al nacer este régimen provee de 125 a 147 kcal/día, lo cual debe ser suficiente ingesta calórica en el periodo neonatal. Fórmulas maternizadas concentradas deben ser consideradas para suplementar la lactancia materna.

surfactante debe ser administrado inmediatamente después del nacimiento utilizando los protocolos establecidos para neonatos con distrés respiratorio. Aproximadamente el 65% de los infantes presentan algún tipo de problemas respiratorios variando desde leve que puede ser manejado con suplementación de oxígeno indirecto hasta acidosis respiratoria franca requiriendo Infancia y Niñez tardía ventilación mecánica.

• Niveles elevados de CO2 (hipercapnia) puede

presentarse. Los bebés con STD tienden a tolerar la hipercapnia relativamente bien. Niveles de CO2 tan altos como 60 a 75 mm Hg mejoran con el uso de CPAP (presión de aire positiva constante) evitando la intubación. Seguimiento neurológico de los pacientes con STD e hipercapnia en el periodo neonatal por más de 15 años no ha demostrado problemas neurológicos ni de desarrollo.

• Si

la ventilación mecánica es inevitable, las presiones del ventilador deben ser establecidas lo más bajas posible para mejorar la hipoxemia y corregir la acidosis respiratoria. Los problemas de ventilación de estos pacientes NO son debido a pobre intercambio de gases a nivel alveolar sino por la insuficiencia mecánica de expansión del tórax. El ventilador mecánico debe ser descontinuado a la mayor brevedad posible.

• Monitoreo constante cardio respiratorio debe ser llevado a cabo mientras exista compromiso respiratorio.

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• Las infecciones del tracto respiratorio deben

ser tratadas agresivamente incluyendo el uso de antibióticos según sea necesario.

• Los

bebés y niños con STD deben ser inmunizados contra el RSV (Virus sincitial respiratorio) todo el año, no solo en la época de temporada de RSV. La inmunización debe ser por los primeros 5 a 7 años de vida 9. La función y tamaño pulmonar de los pacientes con STD a los 5 a 7 años de edad equivalen a las de uno de 3 anos sin STD).

• La terapia respiratoria con broncodilatadores

y esteroideos debe ser utilizada en el manejo de infecciones respiratorias del tracto superior con o sin sibilancias.

• La ventilación mecánica debe ser evitada a menos que sea absolutamente necesaria. Los infantes y niños con STD aparentan tolerar bien los niveles elevados de CO2 sin ninguna complicación. Evaluación

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cardiorespiratoria constante es necesaria. • Terapias físicas, ocupacional y del habla puede apoyar el progreso en el desarrollo normal de estos pacientes. Adolescencia y adultez

• Las

mundialmente. Tenemos que reconocer a estos pacientes lo más temprano en el embarazo, ser capaces de proveer el manejo clínico apropiado de manera consistente y basado en la literatura médica y no en la improvisación. Todavía hoy 80 años más tarde de que el síndrome fuera descrito y a pesar de la caracterización clínica y molecular, no somos capaces de ofrecer un tratamiento “state-of-the-art” a estos pacientes.

infecciones respiratorias deben ser manejadas con manejo médico agresivo. • Seguimiento por ortopedia debe ser llevado a He estado relacionado a esta condición casi toda mi cabo para evaluar la posibilidad de desarrollo de vida profesional como genetista y todavía en Puerto Rico anomalías secundarias. Algunas de estas anomalías y el mundo, estamos lejos de proveerles a los pacientes con Jarcho-Levin las herramientas necesarias. A deberán ser manejadas quirúrgicamente. saber, médicos con conocimiento de causa, diagnóstico • Data preliminar sugiere el desarrollo de prenatal temprano, tratamientos e instrumentación osteoporosis en los tempranos 40 años. No está quirúrgica diseñada para estos pacientes, consejería claro si es debido a anomalías endocrinológicas o genética apropiada y más aún el apoyo médico y como resultado a la falta de actividad física fuerte humanitario necesario. Para más información pueden a través de sus vidas. Atención médica debe ser comunicarse con nosotros al Centro de Investigaciones llevada a cabo. Clínicas del San Jorge Childrens and Women’s Hospital o a Genetic Diagnostic Group al siguiente correo El síndrome de Jarcho Levin es una de las enfermedades electrónico: gdg_sj@yahoo.com , sancor@hotmail.com genéticas a la cual los puertorriqueños estamos asociados o scornier@psm.edu .

Referencias:

1.Berdon WE, Lampl BS, Cornier AS, Ramirez N, Turnpenny PD, Vitale MG, Seimon LP, Cowles RA.Clinical and radiological distinction between spondylothoracic dysostosis (Lavy-Moseley syndrome) and spondylocostal dysostosis (Jarcho-Levin syndrome). Pediatr Radiol. 2011 Mar;41(3):384-8. doi: 10.1007/ s00247-010-1928-8. Epub 2010 Dec 22.PMID:21174082. 2.Cornier, A S, Ramírez N, Arroyo S, Acevedo J, García L, Carlo S, Korf B. Phenotype characterization and natural history of spondylothoracic dysplasia syndrome: a series of 27 new cases. Am JMed Genet A. 2004 Jul 15;128A(2):120-6. PMID:15214000. 3.Cornier AS, Staehling-Hampton K, Delventhal KM, Saga Y, Caubet JF, Sasaki N, Ellard S, Young E, Ramirez N, Carlo SE, Torres J, Emans JB, Turnpenny PD, Pourquié O. Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome. Am J Hum Genet. 2008 Jun;82(6):1334-41. doi: 10.1016/j. ajhg.2008.04.014. Epub 2008 May 15. PMID:18485326.

4.Cornier AS: Spondylothoracic Dysostosis (August 2010) in: GeneReviews at Genetests: Medical genetics Information Resource [database online]. Copyright, University of Wasgington, Seattle, 1997-2010. Available at http://www.genetests.org. 5.Dimeglio A (1993) Growth of the spine before 5 years. J Pediatr Orthop B 1:102-7 Dimeglio A (2005) Growth in pediatric orthopaedics. In: Morrissy T, Weinstein SL (eds) Lovell and Winter’s Pediatric Orthopaedics, 6th ed. pp. 35-65. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania. 6.Offiah A, Alman B, Cornier AS, Giampietro PF, Tassy O, Wade A, Turnpenny PD; ICVAS (International Consortium for Vertebral Anomalies and Scoliosis Pilot assessment of a radiologic classification system for segmentation defects of the vertebrae.). Am J Med Genet A. 2010 Jun;152A(6):1357-71. doi: 10.1002/ ajmg.a.33361.PMID:20503308 Revista Puertorriqueña de Medicina y Salúd Pública

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

62%a 39% 39%a

19%

≥50%

16%a 6%

59%a 36% 34%a

18%

100%

≥75%

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.

Nuevo consenso global para el tratamiento farmacológico del paciente adulto con Diabetes tipo 2: Poniendo el corazón adelante • Cuando las alucinaciones y el delirio te cambian la vida • VIH y el paciente mayor de edad Revista Puertorriqueña de Medicina y Salúd Pública

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

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

Humulin R U-500 (insulin human injection)

HI U500 HCP BS 27SEP2016

MSP ARTÍCULO DE REVISIÓN

Nuevo consenso global para el tratamiento farmacológico del paciente adulto con Diabetes tipo 2:

Poniendo el corazón adelante Por: José M García Mateo, MD, FACE Diplomate of the American Board of Endocrinology, Diabetes and Metabolism Diplomate of the American Board of Clinical Lipidology

Key words: Diabetes, cardiovascular disease, treatments, treatment options Palabras clave: Diabetes, enfermedad cardiovascular, tratamientos, opciones de tratamiento Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

Resumen: La diabetes es una enfermedad que también provoca otras condiciones como la enfermedad cardiovascular. Estadísticas de Estados Unidos estiman que la enfermedad cardiovascular y cerebrovascular es de 2 a 4 veces más común en adultos diabéticos.Todas las entidades profesionales expertas en el manejo de pacientes diabéticos (Asociación Americana de Diabetes, Asociación Americana del Corazón, etc) consideran que la diabetes es parte de un síndrome cardiometabólico. Esto es debido a que aproximadamente 70% de los pacientes diabéticos también sufren de hipertensión y niveles altos de colesterol y otras grasas.

Abstract: Diabetes is a disease that also causes other conditions such as cardiovascular disease. Statistics from the United States estimate that cardiovascular and cerebrovascular disease is 2 to 4 times more common in diabetic adults. All professional entities that are experts in the management of diabetic patients (American Diabetes Association, American Heart Association, etc.) consider that Diabetes is part of a cardiometabolic syndrome. This is because approximately 70% of diabetic patients also suffer from hypertension and high levels of cholesterol and other fats.

La diabetes es un grupo de enfermedades caracterizadas por un alto nivel de glucosa, resultado de defectos en la capacidad del cuerpo para producir o usar insulina.

esto, la situación se agrava con la falta de recursos para prevenir y tratar la enfermedad. Además, la incidencia aumenta directamente con el peso corporal y la edad. Una de las causas de la epidemia de diabetes en países desarrollados es el aumento en la obesidad, enfermedad que a su vez se relaciona a la alta incidencia de vida sedentaria y pobres hábitos alimenticios en la población. La diabetes fue la séptima causa de muerte en Estados Unidos en el 2015, basado en certificados de defunción confirmando a la diabetes como causa subyacente de defunción. En Puerto Rico se ha estimado que la diabetes es la tercera causa de muerte después de la enfermedad cardiovascular y el cáncer. La enfermedad cardiovascular es más común en los pacientes diabéticos. Estadísticas de Estados Unidos estiman que la enfermedad cardiovascular y cerebrovascular es de 2 a 4 veces más común en adultos diabéticos.Todas las entidades profesionales expertas en el manejo de pacientes diabéticos (Asociación Americana de Diabetes, Asociación Americana del Corazón, etc) consideran que la diabetes es parte de un síndrome cardiometabólico. Esto es debido a que aproximadamente 70% de los pacientes diabéticos también sufren de hipertensión y niveles altos de colesterol y otras grasas. Más aún, desde el 2001 se considera a la diabetes un equivalente a enfermedad cardiovascular.

La incidencia de diabetes es mayor en los siguientes grupos étnios: • Hispanos • Afroamericanos • Nativo americanos • Descendientes de las islas del pacífico Entre los hispanos/latinos, la tasa es de: • 8.5% entre los centroamericanos y sudamericanos • 9.3% entre los cubanos • 13.9% entre los estadounidenses de origen mexicano • 14.8% entre los puertorriqueños El Centro para el Control de Enfermedades de los Estados Unidos (CDC, por sus siglas en inglés) estima que el 9.3% de la población en los 50 estados tiene diabetes, pero en Puerto Rico esa incidencia sobrepasa el 16%. Según la Asociación Puertorriqueña de Diabetes, la pobreza, la falta de educación y la escasez de programas preventivos propicia el alto número de casos. Sumado a 82

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MSP ARTÍCULO DE REVISIÓN

Varios medicamentos están disponibles hoy por hoy para el manejo de la diabetes y sus complicaciones, incluyendo las cardiovasculares. Aunque esto es un hecho, no debemos olvidar que la prevención es la clave para el tratamiento temprano y efectivo de dichas complicaciones. Los métodos preventivos no cuestan nada, estos son: • Dieta (reducir azúcares simples y grasas) • Ejercicio (mayor mente aeróbico) • Reducción de peso (por lo menos un 7 a 10%) • E d u c a c i ó n s o b re l a condición (medios de comunicación)

•

El día 5 de octubre de 2018 en Berlín, la Asociación Europea para el Estudio de Diabetes (EASD por sus siglas en inglés) apoyada por la Asociación Americana de Diabetes (ADA por sus siglas en inglés) presentó un nuevo consenso para el manejo de adultos con diabetes tipo 2, enfatizando el tener en cuenta principalmente la presencia concomitante de enfermedad aterosclerótica cardiovascular para decidir el uso de fármacos antihipoglucémicos preferidos por beneficio en eventos y mortalidad cardiovascular probado en estudios clínicos aleatorizado (Figura 1). Estos estudios han demostrado tal beneficio de un 13 a un 14% para fármacos específicos de la clase de inhibidores de cotransportadores de sodio – glucosa tipo 2 y

agonistas del receptor de GLP1 (la hormona incretina glucagón likepeptide 1). Los estudios más conocidos que han servido como data para el desarrollo de estas recomendaciones son EMPA-REG, LEADER y CANVAS para los fármacos empagliflozin, liraglutide y canaglif lozin respectivamente. Estos tres estudios han llevado a sus respectivos fármacos a obtener aprobación por la Administración de Alimentos y Drogas (FDA por sus siglas en inglés) para la reducción de eventos adversos mayores y mortalidad cardiovascular. Otros estudios presentados recientemente han demostrado el mismo camino para medicamentos con mecanismos de acción relacionados a los antes mencionados. Con base en el diseño de estos estudios, pacientes diabéticos tipo 2, con enfermedad aterosclerótica document ada t rat ados con metformina en monoterapia o en combinación con otros fármacos incluyendo insulina que mantengan un A1C mayor de 7% son candidatos a recibir estas terapias con beneficio cardiovascular independientemente del control glucémico que se obtenga. Más aún, si el paciente con estas características presenta un control glucémico aceptable basado en A1C con otras terapias antidiabéticas aprobadas, se debe considerar sustituir uno de los fármacos que no sea metformina por uno de los mencionados con benef icio cardiovascular documentado para este propósito. Al paciente adulto diabético t ipo 2 , con en fer med a d

aterosclerótica cardiovascular que además presenta con fallo cardiaco congestivo o a riesgo de desarrollarlo, debe recomendarse como parte de su terapia un inhibidor de cotransportador sodio-glucosa tipo 2 (SGLT2i o f lozins), independientemente de su control glucémico por el benef icio demostrado en los estudios mencionados y otros mayormente disminuyendo la tasa de hospitalización por esta causa. El paciente con enfermedad crónica renal leve a moderada es también un candidato a terapia con SGLT2i o f lozins y agonistas de receptor de GLP1 por el beneficio también demostrado en estos estudios disminuyendo la progresión del deterioro renal y así retrasando llegar a terapia de reemplazo (diálisis o trasplante). Recientemente, uno de los estudios específicos de beneficio de disminución en función renal progresiva en una población con enfermedad crónica renal diabética con canaglif lozin fue detenido prematuramente por el marcado beneficio en su propósito principal. En el paciente diabético sin en fer me d a d at er o s c ler ót ic a cardiovascular documentada o sin evidencia de las condiciones antes mencionadas, se pueden considerar otros factores que también guían la elección de la terapia particular antidiabética individualizada al paciente a tratar. Estos factores son el peso corporal, riesgo de hipoglucemia o el costo. Estos son importantes a considerar ya que pueden traer otras complicaciones metabólicas o interferir con obtener Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

un control glucémico aceptable. Aquí se encuentran también los fármacos ya mencionados con beneficio cardiovascular, inhibidores de dipeptidilpeptidasa 4 (DPP4 inhibidores), insulina, glitazonas y hasta sulfonilureas o secretagogos. Dependiendo de las características del paciente y su necesidad de control glucémico, los medicamentos se añaden progresivamente, tomando en cuenta la eficacia y la seguridad de la terapia. La diabetes tipo 2 es una enfermedad progresiva y llegará el momento que el paciente necesitará terapia con insulina, lo cual es el defecto principal de esta condición. Estudios retrospectivos han demostrado que en el momento del diagnóstico de la enfermedad, ya el paciente afectado ha perdido de 50 a 80% la capacidad

de secreción de insulina por un daño progresivo en la célula beta pancreática. Este nuevo consenso toma en cuenta esta data para ofrecer recomendaciones para tratar al paciente en el momento que necesita terapia de insulinización. Existen estudios clínicos que han demostrado que el paciente que no obtiene control con terapia antidiabética oral optimizada, la terapia con agonistas del receptor GLP1 puede llevar a un control glucémico no inferior a insulina basal con el beneficio de menos hipoglucemia y pérdida de peso. Tomando en cuenta estos datos, el nuevo consenso recomienda intentar primero un agonista de receptor de GLP1 como terapia inyectable inicial preferida en diabéticos que ya podrían ser considerados para comenzar terapia con insulina

Use principies in Figure 9.1 If HbA above target despite dual/triple therapy INITIATION FOR GLP-1RA Initiate starting dose (varies across calss)

Consider initial injectable combination (l.e.,GLP-1 RA + basasl insulin) or prandial/basal isulin) if HbA >86 mmol/mol (10%) and/or >23 mmol/mol (2%) above target

Consider GLP-1 RA in most prior to insulin Consider - INTIATION - TITRATION

TITRATION FOR GLP-1RA Gradual titration to maintenance dose (varies acroos class)

If above HbA Target

INITIATION FOR BASAL Start 10 IU a day OR 0.1-0.2/kg a day

TITRATION FOR BASAL Patient self titraton is more effectice Set FPG target that correlates to HbA target Choose evidence-based titration algorithm, e.g., increase 2 units every 3 days to reach FPG target without hypoglycemia For hypoglycemia determine cause. if no clear reason lower dose by 10-20%

Consider insulin as first Injectable if HbA very high >97 mmol/mol (11%) Symptoms or evidence of catabolism: weight loss, polyuria, polydipsia which suggest insulin deficiency If type 1 diabetes is a possibility

Add basal insulin Consider .INITIATION .TITRATION

If above HbA target

For patient on GLP-1RA and basal insulin Consiider FRC of GLP-1RA and insulin (iDegLira or iGlarLixi) But note maz dose of insulin in the FRCs

Despite adequately titrated basal isulin OR once basal dose >0.7 /1.0 IU&kg OR FPG at target

TITRATION FOR PRANDIAL Increase dose by 1-2 IU or 10-15% twice weekly For hypoglycemia determine cause. if no clear reason lower corresponding dose by 10-20%

Stepwise addition of prandial isulin every 3 months if HbA > target is associated with lower risk of hypoglycemia and increases with immediate introduction of full basal-bolus regimen

Consider: INITIATINO TITRATION

Stepwlse additional injections of prandlal Insulin (i.e.,two, then three addiotional injections)

Additional basal insulin or additional prandial insulin

INITIATION FOR PRANDIAL

Revista Puertorriqueña de Medicina y Salúd Pública

INITIATION

In insulin-naive patients 10-12 Iu or 0.3 IU/kg

Consider twice or three time dally premix insulin reglmen

If on existing insulin regimen usually unit to unit at the same total insulin dose but may require adjustment to individual needs

Consider: INITIATION TITRATION

If above HbA target

INITIATION FOR PRANDIAL

TITRATION

TITRATION Add prandial insulin Usually one dose with the largest meal or meal with greatest PPG excursion

If above HbA target INITIATION FOR STEPWISE PRANDIAL

INITIATION If on GLP-1RA use 10-16 dose steps (iDegLira) or 10-15 units (iGlarLixi)

Titrate to FPG target and tolerability

INITIATION FOR PRANDIAL 4 IU a day or 10% of basal dose If HbA <64mmol/mol (8%) consider lowering the total dose by 4IU a dat or 10% of basal dose

If already on GLP-1 or if GLP-1 not appropriate OR Insulin preferred

Proceed to FULL basalbolus regimen, i.e., basal Insulin adn prandial Insulin with each meal)

Consider: INITIATION TITRATION

Caution higher risk of hypoglycemia and/or weight gain Consider:

IF HbA DOES NOT IMPROVE REVIEW ONGOING NEED FOR BASAL-BOLUS REGIMEN CONSIDER ADDITIONAL DSMES

INITIATION TITRATION

TITRATION Individual dose adjustment depends on type of biphasic insulin More Complex if on three time daily regimen

MSP ARTÍCULO DE REVISIÓN

"Por esto es que el médico encargado en el tratamiento del paciente diabético debe tener conocimiento tanto en terapias actuales como en terapias convencionales más costo-efectivas mayormente cuando manejamos el paciente con insulina"

por los beneficios adicionales demostrados en estos estudios (Ver figura ). La insulina de elección para iniciar es la tipo basal, la cual se encarga mayormente del control de la glucemia en ayunas. Muchos pacientes se mantienen controlados por tiempo con esta terapia optimizando progresivamente la insulina basal basado en la glucemia en ayunas pero llega el momento en el que hay una exigencia de control postprandial. La opción preferida en este consenso global es intentar añadir un agonista de receptor GLP1 a la insulina basal, con el propósito de control prandial con menos riesgo de aumento de peso e hipoglucemia que añadir insulina de corta o rápida acción. Hasta el momento existen combinaciones fijas premezcladas de insulina basal y agonistas de GLP1 que disminuyen el número de inyecciones y mejoran la adherencia a la terapia. No debemos olvidarnos que hay otras opciones y si el paciente está en estado de hiperglucemia severa con síntomas de deficiencia mayor de insulina (poliuria, polidipsia, pérdida de peso, cetosis, etc), debemos tomar en consideración un reemplazo total con insulina ya sea basal y prandial o presentaciones premezcladas dependiendo de las características del paciente. El costo también es importante en terapias que exigen el uso de insulina y aunque tenemos insulinas análogas con mejor perfil farmacocinético y menos riesgo de hipoglucemia, hay casos en los que tenemos que recurrir a terapias de insulina humana convencional tomando en cuenta el nivel socioeconómico del paciente a tratar. Por esto es que el médico encargado en el tratamiento del paciente diabético debe tener conocimiento tanto en terapias actuales como en terapias convencionales más costoefectivas mayormente cuando manejamos el paciente con insulina. En conclusión, este nuevo consenso apoyado por la escuela americana y europea en diabetes es considerado global y ha llevado a un giro marcado en el manejo de la diabetes. El manejo es más complicado ya

que tenemos terapias que contrario al pasado, han demostrado beneficios aparte de los relacionados al control glucémico, específicamente en la enfermedad aterosclerótica cardiovascular, enfermedad crónica renal y fallo congestivo cardiaco, las cuales son causa de alta mortalidad y morbilidad en el paciente diabético. Hay varios estudios ya presentados en reuniones científicas y en progreso con resultados similares y posiblemente superiores, incluyendo también a pacientes con diabetes tipo 1. Individualizar es la regla en el manejo de la diabetes desde hace unos años atrás, no es una receta a seguir y el juicio clínico tiene que estar presente ante todo a la hora de manejar el paciente con esta enfermedad crónica para mejorar su calidad de vida. No nos olvidemos que el tratamiento de la diabetes es un equipo multidisciplinario que incluye al clínico, nutrición, actividad física, farmacoterapia y sobretodo educación. Referencias:

American Diabetes Association Standards of Care in Diabetes 2019. Diabetes Care Vol 42, Supp 1, January 2019. (Online First) Davies, MJ, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensusreportbythe ADA and the EASD. Diabetes Care 2018; 41: 2669-2701 Bruce Neal, M.B., et al. Canagliflozin and Cardiovascular and Renal Events in T2D. NEJM Aug 17, 2017 ;377;7: 644-657 Zinman B., et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in T2D. NEJM 2015; 373:2117-2128 Wanner C., et al. Empagliflozin and Progression of KidneyDisease in T2D. NEJM 2016; 375: 323-334 Marso S.P., et al. Liraglutide and Cardiovascular Outcomes in T2D. NEJM 2017; 375: 311-322 Mann J.F.E., et al. Liraglutide and Renal Outcomes in T2D. NEJM2017; 377: 839-848

Revista Puertorriqueña de Medicina y Salúd Pública

FOR THE TREATMENT OF SCHIZOPHRENIA IN ADULTS

Tanara

INVEGA TRINZA® patient

Tanara is a real patient living with schizophrenia. Individual experience may vary.

Help Patients Progress Through Their Treatment Journey To the Longest Dosing Interval Available 2

Learn more at invegatrinzahcp.com INDICATIONS INVEGA TRINZA® (paliperidone palmitate) a 3-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA® (1-month paliperidone palmitate) for at least four months. INVEGA SUSTENNA® (paliperidone palmitate) is an atypical antipsychotic indicated for the treatment of schizophrenia in adults. IMPORTANT SAFETY INFORMATION WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

See full Prescribing Information for complete Boxed Warning Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA SUSTENNA® and INVEGA TRINZA® are not approved for use in patients with dementia-related psychosis.

References: 1. INVEGA SUSTENNA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; July 2018. 2. INVEGA TRINZA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; July 2018.

Please refer to Brief Summary of Safety and Prescribing Information on adjacent pages.

IMPORTANT SAFETY INFORMATION (cont’d) Contraindications: INVEGA TRINZA® and INVEGA SUSTENNA® are contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of their formulation. Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementiarelated psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA®, or INVEGA TRINZA® in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including paliperidone. Clinical manifestations include muscle rigidity, fever, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems. QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

B:11.75”

T:11.5”

S:10.3667”

Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly female patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug. Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Orthostatic Hypotension and Syncope: INVEGA TRINZA® and INVEGA SUSTENNA® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA TRINZA® and INVEGA SUSTENNA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern. Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA TRINZA® and INVEGA SUSTENNA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA TRINZA® and INVEGA SUSTENNA®. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/ neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA TRINZA® and INVEGA SUSTENNA® at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA TRINZA® and INVEGA SUSTENNA® in patients with severe neutropenia (absolute neutrophil count <1000/ mm3) and follow their WBC until recovery. Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA TRINZA® and INVEGA SUSTENNA® elevate prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents. Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA TRINZA® and INVEGA SUSTENNA®. INVEGA TRINZA® and INVEGA SUSTENNA® have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA TRINZA® and INVEGA SUSTENNA® do not adversely affect them. Seizures: INVEGA TRINZA® and INVEGA SUSTENNA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older. Administration: For intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA TRINZA® or INVEGA SUSTENNA® kits. Care should be taken to avoid inadvertent injection into a blood vessel. Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA TRINZA® or INVEGA SUSTENNA®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets. Pregnancy/Nursing: INVEGA TRINZA® and INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA TRINZA® or INVEGA SUSTENNA®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA TRINZA® or INVEGA SUSTENNA® during pregnancy. INVEGA TRINZA® and INVEGA SUSTENNA® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA TRINZA® or INVEGA SUSTENNA® and any potential adverse effect on the breastfed infant from INVEGA TRINZA® or INVEGA SUSTENNA® or the mother’s underlying condition. Commonly Observed Adverse Reactions for INVEGA TRINZA®: The most common adverse reactions (incidence ≥5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia and parkinsonism. Commonly Observed Adverse Reactions for INVEGA SUSTENNA®: The most common adverse reactions in clinical trials in patients with schizophrenia (incidence ≥5% and occurring at least twice as often as placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder. cp-64206v1 Please see Brief Summary of Prescribing information on following pages. Before prescribing INVEGA TRINZA® please refer to the full Prescribing Information including Boxed WARNING. Please see full Prescribing Information, including Boxed WARNING for INVEGA SUSTENNA®, available at InvegaSustennahcp.com.

INVEGA TRINZA®

(paliperidone palmitate) extended-release injectable suspension, for intramuscular use Brief Summary BEFORE PRESCRIBING INVEGA TRINZA®, PLEASE SEE FULL PRESCRIBING INFORMATION, INCLUDING BOXED WARNING. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA TRINZA® is not approved for use in patients with dementia-related psychosis. [see Warnings and Precautions]. INDICATIONS AND USAGE INVEGA TRINZA® (paliperidone palmitate), a 3-month injection, is indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA® (1-month paliperidone palmitate extendedrelease injectable suspension) for at least four months [see Dosage and Administration (2.2) and Clinical Studies (14) in Full Prescribing Information]. CONTRAINDICATIONS INVEGA TRINZA® is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA TRINZA® formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone. WARNINGS AND PRECAUTIONS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drugtreated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA TRINZA® is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions]. Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. No studies have been conducted with oral paliperidone, the 1-month paliperidone palmitate extended-release injectable suspension, or INVEGA TRINZA® in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions]. Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. Consideration should be given to the long-acting

INVEGA TRINZA® (paliperidone palmitate) nature of INVEGA TRINZA®. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported. QT Prolongation Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. The effects of paliperidone on the QT interval were evaluated in a doubleblind, active-controlled (moxifloxacin 400 mg single dose), multicenter Thorough QT study with oral paliperidone in adult patients, and in four fixeddose efficacy studies and one maintenance study of the 1-month paliperidone palmitate injectable product. In the Thorough QT study (n=141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD (QT interval corrected for heart rate using the population specified linear derived method) of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate release (Cmax ss=113 ng/mL) was approximately 2-fold the exposure with the maximum recommended 819 mg dose of INVEGA TRINZA® administered in the deltoid muscle (predicted median Cmax ss=56 ng/mL). In this same study, a 4 mg dose of the immediaterelease oral formulation of paliperidone, for which Cmax ss=35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. In the four fixed-dose efficacy studies of the 1-month paliperidone palmitate injectable product, no subject had a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point. In the maintenance study, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett’s QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute. In the long-term maintenance trial of INVEGA TRINZA® in subjects with schizophrenia, an increase in QTcLD exceeding 60 msec was observed in 1 subject (< 1%) in the open-label phase, no subject had an increase in QTcLD exceeding 60 msec after treatment with INVEGA TRINZA® in the double-blind phase, and no subject had a QTcLD value of > 480 msec at any point in the study. Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon. There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown. Given these considerations, INVEGA TRINZA® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

INVEGA TRINZA® (paliperidone palmitate)

If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA TRINZA®, drug discontinuation should be considered. Consideration should be given to the long-acting nature of INVEGA TRINZA®. However, some patients may require treatment with INVEGA TRINZA® despite the presence of the syndrome. Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials. Hyperglycemia and diabetes have been reported in trial subjects treated with INVEGA TRINZA®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Data from the long-term maintenance trial with INVEGA TRINZA® in subjects with schizophrenia are presented in Table 1.

Table 2. Change in Fasting Lipids from the Long-Term Maintenance Trial with INVEGA TRINZA® in Subjects with Schizophrenia

Table 1. Change in Fasting Glucose from the Long-Term Maintenance Trial with INVEGA TRINZA® in Subjects with Schizophrenia

Serum Glucose Change from baseline

Serum Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) a

Double-Blind Phase Open-Label (relative to Phase double-blind baseline) (relative to open-label baseline) Paliperidone Placebo INVEGA TRINZA® Palmitatea Mean change from baseline (mg/dL) n=397 n=120 n=138 1.2 -1.6 -1.2 Proportion of Patients with Shifts n=397 n=128 n=148 2.3% 2.3% 4.1% (9/397)

(3/128)

(6/148)

Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Data from the long-term maintenance trial with INVEGA TRINZA® in subjects with schizophrenia are presented in Table 2.

Cholesterol Change from baseline LDL Change from baseline HDL Change from baseline Triglycerides Change from baseline

Double-Blind Phase Open-Label (relative to Phase double-blind baseline) (relative to open-label baseline) Paliperidone Placebo INVEGA TRINZA® Palmitatea Mean change from baseline (mg/dL) n=400 n=120 n=138 0.5 -0.4 0.9 n=396 n=119 n=138 1.1 -0.4 1.1 n=397 n=119 n=138 -0.2 -0.5 -1.3 n=400 n=120 n=138 0.1 -2.0 5.1 Proportion of Patients with Shifts 2.0% 3.9% 1.4%

Cholesterol Normal to High (<200 mg/dL to (8/400) (5/128) (2/148) ≥240 mg/dL) LDL Normal to High 0.3% 0.8% 0% (<100 mg/dL to (1/396) (1/127) (0/148) ≥160 mg/dL) HDL Normal to Low 8.6% 9.4% 13.5% (34/397) (12/127) (20/148) (≥40 mg/dL to <40 mg/dL) Triglycerides Normal 4.5% 1.6% 8.1% to High (<150 mg/dL to (18/400) (2/128) (12/148) ≥200 mg/dL) a During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® [see Clinical Studies (14) in Full Prescribing Information]. Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the long-term maintenance trial with INVEGA TRINZA® in subjects with schizophrenia are presented in Table 3. Table 3. Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from the Long-Term Maintenance Trial with INVEGA TRINZA® in Subjects with Schizophrenia Open-Label Phase (relative to open-label baseline) Paliperidone Palmitatea n=466 1.42

Double-Blind Phase (relative to double-blind baseline) Placebo

INVEGA TRINZA®

n=142 n=157 -1.28 0.94 Weight (kg) Change from baseline 15.2% 0.7% 9.6% Weight Gain ≥ 7% increase from baseline a During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® [see Clinical Studies (14) in Full Prescribing Information]. Orthostatic Hypotension and Syncope Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity. In the long-term maintenance trial, syncope was reported in < 1% (1/506) of subjects treated

INVEGA TRINZA® (paliperidone palmitate)

with the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase; there were no cases reported during the double-blind phase in either treatment group. In the long-term maintenance trial, orthostatic hypotension was reported as an adverse event by < 1% (1/506) of subjects treated with the 1-month paliperidone palmitate extended-release injectable suspension and < 1% (1/379) of subjects after receiving a single-dose of INVEGA TRINZA® during the open-label phase; there were no cases reported during the double-blind phase in either treatment group. INVEGA TRINZA® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension. Falls Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA TRINZA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including INVEGA TRINZA®. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of druginduced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of INVEGA TRINZA® at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Discontinue INVEGA TRINZA® in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery. Hyperprolactinemia Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs. Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1) in Full Prescribing Information]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive. In a long-term maintenance trial of INVEGA TRINZA®, elevations of prolactin to above the reference range (>13.13 ng/mL in males and >26.72 ng/mL in females) relative to open-label baseline at any time during the double-blind phase were noted in a higher percentage of males in the INVEGA TRINZA® group than in the placebo group (46% vs. 25%) and in a higher percentage of females in the INVEGA TRINZA® group than in the placebo group (32% vs. 15%). During the double-blind phase, 1 female (2.4%) in the INVEGA TRINZA® group experienced an adverse reaction of amenorrhea, while no potentially prolactin-related adverse reactions were noted among females in the placebo group. There were no potentially prolactin-related adverse reactions among males in either group.

Prior to the double-blind phase (during the 29-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline in males (N=368) were 17.1 (13.55) ng/mL and 51.6 (40.85) ng/mL in females (N=122). Twelve weeks after a single injection of INVEGA TRINZA® at the end of the open-label phase, mean (SD) prolactin values were 25.8 (13.49) ng/mL in males (N=322) and 70.6 (40.23) ng/mL in females (N=107). During the open-label phases 27% of females and 42% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (7.9% vs. 3.7%). Amenorrhea (4.7%) and galactorrhea (3.1%) were the most commonly observed (≥3%) potentially prolactin-related adverse reactions in females. Among males in the open-label phase, no potentially prolactin-related adverse reaction was observed with a rate greater than 3%. Potential for Cognitive and Motor Impairment Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA TRINZA® [see Adverse Reactions]. Antipsychotics, including INVEGA TRINZA®, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them. Seizures In the long-term maintenance trial there were no reports of seizures or convulsions. In the pivotal clinical studies with the 1-month paliperidone palmitate extended-release injectable suspension which included four fixeddose, double-blind, placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with the 1-month injection experienced an adverse event of convulsion compared with <1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion. Like other antipsychotic drugs, INVEGA TRINZA® should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older. Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. INVEGA TRINZA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Priapism Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with INVEGA TRINZA®, priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention. Disruption of Body Temperature Regulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA TRINZA® to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions] • Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions] • Neuroleptic malignant syndrome [see Warnings and Precautions] • QT prolongation [see Warnings and Precautions] • Tardive dyskinesia [see Warnings and Precautions] • Metabolic changes [see Warnings and Precautions] • Orthostatic hypotension and syncope [see Warnings and Precautions] • Falls [see Warnings and Precautions] • Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions] • Hyperprolactinemia [see Warnings and Precautions] • Potential for cognitive and motor impairment [see Warnings and Precautions] • Seizures [see Warnings and Precautions] • Dysphagia [see Warnings and Precautions] • Priapism [see Warnings and Precautions] • Disruption of body temperature regulation [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.

INVEGA TRINZA® (paliperidone palmitate)

Patient Exposure The data described in this section include data from two clinical trials. One is a long-term maintenance trial, in which 506 subjects with schizophrenia received several doses of the 1-month paliperidone palmitate extendedrelease injectable suspension during the open-label phase, of which 379 subjects continued to receive a single injection of INVEGA TRINZA® during the open-label phase, and 160 subjects were subsequently randomized to receive at least one dose of INVEGA TRINZA® and 145 subjects received placebo during the double-blind placebo-controlled phase. The mean (SD) duration of exposure during the double-blind phase was 150 (79) days in the placebo group and 175 (90) days in the INVEGA TRINZA® group. The other is a Phase 1 study (N=308), which included patients with schizophrenia who received a single injection of INVEGA TRINZA® concomitantly with other oral antipsychotics. Adverse Reactions in a Double-Blind, Placebo-Controlled (Long-Term Maintenance) Clinical Trial Commonly Observed Adverse Reactions: The most common adverse reactions (incidence at least 5% in the open-label phase, or in the INVEGA TRINZA® group and at least twice the incidence in the placebo group during the double-blind phase) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism. Discontinuation of Treatment Due to Adverse Events: The percentages of subjects who discontinued due to adverse events in the long-term maintenance trial were 5.1% during the open-label phase. During the doubleblind phase, no INVEGA TRINZA®-treated subject and one placebo-treated subject discontinued due to adverse events. Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA TRINZA®-Treated Patients: The safety profile of INVEGA TRINZA® was similar to that seen with the 1-month paliperidone extended-release injectable suspension. Table 4 lists the adverse reactions reported in a longterm maintenance trial in subjects with schizophrenia.

Demographic Differences An examination of population subgroups in the long-term maintenance trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects 65 years of age and older. Extrapyramidal Symptoms (EPS) Data from the long-term maintenance trial provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 5), and (5) incidence of spontaneous reports of EPS (Table 6).

Table 4. Incidences of Adverse Reactions 2% or More of INVEGA TRINZA®-Treated Patients (and Greater than Placebo) for the Open-Label and Double-Blind Phases of a Long-Term Maintenance Trial in Patients with Schizophrenia --- Open Label--- ------- Double Blind -------Placebo INVEGA TRINZA® Paliperidone Palmitatea System Organ Class (N=506) (N=145) (N=160) Adverse Reactionb %c %c %c General disorders and administration site conditions Injection site reaction 12 0 3 Infections and infestations Upper respiratory tract 5 4 10 infection Urinary tract infection <1 1 3 Metabolism and nutrition disorders Weight increased 10 3 9 Nervous system disorders Akathisia 5 2 5 Headache 7 4 9 Parkinsonism 5 0 4 Table includes adverse reactions that were reported in 2% or more of subjects in the INVEGA TRINZA® group during the double-blind phase and which occurred at greater incidence than in the placebo group. a During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® prior to randomization to either placebo or INVEGA TRINZA® in the subsequent double-blind phase [see Clinical Studies (14) in Full Prescribing Information]. b The following terms were combined: Injection site reaction includes Injection site reaction, Injection site erythema, Injection site extravasation, Injection site induration, Injection site inflammation, Injection site mass, Injection site nodule, Injection site pain, Injection site swelling. Weight increased includes Weight increased, Waist circumference increased. Upper respiratory tract infection includes Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis. Akathisia includes Akathisia, Restlessness. Parkinsonism includes Parkinsonism, Cogwheel rigidity, Drooling, Extrapyramidal disorder, Hypokinesia, Muscle rigidity, Muscle tightness, Musculoskeletal stiffness, Salivary hypersecretion. c Incidence is based on the number of subjects experiencing at least one adverse event, not the number of events.

Table 5. Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication Percentage of Subjects Open-label Double-blind Phase Phase Paliperidone Placebo INVEGA TRINZA® Palmitatea (N=506) (N=145) (N=160) Scale % % % 6 3 6 Parkinsonismb Akathisiac 3 1 4 Dyskinesiad 1 3 3 11 9 11 Use of Anticholinergic Medicationse a

During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® [see Clinical Studies (14) in Full Prescribing Information]. b For Parkinsonism, percent of subjects with Simpson-Angus Total score > 0.3 at any time (Global score defined as total sum of items score divided by the number of items) c For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score ≥ 2 at any time d For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Movement Scale at any time e Percent of subjects who received anticholinergic medications to treat EPS Table 6. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term Percentage of Subjects Open-label Double-blind Phase Phase Paliperidone Placebo INVEGA TRINZA® Palmitatea (N=506) (N=145) (N=160) EPS Group % % % 10 3 8 Overall percentage of subjects with EPS-related adverse events Parkinsonism 4 0 4 Hyperkinesia 5 2 5 Tremor 2 0 1 Dyskinesia <1 1 1 Dystonia 1 0 1 a During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® [see Clinical Studies (14) in Full Prescribing Information]. Parkinsonism group includes: Cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonism Hyperkinesia group includes: Akathisia, restlessness Dystonia group includes: Blepharospasm, dystonia, muscle spasms After injection of INVEGA TRINZA® in the open-label phase, 12 (3.2%) subjects had EPS that were new or worsened in severity, with events under the groupings of hyperkinesia (1.6%) and parkinsonism (1.3%) being the most common. After injection of INVEGA TRINZA® in the open-label or double-blind phases, one subject discontinued from the open-label phase due to restlessness.

INVEGA TRINZA® (paliperidone palmitate)

An examination of the time to EPS during the double-blind phase showed no clustering of these events at visits that would be expected to correspond to median peak plasma concentrations of paliperidone for subjects randomized to INVEGA TRINZA®. Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Pain Assessment and Local Injection Site Reactions Investigator ratings of injection site. Redness and swelling were observed in 2% or less of subjects in the INVEGA TRINZA® and placebo groups during the double-blind phase of the long-term maintenance study, and were rated mild based on investigator ratings using a 4-point scale (0=absent; 1=mild; 2=moderate; 3=severe). There were no reports of induration in either group during the double-blind phase, and no subjects discontinued due to INVEGA TRINZA® injection. Subject ratings of injection site pain. Subject evaluations of injection pain during the double-blind phase also were similar for placebo and INVEGA TRINZA®. Subject ratings of injection site pain in the single-dose Phase 1 study allowed for assessment of the temporal course of injection site pain. Residual injection pain peaked 1 or 6 hours after injection, and trended downward 3 days after the injection. Deltoid injections were numerically more painful than gluteal injections, although most pain ratings were below 10 mm on a 100-mm scale. Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA TRINZA® The following additional adverse reactions were identified in the long-term maintenance trial. The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) occurred at an incidence lower than that of placebo-treated patients. Cardiac disorders: tachycardia Gastrointestinal disorders: nausea, vomiting Metabolism and nutrition disorders: hyperinsulinemia Psychiatric disorders: anxiety Additional Adverse Reactions Reported in Clinical Trials with the 1-Month Paliperidone Palmitate Extended-Release Injectable Suspension The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month paliperidone palmitate extended-release injectable suspension: Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome Ear and labyrinth disorders: vertigo Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred Gastrointestinal disorders: abdominal discomfort/abdominal pain upper, diarrhea, dry mouth, toothache General disorders and administration site conditions: asthenia, fatigue Immune system disorders: hypersensitivity Investigations: electrocardiogram abnormal Metabolism and nutrition disorders: decreased appetite, increased appetite Musculoskeletal and connective tissue disorders: back pain, myalgia, pain in extremity, joint stiffness, muscle spasms, muscle twitching, nuchal rigidity Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness, dizziness postural, dysarthria, hypertonia, lethargy, oromandibular dystonia, psychomotor hyperactivity, syncope Psychiatric disorders: agitation, nightmare Reproductive system and breast disorders: breast discharge, erectile dysfunction, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction Respiratory, thoracic and mediastinal disorders: cough Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria Vascular disorders: hypertension

Cardiac disorders: bundle branch block left, sinus arrhythmia Gastrointestinal disorders: abdominal pain, constipation, flatulence, small intestinal obstruction General disorders and administration site conditions: edema, edema peripheral Immune system disorders: anaphylactic reaction Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, torticollis, trismus Nervous system disorders: grand mal convulsion, parkinsonian gait, transient ischemic attack Psychiatric disorders: sleep disorder Reproductive system and breast disorders: breast engorgement, breast tenderness/breast pain, retrograde ejaculation Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration Skin and subcutaneous tissue disorders: rash papular Vascular disorders: hypotension, ischemia Postmarketing Experience The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were 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: angioedema, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention. Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone. Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions sections of the package inserts for those products.

Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:

DRUG INTERACTIONS Drugs Having Clinically Important Interactions with INVEGA TRINZA® Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3) in Full Prescribing Information], results from studies with oral paliperidone should be taken into consideration when assessing drugdrug interaction potential. In addition, consider the 3-month dosing interval and long half-life of INVEGA TRINZA® [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 7. Clinically Important Drug Interactions with INVEGA TRINZA® Concomitant Drug Name or Drug Class Drugs with Potential for Inducing Orthostatic Hypotension

Strong Inducers of CYP3A4 and P-gp (e.g., carbamazepine, rifampin, or St. John’s Wort)

Levodopa and Other Dopamine Agonists

Clinical Rationale

Clinical Recommendation

Because INVEGA TRINZA® has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA TRINZA® is administered with other therapeutic agents that have this potential [see Warnings and Precautions]. The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions].

Paliperidone may antagonize the effect of levodopa and other dopamine agonists.

Avoid using CYP3A4 and/or P-gp inducers with INVEGA TRINZA® during the 3-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets [see Dosage and Administration (2.7) in Full Prescribing Information]. Monitor and manage patient as clinically appropriate.

INVEGA TRINZA® (paliperidone palmitate)

Drugs Having No Clinically Important Interactions with INVEGA TRINZA® Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA TRINZA® is required when administered concomitantly with valproate [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA TRINZA® [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Pharmacokinetic interaction between lithium and INVEGA TRINZA® is unlikely. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data No developmental toxicity studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with 1-month paliperidone palmitate extendedrelease injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 3 times the MRHD of 819 mg of the 3-month paliperidone palmitate extended-release injectable suspension based on mg/m2 body surface area. In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m2 body surface area; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/ m2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed. In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL® package insert). Lactation Risk Summary Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone’s parent compound, risperidone (see Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of INVEGA TRINZA®, and the clinical significance on the breastfed infant is not known [see Clinical Pharmacology (12.3) in Full Prescribing Information]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA TRINZA® and any potential adverse effects on the breastfed child from INVEGA TRINZA® or from the mother’s underlying condition. Clinical Considerations Infants exposed to INVEGA TRINZA® through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with INVEGA TRINZA® may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA TRINZA®, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-andresearch-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA TRINZA® during pregnancy (see Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of INVEGA TRINZA® [see Clinical Pharmacology (12.3) in Full Prescribing Information], and the clinical significance of INVEGA TRINZA® administered before pregnancy or anytime during pregnancy is not known. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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. In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone based on mg/m2 body surface area. There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based on mg/m2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data). Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including INVEGA TRINZA®, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective

Pediatric Use Safety and effectiveness of INVEGA TRINZA® in patients less than 18 years of age have not been established. Use of INVEGA TRINZA® is not recommended in pediatric patients because of the potential longer duration of an adverse event compared to shorter-acting products. In clinical trials of oral paliperidone, there were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies.

INVEGA TRINZA® (paliperidone palmitate)

Juvenile Animal Studies No juvenile animal studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2-3 times those in adolescents. Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period. The long-term effects of INVEGA TRINZA® on growth and sexual maturation have not been fully evaluated in children and adolescents.

symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone. Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert. Management of Overdosage Contact a Certified Poison Control Center for the most up to date information on the management of paliperidone and INVEGA TRINZA® overdosage (1-800-222-1222 or www.poison.org). Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to paliperidone. Consider the prolonged-release characteristics of INVEGA TRINZA® and the long apparent half-life of paliperidone when assessing treatment needs and recovery.

Geriatric Use Clinical studies of INVEGA TRINZA® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information], who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, monitor renal function and adjust dosage [see Dosage and Administration (2.5) in Full Prescribing Information]. Renal Impairment Use of INVEGA TRINZA® is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Use of INVEGA TRINZA® in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min) is based on the previous dose of the 1-month paliperidone palmitate extended-release injectable suspension that the patient was stabilized on prior to initiation of INVEGA TRINZA® [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Hepatic Impairment INVEGA TRINZA® has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Patients with Parkinson’s Disease or Lewy Body Dementia Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased sensitivity to INVEGA TRINZA®. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome. DRUG ABUSE AND DEPENDENCE Controlled Substance INVEGA TRINZA® (paliperidone) is not a controlled substance. Abuse Paliperidone has not been systematically studied in animals or humans for its potential for abuse. Dependence Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence. OVERDOSAGE Human Experience No cases of overdose were reported in premarketing studies with paliperidone palmitate injection. Because INVEGA TRINZA® is to be administered by health care professionals, the potential for overdosage by patients is low. While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and

INVEGA TRINZA® (paliperidone palmitate) Extended-Release Injectable Suspension Product of Ireland Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 © 2015 Janssen Pharmaceutical Companies cp-64092v1

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NOW APPROVED

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

INDICATION SYMTUZA™ is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults: • who have no prior antiretroviral treatment history or • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

IMPORTANT SAFETY INFORMATION BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

• Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of SYMTUZA™. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA™. If appropriate, anti-hepatitis B therapy may be warranted.

CONTRAINDICATIONS

• Do not coadminister SYMTUZA™ and the following drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect: alfuzosin, carbamazepine, cisapride, colchicine (in patients with renal and/or hepatic impairment), dronedarone, elbasvir/grazoprevir, ergot derivatives (such as: dihydroergotamine, ergotamine, methylergonovine), lovastatin, lurasidone, oral midazolam, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam.

WARNINGS AND PRECAUTIONS

• Severe Acute Exacerbation of Hepatitis B in Patients Coinfected With HIV-1 and HBV: Patients with HIV-1 should be tested for the presence of chronic HBV before initiating antiretroviral therapy. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA™. Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA™ should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING, on the following pages.

Start With the Protective Barrier of Darunavir treatment-emergent darunavir, primary PI or TAF mutations across clinical trial populations1*†‡§

• Only 1 patient receiving SYMTUZA™ was found to have M184I/V 2¶

IMPORTANT SAFETY INFORMATION (cont) • Hepatotoxicity: Drug-induced hepatitis and cases of liver injury, including some fatalities, have been reported in patients receiving darunavir, a component of SYMTUZA™. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions.

Appropriate laboratory testing should be conducted prior to initiating and during therapy with SYMTUZA™. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA™.

• Severe Skin Reactions: In patients receiving darunavir, a component of SYMTUZA™, severe skin reactions may occur. StevensJohnson syndrome was reported with darunavir coadministered with cobicistat in clinical trials at a rate of 0.1%. During darunavir postmarketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported.

Discontinue SYMTUZA™ immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING, on the following pages. *AMBER was a Phase 3, randomized, double-blind, active-controlled, international, multicenter, noninferiority study assessing the efficacy and safety of once-daily SYMTUZA™ (DRV 800 mg/ COBI 150 mg/FTC 200 mg/TAF 10 mg) vs DRV/COBI + FTC/TDF in treatment-naïve adults (N=725). Primary endpoint was the proportion of patients with VL <50 copies/mL at 48 weeks (noninferiority margin 10% by FDA Snapshot).1,2 EMERALD was a Phase 3, randomized, open-label, international, multicenter, noninferiority study of switching to SYMTUZA™ (DRV 800 mg/COBI 150 mg/FTC 200 mg/TAF 10 mg) vs continuing on bPI + FTC/TDF therapy in treatment-experienced adults who had been on therapy for ≥6 months with no history of virologic failure on darunavir-based regimens, and who were virologically suppressed prior to and at screening (N=1141). Primary endpoint was the proportion of patients with virologic rebound at Week 48 (noninferiority margin 4%), and a key secondary endpoint was the proportion of subjects who have VL <50 copies/mL at 48 weeks.1,3

†

‡

In the AMBER trial, of 362 treatment-naïve patients taking SYMTUZA™, 8 met the criteria for virologic failure and 7 patients experiencing virologic failure were analyzed for resistance.1,2

In the EMERALD trial, of 763 virologically suppressed patients taking SYMTUZA™, 6 met the criteria for virologic failure and 1 patient experiencing virologic failure was analyzed for resistance.1,3

This patient also had a transmitted K103N mutation at screening. M184V was detected pretreatment by deep sequencing (Illumina MiSeq) as a minority variant (9.4%).2

bPI=boosted protease inhibitor; COBI=cobicistat; DRV=darunavir; FTC=emtricitabine; PI=protease inhibitor; TAF=tenofovir alafenamide; TDF=tenofovir disoproxil fumarate; VL=viral load.

Formulated for Improved Tolerability SYMTUZA™ demonstrated a favorable tolerability profile vs control arm in treatment-naïve patients1

of treatment-naïve subjects discontinued due to adverse events in the SYMTUZA™ arm vs 4% in the control arm1

• The most common adverse reactions occurring in ≥2% of treatmentnaïve patients were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and ﬂatulence1 • This is not a complete list of adverse reactions. Please refer to the full Prescribing Information for more information

IMPORTANT SAFETY INFORMATION (cont) • Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant

use of SYMTUZA™ and other drugs may result in known or potentially significant drug interactions, some of which may lead to the loss of therapeutic effect of SYMTUZA™ and possible development of resistance or possible clinically significant adverse reactions from greater exposures of concomitant drugs.

Consult the full Prescribing Information for potential drug interactions prior to and during SYMTUZA™ therapy, review concomitant medications during SYMTUZA™ therapy, and monitor for the adverse reactions associated with concomitant medications.

• Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, had been reported in patients treated with combination antiretroviral therapy.

• New Onset or Worsening Renal Impairment: Renal impairment, including cases of acute renal failure and Fanconi

syndrome, has been reported with the use of tenofovir prodrugs. SYMTUZA™ is not recommended in patients with creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including nonsteroidal anti-inﬂ ammatory drugs are at increased risk of developing renal-related adverse reactions. In all patients, monitor serum creatinine, creatinine clearance, urine glucose, and urine protein prior to or when initiating SYMTUZA™ and during therapy. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue SYMTUZA™ in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

• Sulfa Allergy: Monitor patients with a known sulfonamide allergy after initiating SYMTUZA™. • Lactic Acidosis/Severe Hepatomegaly With Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA™, and tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, alone or in combination with other antiretrovirals. Discontinue SYMTUZA™ in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING, on the following pages.

91% Virologic Response Achieved in Treatment-Naïve Patients 1

% of Patients Achieving Virologic Response (VL <50 copies/mL)

100

Control=DRV/c + FTC/TDF.

‡

Included subjects who had ≥50 copies/mL in the Week 48 window (days 295-378); subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL. CD4+=cluster of differentiation 4; DRV/c=darunavir/cobicistat; FTC/TDF=emtricitabine/tenofovir disoproxil fumarate; MH=Mantel-Haenszel; VL=viral load.

of patients treated with SYMTUZA™ had

at Week 48 (<50 copies/mL)*

undetectable VLs (n=362)

(n=363)

SYMTUZA™

Control†

• 4% virologic failure rate in the SYMTUZA™ arm vs 3% in the control arm1‡ 100

91% 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)

†

88%

*Based on stratum adjusted MH test where stratification factors are HIV-1 RNA level (≤100,000 or >100,000 copies/mL) and CD4+ cell count (<200 or ≥200 cells/µL).

91%

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.

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

USE IN SPECIFIC POPULATIONS • Pregnancy: SYMTUZA™ is not recommended for use during pregnancy because of substantially lower exposures of darunavir and

SYMTUZA™

(darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use Brief Summary of Prescribing Information. For complete prescribing information, please consult official package insert. WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of SYMTUZA. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions]. INDICATIONS AND USAGE SYMTUZA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults: • who have no prior antiretroviral treatment history or • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. DOSAGE AND ADMINISTRATION Testing Prior to Initiation of SYMTUZA Prior to or when initiating SYMTUZA, test patients for hepatitis B (HBV) virus infection [see Warnings and Precautions]. Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions]. Recommended Dosage SYMTUZA is a four-drug fixed dose combination product containing 800 mg of darunavir (DRV), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of SYMTUZA is one tablet taken orally once daily with food in adults. For patients who are unable to swallow the whole tablet, SYMTUZA may be split into two pieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Not Recommended in Patients with Severe Renal Impairment SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute [see Use in Specific Populations]. Not Recommended in Patients with Severe Hepatic Impairment SYMTUZA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations]. Not Recommended During Pregnancy SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy [see Use in Specific Populations and Clinical Pharmacology (12.3) in Full Prescribing Information]. SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with SYMTUZA. DOSAGE FORMS AND STRENGTHS Each SYMTUZA tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine (FTC), and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide (TAF). The yellow to yellowish-brown, capsule-shaped, film-coated tablet is debossed with “8121” on one side and “JG” on the other side. CONTRAINDICATIONS SYMTUZA is contraindicated with the following co-administered drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions]. • Alpha 1-adrenoreceptor antagonist: alfuzosin • Antianginal: ranolazine • Antiarrhythmic: dronedarone • Anticonvulsants: carbamazepine, phenobarbital, phenytoin • Anti-gout: colchicine, in patients with renal and/or hepatic impairment • Antimycobacterial: rifampin • Antipsychotics: lurasidone, pimozide • Ergot derivatives, e.g., dihydroergotamine, ergotamine, methylergonovine • GI motility agent: cisapride • Herbal product: St. John’s wort (Hypericum perforatum) • Hepatitis C direct acting antiviral: elbasvir/grazoprevir • HMG-CoA reductase inhibitors: lovastatin, simvastatin • PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension • Sedatives/hypnotics: orally administered midazolam, triazolam

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets WARNINGS AND PRECAUTIONS Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy [see Dosage and Administration]. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA. Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir, a component of SYMTUZA. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse reactions. Post-marketing cases of liver injury, including some fatalities, have been reported with darunavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with SYMTUZA and patients should be monitored during treatment as clinically appropriate. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of SYMTUZA treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA. Severe Skin Reactions In patients receiving darunavir, a component of SYMTUZA, severe skin reactions may occur. These include conditions accompanied by fever and/or elevations of transaminases. Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%. During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported. Discontinue SYMTUZA immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia. Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with SYMTUZA in the AMBER trial [see Adverse Reactions]. Rash events were mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using SYMTUZA was 2%. Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of SYMTUZA and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications and Drug Interactions]: • Loss of therapeutic effect of SYMTUZA and possible development of resistance. • Possible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during SYMTUZA therapy; review concomitant medications during SYMTUZA therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications and Drug Interactions]. When used with concomitant medications, SYMTUZA, which contains darunavir boosted with cobicistat, may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain SYMTUZA interactions [see Drug Interactions and Clinical Pharmacology (12.3) in Full Prescribing Information]. Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and GuillainBarré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment. New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of SYMTUZA, there were no cases of proximal renal tubulopathy (PRT), including Fanconi syndrome, reported in the SYMTUZA group through Week 48. SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions. Prior to or when initiating SYMTUZA and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue SYMTUZA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Cobicistat, a component of SYMTUZA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating SYMTUZA, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety. Sulfa Allergy Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating SYMTUZA. In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy. Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with SYMTUZA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established. Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors (PIs). In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established. ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Severe acute exacerbations of hepatitis B [see Warnings and Precautions] • Hepatotoxicity [see Warnings and Precautions] • Severe skin reactions [see Warnings and Precautions]

• Immune reconstitution syndrome [see Warnings and Precautions] • New onset or worsening renal impairment [see Warnings and Precautions] • Lactic acidosis/severe hepatomegaly with steatosis [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults with No Prior Antiretroviral Treatment History The safety profile of SYMTUZA in HIV-1 infected adults with no prior antiretroviral treatment history is based on Week 48 data from the AMBER trial, a randomized, double-blind, active-controlled trial where a total of 362 subjects received SYMTUZA once daily and 363 subjects received a combination of PREZCOBIX® (fixed-dose combination of darunavir and cobicistat) and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). The proportion of subjects who discontinued treatment with SYMTUZA or PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4% respectively. An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX and F/TDF are presented in Table 3. Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade 3 reaction was reported and no grade 4 adverse reactions were reported during treatment with SYMTUZA. Table 1: Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA PREZCOBIX+FTC/TDF (N=362) (N=363) All At least All At least Grades Grade 2 Grades Grade 2 Diarrhea 9% 2% 11% 2% Rasha 8% 4% 7% 5% Nausea 6% 1% 10% 3% Fatigue 4% 1% 4% 1% Headache 3% 1% 2% 1% Abdominal discomfort 2% 4% <1% Flatulence 2% <1% 1% a Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria Adverse Reactions in Virologically-Suppressed Adults The safety profile of SYMTUZA in virologically-suppressed HIV-1 infected adults is based on Week 48 data from 1,141 subjects in the EMERALD trial, a randomized, open-label, active-controlled trial where 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with FTC and TDF switched to SYMTUZA, and 378 subjects who continued their treatment regimen of a boosted protease inhibitor with FTC and TDF. Overall, the safety profile of SYMTUZA in subjects in this study was similar to that in subjects with no prior antiretroviral treatment history. The proportion of subjects who discontinued treatment with SYMTUZA due to adverse events, regardless of severity, was 1%. Less Frequent Adverse Reactions The following adverse reactions occurred in less than 2% of adults with no antiretroviral treatment history or virologically suppressed subjects receiving SYMTUZA, or are from studies described in the prescribing information of the individual component PREZISTA (darunavir). Gastrointestinal Disorders: dyspepsia, pancreatitis (acute), vomiting Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, StevensJohnson syndrome Metabolism and Nutrition Disorders: anorexia, diabetes mellitus, lipodystrophy Reproductive system and Breast disorders: gynecomastia Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis Psychiatric Disorders: abnormal dreams Immune System Disorders: (drug) hypersensitivity, immune reconstitution inflammatory syndrome Hepatobiliary Disorders: acute hepatitis

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Laboratory Abnormalities

In the EMERALD trial which had 1,141 virologically-suppressed adults treated with an HIV protease inhibitor and TDF containing regimen with a median baseline eGFR of 104 mL/min (SYMTUZA) and 103 mL/min (bPI+FTC/ TDF) who were randomized to continue their treatment regimen or switch to SYMTUZA, at Week 48, mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to SYMTUZA. Mean (SD) serum creatinine was 0.98 (0.18) mg/dL (SYMTUZA) and 0.98 (0.19) mg/dL (bPI+FTC/TDF) at baseline and 0.99 (0.18) mg/dL (SYMTUZA) and 0.99 (0.21) mg/dL (bPI+FTC/TDF) at Week 48. Median serum creatinine was 0.97 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at baseline and 1.0 mg/dL (SYMTUZA) and 0.97 mg/dL (bPI+FTC/TDF) at Week 48. Median UPCR was 62 mg per gram (SYMTUZA) and 63 mg/g (bPI+FTC/TDF) at baseline and 37 mg per gram (SYMTUZA) and 53 mg/g (bPI+FTC/TDF) at Week 48. Bone Mineral Density AMBER The effects of SYMTUZA compared to PREZCOBIX + FTC/TDF on bone mineral density (BMD) change from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 48 was −0.7% with SYMTUZA compared to −2.4% with DRV/COBI + FTC/TDF at the lumbar spine and 0.2% compared to −2.7% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 16% of SYMTUZA subjects and 22% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 2% of SYMTUZA subjects and 15% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known. EMERALD In EMERALD, boosted Protease Inhibitor (bPI) and TDF-treated subjects were randomized to continue their TDF-based regimen or switch to SYMTUZA; changes in BMD from baseline to Week 48 were assessed by DXA. The mean percentage change in BMD from baseline to Week 48 was 1.5% with SYMTUZA compared to −0.6% with PREZCOBIX + FTC/TDF at the lumbar spine and 1.4% compared to -0.3% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of SYMTUZA subjects and 9% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by no SYMTUZA subjects and 2% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known. Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving a darunavir-containing regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Metabolism and Nutrition Disorders Redistribution of body fat Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors) Skin and Subcutaneous Tissue Disorders Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions]. DRUG INTERACTIONS Not Recommended With Other Antiretroviral Medications SYMTUZA is a complete regimen for HIV-1 infection and coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. For this reason, information regarding potential drugdrug interactions with other antiretroviral medications is not provided. Potential for SYMTUZA to Affect Other Drugs Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of SYMTUZA with drugs that are primarily metabolized by CYP3A and/or CYP2D6, or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events (see Table 4). Potential for Other Drugs to Affect SYMTUZA Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Co-administration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 4). Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF, which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit P-gp may increase the absorption and plasma concentrations of TAF (see Table 4).

Table 2: Laboratory Abnormalities (Grade 2-4) Reported in ≥2% of Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) Laboratory Parameter SYMTUZA Grade Limit N=362 Creatinine Grade 2 >1.3 to 1.8 x ULN 4% Grade 4 ≥3.5x ULN <1% Triglycerides Grade 2 301-500 mg/dL 7% Grade 3 501-1,000 mg/dL 1% Grade 4 > 1,000 mg/dL <1%% Total Cholesterol Grade 2 240-<300 mg/dL 17% Grade 3 >= 300 mg/dL 2% Low-Density Lipoprotein Cholesterol Grade 2 160-189 mg/dL 9% Grade 3 ≥ 190 mg/dL 5% Elevated Glucose Levels Grade 2 126-250 mg/dL 6% Grade 3 251-500 mg/dL <1%

PREZCOBIX+ FTC/TDF N=363 14% 0 4% 1% <1% 4% 1%

4% 1%

6% 0

ALT and/or AST elevations (Grade 2-4 combined) occurred in 2% of adult subjects receiving SYMTUZA with no antiretroviral treatment history in AMBER (Week 48 Analysis). Results were consistent in subjects receiving PREZCOBIX+FTC/TDF. Table 3: Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis)a SYMTUZA PREZCOBIX+FTC/TDF N=356 N=355 Baseline Week 48 Baseline Week 48 Meanb mg/dL Change mg/dL Change N=304c N=290 Total cholesterol 168 +30 164 +11 HDL cholesterol 45 +6 44 +2 LDL cholesterol 199 +19 98 +5 Triglycerides 117 +34 112 +21 Total cholesterol to 4.1 0.2 4.0 0.1 HDL ratio a Subjects on lipid-lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on PREZCOBIX+FTC/TDF). Subjects initiating a lipid-lowering agent postbaseline had their last fasted on-treatment value (prior to starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF). b The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the last value carried forward prior to initiating lipid-lowering agent post-baseline. c One subject did not have a Week 48 result for LDL cholesterol (n=303). The percentage of subjects starting any lipid lowering drug during treatment in the SYMTUZA and PREZCOBIX + FTC/TDF arm were 1.7% (n=6) and 0.6% (n=2), respectively. Renal Laboratory Tests In the AMBER trial, which had 670 adults with no prior antiretroviral treatment history with a median baseline eGFR of 119 mL/min (SYMTUZA) and 118 mL/min (PREZCOBIX + FTC/TDF), mean (SD) serum creatinine increased by 0.05 (0.10) mg/dL in the SYMTUZA group and by 0.09 (0.11) mg/dL in the PREZCOBIX + FTC/TDF group from baseline to Week 48. Median serum creatinine was 0.90 mg/dL (SYMTUZA) and 0.89 mg/ dL (PREZCOBIX + FTC/TDF) at baseline and 0.95 mg/dL (SYMTUZA) and 0.97 mg/dL (PREZCOBIX +FTC/TDF) at Week 48. Increases in serum creatinine occurred by Week 2 of treatment and remained stable. Median urine protein-to-creatinine ratio (UPCR) was 47 mg per gram (SYMTUZA) and 51 mg/g (PREZCOBIX + FTC/TDF) at baseline and 30 mg per gram (SYMTUZA) and 34 mg/g (PREZCOBIX + FTC/TDF) at Week 48.

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily excreted by the kidneys through glomerular filtration and active tubular secretion, co-administration of SYMTUZA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions]. Significant Drug Interactions Table 4 provides a listing of established or potentially clinically significant drug interactions with SYMTUZA and recommended steps to prevent or manage these interactions. These recommendations are based on drug interaction trials conducted with the components of SYMTUZA, as individual agents or in combination, or are predicted interactions. No drug interaction trials have been performed with SYMTUZA or with all the components administered together. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs. Table 4: Significant Drug Interactions: Concomitant Drug Class: Drug Name, Clinical Comment Alpha 1-adrenoreceptor antagonist: alfuzosin. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. Antianginal: ranolazine. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. Antiarrhythmics: dronedarone. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. other antiarrhythmics, e.g., amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine. Clinical monitoring is recommended upon co-administration with antiarrhythmics. digoxin. When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations. Antibacterials: clarithromycin, erythromycin, telithromycin. Consider alternative antibiotics with concomitant use of SYMTUZA. Anticancer agents: dasatinib, nilotinib. A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary when co-administered with SYMTUZA. Consult the dasatinib and nilotinib prescribing information for dosing instructions. vinblastine, vincristine. For vincristine and vinblastine, consider temporarily withholding the cobicistat-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when SYMTUZA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consider initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. Anticoagulants: Direct Oral Anticoagulants (DOACs). apixaban. Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with SYMTUZA depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. rivaroxaban. Coadministration of rivaroxaban with SYMTUZA is not recommended because it may lead to an increased bleeding risk. betrixaban, dabigatran, edoxaban. No dose adjustment is needed when betrixaban, dabigatran, or edoxaban is co-administered with SYMTUZA. warfarin. Monitor international normalized ratio (INR) upon co-administration of SYMTUZA with warfarin. Anticonvulsants: carbamazepine, phenobarbital, phenytoin. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g., eslicarbazepine, oxcarbazepine. Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If co-administration is necessary, monitor for lack or loss of virologic response. Anticonvulsants that are metabolized by CYP3A: e.g., clonazepam. Clinical monitoring of anticonvulsants is recommended. Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., paroxetine, sertraline. Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline. Other antidepressants: trazodone. When co-administering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended. Antifungals: itraconazole, ketoconazole, posaconazole. Monitor for increased darunavir or cobicistat adverse reactions. Specific dosing recommendations are not available for co-administration with itraconazole or ketoconazole. Monitor for increased itraconazole or ketoconazole adverse reactions. voriconazole. Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole.

Anti-gout: colchicine. Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or lifethreatening reactions. For patients without renal or hepatic impairment: • Treatment of gout flares – co-administration of colchicine: 0.6 mg (1 tablet) ×1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. • Prophylaxis of gout flares – co-administration of colchicine: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. • Treatment of familial Mediterranean fever – co-administration of colchicine: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimalarial: artemether/lumefantrine. Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation. Antimycobacterials: rifampin. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. rifabutin. Co-administration of SYMTUZA with rifabutin is not recommended. If the combination is needed, the recommended dose of rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis. rifapentine. Co-administration with rifapentine is not recommended. Antipsychotics: lurasidone. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. pimozide. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. other antipsychotics, e.g., perphenazine, risperidone, thioridazine. A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with SYMTUZA. quetiapine. Initiation of SYMTUZA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking SYMTUZA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. β-Blockers: e.g., carvedilol, metoprolol, timolol. Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized by CYP2D6. Calcium channel blockers: e.g., amlodipine, diltiazem, felodipine, nifedipine, verapamil. Clinical monitoring is recommended for co-administration with calcium channel blockers metabolized by CYP3A. Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone methylprednisolone, mometasone, triamcinolone. Co-administration with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to SYMTUZA. Consider alternative corticosteroids. Co-administration with corticosteroids of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use. Endothelin receptor antagonists: bosentan. Initiation of bosentan in patients taking SYMTUZA: In patients who have been receiving SYMTUZA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Initiation of SYMTUZA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of SYMTUZA. After at least 10 days following the initiation of SYMTUZA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Switching from darunavir co-administered with ritonavir to SYMTUZA in patients on bosentan: Maintain bosentan dose. Ergot derivatives: e.g., dihydroergotamine, ergotamine, methylergonovine. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI motility agent: cisapride. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir. Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations. simeprevir. Co-administration with simeprevir is not recommended. Herbal product: St. John’s wort (Hypericum perforatum). Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. HMG-CoA reductase inhibitors: lovastatin, simvastatin. Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

other HMG-CoA reductase inhibitors, e.g., atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin. For atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin, start with the lowest recommended dose and titrate while monitoring for safety. Dosage recommendations with atorvastatin or rosuvastatin are as follows: • atorvastatin dosage should not exceed 20 mg/day • rosuvastatin dosage should not exceed 20 mg/day Hormonal contraceptives: Additional or alternative (non-hormonal) forms of contraception should be considered when estrogen based contraceptives are coadministered with SYMTUZA. drosperinone/ethinylestradiol. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. other progestin/estrogen, contraceptives. No data are available to make recommendations on co-administration with oral or other hormonal contraceptives. Immunosuppressants: cyclosporine, sirolimus, tacrolimus. These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended with concomitant use. Immunosuppressant/neoplastic: everolimus. Co-administration of everolimus and SYMTUZA is not recommended. Inhaled beta agonist: salmeterol. Co-administration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Narcotic analgesics metabolized by CYP3A: e.g., fentanyl, oxycodone. Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. tramadol. A dose decrease may be needed for tramadol with concomitant use. Narcotic analgesic for treatment of opioid dependence: buprenorphine, buprenorphine/naloxone, methadone. Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking SYMTUZA: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of SYMTUZA in patients taking buprenorphine, buprenorphine/ naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms. Phosphodiesterase PDE-5 inhibitors: e.g., avanafil, sildenafil, tadalafil, vardenafil. Co-administration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established. Co-administration with PDE-5 inhibitors may result in an increase in PDE-5 inhibitor-associated adverse reactions including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). The following dose adjustments are recommended for use of tadalafil with SYMTUZA: • Initiation of tadalafil in patients taking SYMTUZA: In patients receiving SYMTUZA for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. • Initiation of SYMTUZA in patients taking tadalafil: Avoid use of tadalafil during the initiation of SYMTUZA. Stop tadalafil at least 24 hours prior to starting SYMTUZA. After at least one week following the initiation of SYMTUZA, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. • Patients switching from darunavir co-administered with ritonavir to SYMTUZA: Maintain tadalafil dose. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitorassociated adverse reactions. Platelet aggregation inhibitor: ticagrelor. Co-administration of SYMTUZA and ticagrelor is not recommended. Sedatives/hypnotics: orally administered midazolam, triazolam. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. metabolized by CYP3A: e.g., buspirone, diazepam, estazolam, zolpidem. With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions. parenterally administered midazolam. Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered. This table is not all inclusive

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SYMTUZA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of SYMTUZA in pregnant individuals from the APR to inform on a potential drug-associated risk of birth defects and miscarriage. Available data from the APR show no difference in rate of overall birth defects for darunavir and emtricitabine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates pregnant individuals and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. In animal reproduction studies, no adverse developmental effects were observed when the components of SYMTUZA were administered separately at darunavir exposures less than 1- (mice and rabbits) and 2.6-times (rats) higher, at cobicistat exposures 1.7- and 4.1-times higher (rats and rabbits respectively) at emtricitabine exposures 88- and 7.3- times higher (mice and rabbits, respectively), and tenofovir alafenamide exposures equal to or 85- times higher (rats and rabbits, respectively) than human exposures at the recommended daily dose of these components in SYMTUZA (see Data). No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.1 times the human exposure at the recommended therapeutic dose. Clinical Considerations Not Recommended During Pregnancy SYMTUZA is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy (see Data) and [see Clinical Pharmacology (12.3) in Full Prescribing Information]. SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with SYMTUZA. Data Human Data Darunavir/Cobicistat: Darunavir and cobicistat in combination with a background regimen was evaluated in a clinical trial of 7 pregnant individuals taking darunavir and cobicistat prior to enrollment and who were willing to remain on darunavir and cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals completed the trial. Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum [see Clinical Pharmacology (12.3) in Full Prescribing Information]. One out of 6 pregnant individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five pregnant individuals had sustained virologic response (HIV RNA <50 copies/mL) throughout the study period. There are no clinical data on the virologic response when darunavir and cobicistat are initiated during pregnancy. Darunavir: Based on prospective reports to the APR of 679 live births following exposure to darunavir-containing regimens during pregnancy (including 425 exposed in the first trimester and 254 exposed in the second/ third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.1% (95% CI: 1.0% to 4.0%) with first trimester exposure to darunavir containing-regimens and 2.4% (95% CI: 0.9% to 5.1%) with second/third trimester exposure to darunavircontaining regimens. Cobicistat: Insufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects. Emtricitabine: Based on prospective reports to the APR of 3749 exposures to emtricitabine-containing regimens during pregnancy (including 2614 exposed in the first trimester and 1135 exposed in the second/third trimester), there was no difference between emtricitabine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to emtricitabine-containing regimens and 2.1% (95% CI: 1.4% to 3.1%) with the second/third trimester exposure to emtricitabine-containing regimens.

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Tenofovir alafenamide: Insufficient numbers of pregnancies with exposure to tenofovir alafenamide have been reported to the APR to estimate the rate of birth defects. Animal Data Darunavir: Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (2.6-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended daily dose of darunavir in SYMTUZA. Cobicistat: Cobicistat was administered orally to pregnant rats at doses up to 125 mg/kg/day on GD 6-17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.7 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. In pregnant rabbits, cobicistat was administered orally at doses up to 100 mg/kg/day during GD 7-20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 4.1 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses up to 75 mg/kg from GD 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.1 times the human exposures at the recommended daily dose of cobicistat in SYMTUZA. Emtricitabine: Emtricitabine was administered orally to pregnant mice and rabbits (up to 1000 mg/kg/day) through organogenesis (on GD 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 88 times higher and in rabbits approximately 7.3 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA. In a pre/postnatal development study, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures of approximately 88 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA. Tenofovir Alafenamide (TAF): TAF was administered orally to pregnant rats (up to 250 mg/kg/day) and rabbits (up to 100 mg/kg/day) through organogenesis (on GD 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures approximately similar to (rats) and 85 times higher (rabbits) than the exposure in humans at the recommended daily dose. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 51 (rats) and 80 (rabbits) times higher than human tenofovir exposures at the recommended daily dose of TAF in SYMTUZA. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF (another prodrug of tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on GD 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposure in humans at the recommended daily dose of TDF. Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIVinfected mothers in the United States not to breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Based on published data, emtricitabine has been shown to be present in human breast milk. There are no data on the presence of darunavir, cobicistat, or TAF in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir and cobicistat are present in the milk of lactating rats. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF (see Data). Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infants, instruct mothers not to breastfeed if they are receiving SYMTUZA. Data Animal Data Darunavir: Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is excreted in milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 66% of those obtained in humans at the recommended clinical dose of darunavir with ritonavir.

Cobicistat: During the pre/postnatal developmental toxicology study, at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10. Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is excreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating rhesus monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure. Pediatric Use The safety and effectiveness of SYMTUZA in pediatric patients less than 18 years of age have not been established. Darunavir, a component of SYMTUZA is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir. Juvenile Animal Toxicity Data Darunavir: In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on postnatal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels. Geriatric Use Clinical trials of SYMTUZA included 35 subjects aged above 65 years of which 26 received SYMTUZA. No differences in safety or efficacy have been observed between elderly subjects and those aged 65 years or less. In general, caution should be exercised in the administration and monitoring of SYMTUZA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Renal Impairment SYMTUZA is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL per minute). No dosage adjustment of SYMTUZA is required in patients with creatinine clearance greater than or equal to 30 mL per minute [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Cobicistat has been shown to decrease creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosage adjustment for renal impairment when used in combination with SYMTUZA [see Warnings and Precautions]. Hepatic Impairment No dosage adjustment of SYMTUZA is required in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. SYMTUZA has not been studied in patients with severe hepatic impairment (Child Pugh Class C) and there are only limited data regarding the use of SYMTUZA components in this population. Therefore, SYMTUZA is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information]. OVERDOSAGE Human experience of acute overdose with SYMTUZA is limited. There is no specific antidote for overdose with SYMTUZA. Treatment of overdose with SYMTUZA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis. Product of Canada Manufactured by: Patheon Inc, 2100 Syntex Ct Mississauga ON L5N 7K9, Canada Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560 © 2018 Janssen Pharmaceutical Companies cp-62058v1

MSP ARTÍCULO DE REVISIÓN

VIH y el paciente

mayor de edad

Por: Marisel Bosques, MD Infectóloga Vice presidenta HIV treaters Medical Association of Puerto Rico (HIVTMD)

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MSP ARTÍCULO DE REVISIÓN

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

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

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

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

Las recomendaciones para el manejo y tratamiento de la infección por VIH en personas de edad avanzada son las mismas que aquellas indicadas a adolescentes y adultos. Sin embargo, se deben tomar en cuenta varios asuntos importantes. A continuación, discutiré varios puntos específicos para la población de edad avanzada que vive con VIH. Epidemiología En Puerto Rico, hasta el 30 de abril de 2018, la tasa acumulativa de casos reportados de personas mayores de 55 años con VIH (no SIDA) era 937. Para esa misma

fecha, en el 2017, el número de casos era 8941. Poco a poco, la prevalencia del VIH dentro de los grupos de edad avanzada está en aumento. Esto ocurre mayormente a consecuencia de dos cosas: la protección otorgada por los medicamentos antirretrovirales, pues estos ayudan a prolongar la vida, y, por un aumento en la identificación y diagnóstico de casos. La exposición sexual es el modo más común de transmisión del VIH en adultos mayores 2. Desafortunadamente, todavía existe la duda que una persona mayor de 55 años está en riesgo de contraer el

VIH, por lo que es menos probable que se le haga la prueba3,4. Incluso, cuando se realiza la prueba de VIH en el paciente mayor, a menudo el diagnóstico se hace más tarde en su enfermedad, lo que aumenta el riesgo de infecciones oportunistas y de transmisión a otros. Muchos estudios han demostrado que, a pesar de la supresión viral otorgada por una terapia antirretroviral efe c t iv a , la r e c up er a c ión inmunológica es menos robusta con el aumento en edad. He aquí la importancia de diagnosticar y dar tratamiento de VIH a una edad más temprana. Revista Puertorriqueña de Medicina y Salúd Pública

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MSP ARTÍCULO DE REVISIÓN

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

Uso de retroviales Sabemos que el régimen antirretroviral debe iniciarse independientemente del conteo de células CD4.5 Esto aplica para toda persona infectada con el virus de inmunodeficiencia humana, incluyendo la población mayor de edad. Para la selección del régimen debe tomarse en cuenta los medicamentos que ya están en uso, comorbilidades, y las posibles insuficiencias en sistemas de órganos5. Los pacientes de edad más alta pueden estar en riesgo de una función hepática o renal deteriorada, y éstas deben examinarse continuamente. Adicionalmente, la polifarmacia (el uso de 5 fármacos o más) es común en adultos mayores de edad. El potencial de interacciones entre medicamentos es una consideración primordial al momento de seleccionar y manejar los regímenes antirretrovirales en esta población. Morbilidad no relacionada al Sida Como se mencionó anteriormente, la terapia antirretroviral exitosa ha prolongado la supervivencia de las personas que viven con VIH y ha producido cambios en los patrones de morbilidad y mortalidad. Aunque las muertes a consecuencia del SIDA o enfermedades oportunistas han reducido, no obstante, el VIH desencadena secuelas a largo plazo que se piensan son el resultado de un estado de inflamación persistente creado por el virus. Por otro lado, la prevalencia de condiciones medicas relacionadas a la edad ha aumentado. Debido a la sobreposición epidemiológica entre las condiciones médicas asociadas a la edad y aquellas relacionadas al VIH, se generó el concepto de condiciones asociadas al VIH-no SIDA (HANA, por sus siglas en inglés). Éstas incluyen enfermedad cardiovascular, diabetes mellitus tipo 2, enfermedad pulmonar crónica obstructiva, osteopenia/osteoporosis, enfermedad crónica de riñón, enfermedad crónica de hígado, trastorno neurocognitivo asociado a VIH, y ciertos cánceres6. Por último, con el pasar de los años, el envejeciente con VIH experimenta debilidad y disminución de la reserva fisiológica. 112

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Este estado de declive y vulnerabilidad se conoce como "fragilidad" y produce aumento en el riesgo de resultados adversos. Esta fragilidad parece afectar a la persona que vive con VIH a una edad más temprana que a las personas que no han adquirido el virus. Conclusión Es importante reconocer que existe una interacción entre el envejecimiento, el VIH, sus comorbilidades asociadas, y el uso concurrente de medicamentos antirretrovirales y medicamentos de otras enfermedades crónicas. A pesar de que el manejo clínico de las personas mayores de edad que viven con VIH puede ser complejo, podemos aliviar el impacto que crea sobre la vida de los pacientes dentro de este grupo de edad. Referencias:

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

DOLUTEGRAVIR is the… #1 PRESCRIBED INSTI for HIV-1 in the United States* *As of the date of printing, based on data since May 2016 from IMS Health National Prescription Audit for total prescription (TRx) volume for the most recent rolling 4 weeks across retail, mail-order, and long-term care channels. Includes any INSTI for a new prescription or refill prescription, whether part of a multi-tablet regimen or fixed-dose combination. Data are not intended to suggest comparison of safety or efficacy to any other antiretroviral agents. INSTI=integrase strand transfer inhibitor.

Indications and Usage for TRIUMEQ and TIVICAY TRIUMEQ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and in pediatric patients weighing at least 40 kg. TIVICAY, a component of TRIUMEQ, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection: ` in adults and pediatric patients weighing at least 30 kg ` with rilpivirine as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable antiretroviral regimen for ≥6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent

Hypersensitivity Reactions: (cont’d) ` TRIUMEQ is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701– positive patients. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy or reinitiation of therapy with TRIUMEQ unless patients have a previously documented HLA-B*5701 allele assessment ` Discontinue TRIUMEQ as soon as hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue TRIUMEQ if hypersensitivity cannot be ruled out, even when other diagnoses are possible ` Following a hypersensitivity reaction to TRIUMEQ, NEVER restart TRIUMEQ or any other abacavir-containing product

Exacerbations of Hepatitis B: ` Severe acute exacerbations of HBV have been reported in patients who are co-infected with HBV and HIV-1 and have discontinued lamivudine, a component of TRIUMEQ. Monitor Limitations of Use: hepatic function closely in these patients and, if appropriate, TRIUMEQ alone is not recommended in patients with resistanceinitiate anti-hepatitis B treatment associated integrase substitutions or clinically suspected INSTI CONTRAINDICATIONS resistance because the dose of dolutegravir in TRIUMEQ ` Do not use TRIUMEQ in patients who have the HLA-B*5701 is insufficient in these subpopulations. See full prescribing allele information for TIVICAY. ` Do not use TRIUMEQ in patients with previous hypersensitivity reaction to abacavir, dolutegravir, or Important Safety Information lamivudine. Do not use TIVICAY in patients with previous for TRIUMEQ and TIVICAY hypersensitivity reaction to dolutegravir BOXED WARNING FOR TRIUMEQ: HYPERSENSITIVITY ` Do not use TRIUMEQ or TIVICAY in patients receiving REACTIONS AND EXACERBATIONS OF HEPATITIS B VIRUS (HBV) dofetilide ` Do not use TRIUMEQ in patients with moderate or severe Hypersensitivity Reactions: hepatic impairment ` Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products ` Hypersensitivity to abacavir is a multi-organ clinical syndrome ` Patients who carry the HLA-B*5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir, although hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele

Please see additional Important Safety Information for TIVICAY and TRIUMEQ on the following pages. Please see Brief Summaries of Prescribing Information for TIVICAY and TRIUMEQ, including Boxed Warning for TRIUMEQ, on the following pages.

DOLUTEGRAVIR is an INSTI with PRESCRIBING OPTIONS: Available as a single-pill coformulation*, a single agent for use in combination with other ARVs†, and a complete regimen with rilpivirine.‡ *For HLA-B*5701–negative adults and pediatric patients weighing at least 40 kg. † For adults and pediatric patients weighing at least 30 kg. ‡ With rilpivirine 25 mg for virologically suppressed patients. See previous page for indications for TIVICAY. ARVs=antiretrovirals.

Important Safety Information for TRIUMEQ and TIVICAY (cont’d) WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: ` Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury ` Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ would be caused by abacavir or dolutegravir ` Discontinue TRIUMEQ or TIVICAY immediately if signs or symptoms of hypersensitivity reaction develop, as a delay in stopping treatment may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated Hepatotoxicity: ` Hepatic adverse events have been reported, including cases of hepatic toxicity (elevated serum liver biochemistries, hepatitis, and acute liver failure) in patients receiving a dolutegravircontaining regimen without pre-existing hepatic disease or other identifiable risk factors ` Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with the use of TRIUMEQ or TIVICAY. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn ` Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ ` Monitoring for hepatotoxicity is recommended Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir and lamivudine. Female sex and obesity may be risk factors in patients treated with nucleoside analogues. Embryofetal Toxicity: ` Avoid use of TIVICAY (dolutegravir), also a component of TRIUMEQ, at the time of conception through the first trimester due to the risk of neural tube defects ` Perform pregnancy testing before use of dolutegravir and advise that consistent use of effective contraception is recommended while using dolutegravir in adolescents and adults of childbearing potential

WARNINGS AND PRECAUTIONS (cont’d) Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of TRIUMEQ or TIVICAY and other drugs may result in known or potentially significant drug interactions (see Contraindications and Drug Interactions). Use with Interferon- and Ribavirin-based Regimens: Hepatic decompensation, some fatal, has occurred in HIV-1/hepatitis C virus (HCV) co-infected patients receiving combination antiretroviral therapy and interferon alfa with or without ribavirin. Patients receiving interferon alfa, with or without ribavirin, and TRIUMEQ should be closely monitored. Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with TRIUMEQ and TIVICAY. Myocardial Infarction (MI): ` Several observational studies have reported an association with the use of abacavir and the risk of MI; meta-analyses of randomized controlled clinical trials did not show increased risk. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data show inconsistency; therefore, evidence for a causal relationship between abacavir and the risk of MI is inconclusive ` The underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (eg, hypertension, hyperlipidemia, diabetes mellitus, smoking) ADVERSE REACTIONS The most common adverse reactions (incidence ≥2%, Grades 2-4) in treatment-naïve adults receiving TRIUMEQ or TIVICAY in a combination regimen were insomnia (3%), headache (2%), and fatigue (2%). DRUG INTERACTIONS ` Coadministration of TRIUMEQ or TIVICAY with drugs that induce or inhibit UGT1A1 and/or CYP3A may affect plasma concentrations ` Administer TRIUMEQ or TIVICAY 2 hours before or 6 hours after taking antacids, polyvalent cation-containing products or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications ` Consult the full Prescribing Information for TRIUMEQ or TIVICAY for more information on potentially significant drug interactions, including clinical comments

DOLUTEGRAVIR-BASED REGIMENS have been studied in 6 TREATMENT-NAÏVE TRIALS vs INSTI-, NNRTI-, or PI-containing 1-6§II combination therapies Based on data from ViiV-sponsored trials: SPRING-2,1 SINGLE,2 FLAMINGO,3 and ARIA4—randomized, active-control, noninferiority trials in treatmentnaïve adults (≥18 years) with HIV-1 and CrCl ≥50 mL/min. Patients who received ABC/3TC were HLA-B*5701 negative. SPRING-2 (double blind) compared DTG 50 mg once daily + ABC/3TC or TDF/FTC (n=411) vs RAL 400 mg twice daily + ABC/3TC or TDF/FTC (n=411). SINGLE (double blind to Week 96; open label from Week 96 to Week 144) compared DTG 50 mg once daily + ABC/3TC (n=414) vs EFV/TDF/FTC once daily (n=419). FLAMINGO (open label) compared DTG 50 mg once daily + ABC/3TC or TDF/FTC (n=243) vs DRV/r 800 mg/100 mg once daily + ABC/3TC or TDF/FTC (n=242). ARIA (open label in female patients) compared TRIUMEQ once daily (n=248) vs ATV/r 300 mg/100 mg once daily + TDF/FTC (n=247). II Based on data from 2 Gilead-sponsored trials: randomized, active-control, noninferiority trials in treatment-naïve adults (≥18 years) with HIV-1. GS-US-380-1489 (double blind) compared TRIUMEQ once daily (n=315) vs coformulated BIC/FTC/TAF once daily (n=314) in HLA-B*5701– negative patients with eGFR ≥50 mL/min. GS-US-380-1490 (double blind) compared DTG 50 mg + FTC/TAF 200 mg/25 mg once daily (n=325) vs coformulated BIC/FTC/TAF (n=320) in patients with eGFR ≥30 mL/min. NNRTI=non-nucleoside reverse transcriptase inhibitor; PI=protease inhibitor; CrCl=creatinine clearance; ABC=abacavir; 3TC=lamivudine; DTG=dolutegravir; TDF=tenofovir disoproxil fumarate; FTC=emtricitabine; RAL=raltegravir; EFV=efavirenz; DRV=darunavir; r=ritonavir; ATV=atazanavir; BIC=bictegravir; TAF=tenofovir alafenamide fumarate; eGFR=estimated glomerular filtration rate. §

Important Safety Information for TRIUMEQ and TIVICAY (cont’d) USE IN SPECIFIC POPULATIONS ` Pregnancy: There are insufficient human data on the use of TRIUMEQ or TIVICAY during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established. Avoid use of TIVICAY (dolutegravir), also a component of TRIUMEQ, at the time of conception through the first trimester of pregnancy. If planning a pregnancy or if pregnancy is confirmed while taking dolutegravir during the first trimester, if possible, switch to an alternative regimen ` Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant

USE IN SPECIFIC POPULATIONS (cont’d) ` Females and Males of Reproductive Potential: Perform pregnancy testing before initiation of dolutegravir. Advise adolescents and adults of childbearing potential to consistently use effective contraception while taking dolutegravir ` Patients with Impaired Renal Function: TRIUMEQ is not recommended in patients with creatinine clearance <50 mL/min ` Patients with Impaired Hepatic Function: If a dose reduction of abacavir is required for patients with mild hepatic impairment, then the individual components of TRIUMEQ should be used Please see additional Important Safety Information for TIVICAY and TRIUMEQ on the previous pages. Please see Brief Summaries of Prescribing Information for TIVICAY and TRIUMEQ, including Boxed Warning for TRIUMEQ, on the following pages.

References: 1. Raffi F, Jaeger H, Quiros-Roldan E, et al; on behalf of the SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927-935. 2. Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naïve patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015;70(5):515-519. 3. Molina J-M, Clotet B, van Lunzen J, et al; on behalf of the FLAMINGO Study Team. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomized, open-label, phase 3b study. Lancet HIV. 2015;2:e127-e136. 4. Orrell C, Hagins DP, Belonosova E, et al; on behalf of the ARIA study team. Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study. Lancet HIV. 2017;4:e536-e546. 5. Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063-2072. 6. Sax P, Pozniak A, Montes M, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380–1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017;390(10107):2073-2082. Trademarks are owned by or licensed to the ViiV Healthcare group of companies. The other brands listed are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies.

BRIEF SUMMARY

TRIUMEQ for oral use

(abacavir, dolutegravir, and lamivudine) tablets,

The following is a brief summary only; see full prescribing information, including boxed warning, for complete product information. WARNING: HYPERSENSITIVITY REACTIONS AND EXACERBATIONS OF HEPATITIS B Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of TRIUMEQ (abacavir, dolutegravir, and lamivudine). Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele. TRIUMEQ is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ or reinitiation of therapy with TRIUMEQ, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue TRIUMEQ immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible. Following a hypersensitivity reaction to TRIUMEQ, NEVER restart TRIUMEQ or any other abacavir-containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity. Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of TRIUMEQ. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TRIUMEQ and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted. CONTRAINDICATIONS TRIUMEQ is contraindicated in patients: who have the HLA-B*5701 allele; with prior hypersensitivity reaction to abacavir, dolutegravir, or lamivudine; receiving dofetilide, due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir; with moderate or severe hepatic impairment. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Hypersensitivity reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ. Abacavir: Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing regimens. Abacavir hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ or reinitiation of therapy with TRIUMEQ, unless patients have a previously documented HLA-B*5701 allele assessment; TRIUMEQ is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients; Before starting TRIUMEQ, review medical history for prior exposure to any abacavir-containing product. NEVER restart TRIUMEQ or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status; To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue TRIUMEQ immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). Clinical status, including liver chemistries, should be monitored and appropriate therapy initiated; If a hypersensitivity reaction cannot be ruled out, do not restart TRIUMEQ or any other abacavir- containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours; Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ due to a hypersensitivity reaction; If a hypersensitivity reaction is ruled out, patients may restart TRIUMEQ. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIUMEQ, or any other abacavir-containing product, is recommended only if medical care can be readily accessed; A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions

should be dispensed with each new prescription and refill. Dolutegravir: Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TRIUMEQ and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TRIUMEQ or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ due to a hypersensitivity reaction. Posttreatment Exacerbations of Hepatitis in Patients with Hepatitis B Co-infection: Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Emergence of Lamivudine-Resistant HBV: Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudinecontaining antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a dolutegravircontaining regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity including elevated serum liver biochemistries, hepatitis, and acute liver failure have also been reported in patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ. Monitoring for hepatotoxicity is recommended. Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir and lamivudine (components of TRIUMEQ). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with TRIUMEQ 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. Embryo-Fetal Toxicity: Preliminary data from an observational study showed that dolutegravir, a component of TRIUMEQ, was associated with increased risk of neural tube defects when administered at the time of conception and in early pregnancy. As there is limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, avoid use of TRIUMEQ at the time of conception through the first trimester of pregnancy. If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on TRIUMEQ, if possible, switch to an alternative regimen. Perform pregnancy testing before initiation of TRIUMEQ in adolescents and adults of childbearing potential to exclude use of TRIUMEQ during the first trimester of pregnancy. Advise adolescents and adults of childbearing potential to consistently use effective contraception. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of TRIUMEQ and other drugs may result in known or potentially significant drug interactions, some of which may lead to: Loss of therapeutic effect of TRIUMEQ and possible development of resistance; Possible clinically significant adverse reactions from greater exposures of concomitant drugs. See the Drug Interactions section for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TRIUMEQ; review concomitant medications during therapy with TRIUMEQ; and monitor for the adverse reactions associated with the concomitant drugs. Use with Interferon- and Ribavirin-Based Regimens: Patients receiving interferon alfa with or without ribavirin and TRIUMEQ should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of TRIUMEQ should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIUMEQ. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré 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 treatment. Myocardial Infarction: Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established

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BRIEF SUMMARY for TRIUMEQ® (abacavir, dolutegravir, and lamivudine) tablets (cont’d) biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir and the risk of MI is inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). ADVERSE REACTIONS Clinical Trials Experience: Clinical Trials in Adults: Serious and Fatal Abacavir-Associated Hypersensitivity Reactions: In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIUMEQ. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome. Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized). Serious Dolutegravir Hypersensitivity Reactions: In clinical trials, hypersensitivity reactions have occurred with dolutegravir, a component of TRIUMEQ. These hypersensitivity reactions have been characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. Additional Treatment-Emergent Adverse Drug Reactions (ADRs) with Use of TRIUMEQ: The safety assessment of TRIUMEQ is primarily based on the analyses of data from a randomized, international, multicenter, double-blind, active-controlled trial, SINGLE (ING114467) and supported by data in treatment-experienced, INSTI-naïve subjects from SAILING (ING111762) and by data from other treatment-naïve trials. Treatment-Naïve Subjects: In SINGLE, 833 adult subjects were randomized and received at least one dose of either dolutegravir (TIVICAY) 50 mg with fixed-dose abacavir and lamivudine (EPZICOM) once daily (n = 414) or fixeddose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (n = 419) (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rate of adverse events leading to discontinuation was 4% in subjects receiving TIVICAY + EPZICOM and 14% in subjects receiving ATRIPLA once daily. Treatment-emergent ADRs of moderate to severe intensity (Grades 2 to 4) observed in at least 2% of subjects in either treatment arm of SINGLE (Week 144 analysis) were – TIVICAY + EPZICOM (n = 414) vs ATRIPLA (n= 419), respectively: Psychiatric – insomnia (3%, 3%), depression (1%, 2%), abnormal dreams (<1%, 2%); Nervous System – dizziness (<1%, 5%), headache (2%, 2%); Gastrointestinal – nausea (<1%, 3%), diarrhea (<1%, 2%); General Disorders – fatigue (2%, 2%); Skin and Subcutaneous Tissue – rash (<1%, 6%, includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption); Ear and Labyrinth – vertigo (0%, 2%). Treatment-Experienced Subjects: SAILING is an international, double-blind trial in INSTI-naïve, antiretroviral treatment-experienced adult subjects. Subjects were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rate of adverse events leading to discontinuation was consistent with that seen in the overall treatment-naïve patient population. The ADRs observed in the subset of subjects who received TIVICAY + EPZICOM were generally consistent with those seen in the overall treatment-naïve patient population. Less Common Adverse Reactions Observed in Clinical Trials: The following adverse reactions occurred in less than 2% of treatment-naïve or treatmentexperienced subjects in any one trial. These events have been included because of their seriousness and/or assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal distention, abdominal discomfort, dyspepsia, flatulence, gastroesophageal reflux disease, upper abdominal pain, vomiting. General Disorders: Fever, lethargy. Hepatobiliary Disorders: Hepatitis. Metabolism and Nutrition Disorders: Anorexia, hypertriglyceridemia. Musculoskeletal Disorders: Arthralgia, myositis. Nervous System Disorders: Somnolence. Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Nightmare and sleep disorder. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Treatment-Naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of Treatment-Naïve Subjects in SINGLE (Week 144 Analysis) were – TIVICAY + EPZICOM vs ATRIPLA, respectively: ALT Grade 2 (>2.5-5.0 x Upper Limit of Normal [ULN]) 3%, 5%; ALT Grade 3 to 4 (>5.0 x ULN) 1%, <1%; AST Grade 2 (>2.5-5.0 x ULN) 3%, 4%; AST Grade 3 to 4 (>5.0 x ULN) 1%, 3%; Creatine kinase Grade 2 (6.0-9.9 x ULN) 5%, 3%; Creatine kinase Grade 3 to 4 (≥10.0 x ULN) 7%, 8%; Hyperglycemia Grade 2 (126-250 mg/dL) 9%, 6%; Hyperglycemia Grade 3 (>250 mg/dL) 2%, <1%; Lipase Grade 2 (>1.5-3.0 x ULN) 11%, 11%; Lipase Grade 3 to 4 (>3.0 ULN) 5%, 4%; Total neutrophils Grade 2 (0.75-0.99 x 109) 4%, 5%; Total neutrophils Grade 3 to 4 (<0.75 x 109) 3%, 3%. The mean change from baseline in selected fasted lipid values in treatment-naïve subjects in SINGLE (Week 144 Analysis) were – TIVICAY + EPZICOM vs ATRIPLA, respectively (mg/dL): Cholesterol

24.0, 26.7; HDL cholesterol 5.4, 7.2; LDL cholesterol 16.0, 14.6; Triglycerides 13.6, 31.9. Subjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Seventy-two subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (TIVICAY + EPZICOM n = 36 and ATRIPLA n = 36). Treatment-Experienced Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve trials. Hepatitis C Virus Co-infection: In SINGLE, the pivotal Phase 3 trial, subjects with hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal; subjects with hepatitis B co-infection were excluded. Overall, the safety profile in subjects with hepatitis C virus co-infection was similar to that observed in subjects without hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis C virus co-infection for both treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis C co-infected compared with HIV mono-infected subjects receiving TRIUMEQ were observed in 15% and 2% (vs. 24% and 4% of subjects treated with ATRIPLA) (Week 96 analysis), respectively. Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 144 weeks. In SINGLE, a mean change from baseline of 0.14 mg per dL (range: -0.25 mg per dL to 0.81 mg per dL) was observed after 144 weeks of treatment. Creatinine increases were similar in treatment-experienced subjects. Abacavir and Lamivudine: Laboratory abnormalities observed in clinical trials of ZIAGEN (in combination with other antiretroviral treatment) were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR (in combination with other antiretroviral treatment) were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase. Clinical Trials Experience in Pediatric Subjects: Abacavir and Lamivudine: The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as EPZICOM, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects compared with historical data in adults. Dolutegravir: IMPAACT P1093 is a 48-week multicenter, open-label, non-comparative trial of approximately 160 HIV-1-infected pediatric subjects aged 4 weeks to less than 18 years, of which, 23 treatment-experienced, INSTI-naïve subjects aged 12 to less than 18 years were enrolled. The ADR profile was similar to that for adults. Grade 2 ADRs reported by more than one subject were decreased neutrophil count (n = 2). No Grade 3 or 4 ADRs were reported. No ADRs led to discontinuation. The Grade 3 laboratory abnormalities reported in 1 subject each were elevated total bilirubin, elevated lipase, and decreased white blood cell count. There was one Grade 4 decreased neutrophil count. The changes in mean serum creatinine were similar to those observed in adults. Postmarketing Experience: In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use with one or more of the components of TRIUMEQ. 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 Systems: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly; Digestive: Stomatitis; Gastrointestinal: Pancreatitis; General: Weakness; Hepatobiliary Disorders: Acute liver failure, liver transplant; Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria; Investigations: Weight increased; Metabolism and Nutrition Disorders: Hyperlactemia; Musculoskeletal: CPK elevation, muscle weakness, myalgia, rhabdomyolysis; Nervous: Paresthesia, peripheral neuropathy, seizures; Psychiatric: Anxiety; Respiratory: Abnormal breath sounds/wheezing; Skin: Alopecia, erythema multiforme. Suspected StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. DRUG INTERACTIONS Effect of Dolutegravir on the Pharmacokinetics of Other Agents. In vitro, dolutegravir inhibited the renal organic cation transporters (OCT)2 (IC50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE)1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin). In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3. In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1, UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, or multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters. In drug interaction trials, dolutegravir did

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BRIEF SUMMARY for TRIUMEQ® (abacavir, dolutegravir, and lamivudine) tablets As defects related to closure of the neural tube occur from conception through the first 6 weeks (cont’d) of gestation, embryos exposed to dolutegravir from the time of conception through the first not have a clinically relevant effect on the pharmacokinetics of the following drugs: daclatasvir, tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir. Effect of Other Agents on the Pharmacokinetics of Dolutegravir: Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir (see below). In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Darunavir/ritonavir, lopinavir/ ritonavir, rilpivirine, tenofovir, boceprevir, daclatasvir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir. Established and Other Potentially Significant Drug Interactions: There were no drug-drug interaction trials conducted with the abacavir, dolutegravir, and lamivudine fixed-dose combination tablets. Information regarding potential drug interactions with the individual components of TRIUMEQ are provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. Alterations in dose may be recommended based on drug interaction trials or predicted interactions for the following drugs when coadministered with TRIUMEQ: • Antiarrhythmic: dofetilide – coadministration is contraindicated with TRIUMEQ • Non-nucleoside reverse transcriptase inhibitor: etravirine – use of TRIUMEQ with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended. • Non-nucleoside reverse transcriptase inhibitor: efavirenz – adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ. • Non-nucleoside reverse transcriptase inhibitor: nevirapine – avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations. • Protease inhibitors: fosamprenavir/ritonavir, tipranavir/ritonavir – adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ. • Carbamazepine – adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ. • Oxcarbazepine, phenytoin, phenobarbital, St. John’s wort (Hypericum perforatum) – avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations. • Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids or laxatives, sucralfate, buffered medications – administer TRIUMEQ 2 hours before or 6 hours after taking medications containing polyvalent cations. • Oral calcium and iron supplements, including multivitamins containing calcium or iron – administer TRIUMEQ 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TRIUMEQ and supplements containing calcium or iron can be taken together with food. • Metformin – with concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TRIUMEQ. When stopping TRIUMEQ, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TRIUMEQ is recommended. • Rifampin – adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ. Consult the full Prescribing Information for potential drug interactions; this list is not all inclusive. Methadone: Abacavir: In a trial of 11 HIV–1 infected subjects receiving methadone-maintenance therapy with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. Sorbitol: Lamivudine: Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TRIUMEQ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Preliminary data from an observational study has identified a possible increased risk of neural tube defects when dolutegravir, a component of TRIUMEQ, is administered at the time of conception compared with non-dolutegravir-containing antiretroviral regimens.

6 weeks of gestation are at potential risk. In addition, 2 of the 4 birth defects (encephalocele and iniencephaly), which have been observed with dolutegravir use, although often termed neural tube defects, may occur post-neural tube closure, the time period of which may be later than 6 weeks of gestation, but within the first trimester. Due to the limited understanding of the types of reported neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, avoid use of TRIUMEQ at the time of conception through the first trimester of pregnancy. No neural tube defects have been reported in infants born to mothers who have started dolutegravir after the first trimester of pregnancy. If there are plans to become pregnant or if pregnancy is confirmed while on TRIUMEQ during the first trimester, if possible, switch to an alternative regimen. Advise pregnant adolescents and adults of the potential risk to the embryo exposed to TRIUMEQ from the time of conception through the first trimester of pregnancy. There are insufficient human data on the use of TRIUMEQ during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. Lactation: The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir and lamivudine are present in human milk. When administered to lactating rats, dolutegravir was present in milk. There is no information on the effects of TRIUMEQ or its components on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TRIUMEQ. Females and Males of Reproductive Potential: Perform pregnancy testing in adolescents and adults of childbearing potential before initiation of TRIUMEQ. Adolescents and adults of childbearing potential should avoid use of TRIUMEQ at the time of conception through the first trimester of pregnancy because of the potential risk of neural tube defects. Advise adolescents and adults of childbearing potential who are taking TRIUMEQ to consistently use effective contraception. Pediatric Use: The clinical data supporting use of TRIUMEQ in HIV-1 infected pediatric patients weighing at least 40 kg is derived from the following previously conducted pediatric trials using the individual components of TRIUMEQ: The safety and efficacy of once-daily abacavir and lamivudine were established with a randomized, multicenter trial (ARROW [COL105677]) in HIV-1–infected, treatment-naïve subjects aged 3 months to 17 years with a first-line regimen containing abacavir and lamivudine, using either the combination of EPIVIR and ZIAGEN or EPZICOM; The safety and antiviral activity (efficacy) of dolutegravir was established through a 48-week, open-label, multicenter, dose-finding clinical trial (IMPAACT P1093), in which treatment-experienced, INSTI-naïve, HIV-1–infected subjects aged 6 to less than 18 years were treated with dolutegravir (TIVICAY) plus optimized background therapy. TRIUMEQ is a fixed-dose combination tablet which cannot be adjusted for patients weighing less than 40 kg. Geriatric Use: Clinical trials of abacavir, dolutegravir, or lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TRIUMEQ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Patients with Impaired Renal Function: TRIUMEQ is not recommended for patients with creatinine clearance less than 50 mL per min because TRIUMEQ is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of TRIUMEQ, is required for patients with creatinine clearance less than 50 mL per min, then the individual components should be used. Patients with Impaired Hepatic Function: TRIUMEQ is a fixeddose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of TRIUMEQ, is required for patients with mild hepatic impairment (Child-Pugh Score A), then the individual components should be used. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Score B) or severe (Child-Pugh Score C) hepatic impairment; therefore, TRIUMEQ is contraindicated in these patients. OVERDOSAGE There is no known specific treatment for overdose with TRIUMEQ. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. Dolutegravir: As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. Abacavir: It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis. Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

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BRIEF SUMMARY

TIVICAY

(dolutegravir) tablets, for oral use The following is a brief summary only; see full prescribing information for complete product information. CONTRAINDICATIONS TIVICAY is contraindicated in: patients with previous hypersensitivity reaction to dolutegravir; and patients receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in <1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TIVICAY or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. TIVICAY is contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir. Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving a dolutegravircontaining regimen without pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended. Embryo-Fetal Toxicity: Preliminary data from an observational study showed that TIVICAY was associated with increased risk of neural tube defects when administered at the time of conception and in early pregnancy. As there is limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, avoid use of TIVICAY at the time of conception through the first trimester of pregnancy. If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on TIVICAY, if possible, switch to an alternative regimen. Perform pregnancy testing before initiation of TIVICAY in adolescents and adults of childbearing potential to exclude use of TIVICAY during the first trimester of pregnancy. Advise adolescents and adults of childbearing potential to consistently use effective contraception. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of TIVICAY and other drugs may result in known or potentially significant drug interactions, some of which may lead to: Loss of therapeutic effect of TIVICAY and possible development of resistance; Possible clinically significant adverse reactions from greater exposures of concomitant drugs. For concomitant drugs for which the interaction can be mitigated, see Drug Interactions section for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TIVICAY; review concomitant medications during therapy with TIVICAY; and monitor for the adverse reactions associated with the concomitant drugs. Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TIVICAY. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré 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 treatment. ADVERSE REACTIONS Clinical Trials Experience: Clinical Trials Experience in Adult Subjects: TreatmentNaïve Subjects: The safety assessment of TIVICAY in HIV-1-infected treatment-naïve subjects is based on the analyses of data from 2 international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and data from the international, multicenter, open-label FLAMINGO (ING114915) trial. In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]). There were

808 subjects included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms. In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rates of adverse events leading to discontinuation were 4% in subjects receiving TIVICAY 50 mg once daily + EPZICOM and 14% in subjects receiving ATRIPLA once daily. Treatment-emergent adverse reactions (ARs) of moderate to severe intensity (Grades 2 to 4) observed in at least 2% of subjects in either treatment arm of: • SPRING-2 (week 96 analysis) were – TIVICAY + 2 NRTIs (n=403) vs raltegravir + 2 NRTIs (n=405), respectively: Psychiatric – insomnia (<1%, <1%), depression (<1%, <1%), abnormal dreams (<1%, <1%); Nervous System – dizziness (<1%, <1%), headache (<1%, <1%); Gastrointestinal – nausea (1%, 1%), diarrhea (<1%, <1%); Skin and Subcutaneous Tissue – rash (0%, <1%, includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption); General Disorders – fatigue (<1%, <1%); Ear and Labyrinth – vertigo (0%, <1%). • SINGLE (week 144 analysis) were – TIVICAY + EPZICOM (n=414) vs ATRIPLA (n=419), respectively: Psychiatric – insomnia (3%, 3%), depression (1%, 2%), abnormal dreams (<1%, 2%); Nervous System – dizziness (<1%, 5%), headache (2%, 2%); Gastrointestinal – nausea (<1%, 3%), diarrhea (<1%, 2%); Skin and Subcutaneous Tissue – rash (<1%, 6%, includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption); General Disorders – fatigue (2%, 2%); Ear and Labyrinth – vertigo (0%, 2%). Direct comparisons across trials should not be made due to differing trial designs. In addition, Grade 1 insomnia was reported by 1% and <1% of subjects receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting. In a multicenter, open-label trial (FLAMINGO), 243 subjects received TIVICAY 50 mg once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 subjects included in the efficacy and safety analyses. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY and 6% in subjects receiving darunavir/ritonavir. The ARs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV-1-infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY 50 mg once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen. The only treatment-emergent AR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving TIVICAY 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 HIV-1-infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48. Treatment-emergent ARs in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials. Virologically Suppressed Subjects: The ARs observed for TIVICAY plus rilpivirine in the Week 48 analysis of pooled data from 2 identical, international, multicenter, open-label trials (SWORD-1 and SWORD-2) of 513 HIV-1-infected, virologically suppressed subjects switching from their current antiretroviral regimen to dolutegravir plus rilpivirine, were consistent with the AR profiles and severities for the individual components when administered with other antiretroviral agents. There were no ARs (Grades 2 to 4) with an incidence of at least 2% in either treatment arm. The rates of adverse events leading to discontinuation were 4% in subjects receiving TIVICAY plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Trials: The following ARs occurred in less than 2% of treatment-naïve or treatment-experienced subjects receiving TIVICAY in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting. Hepatobiliary Disorders: Hepatitis. Musculoskeletal Disorders: Myositis. Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression (cont’d on next page)

BRIEF SUMMARY for TIVICAY® (dolutegravir) tablets (cont’d) or other psychiatric illness. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: TreatmentNaïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects from: • SPRING-2 (Week 96 Analysis) were – TIVICAY + 2 NRTIs vs raltegravir + 2 NRTIs, respectively: ALT Grade 2 (>2.5-5.0 x Upper Limit of Normal [ULN]) 4%, 4%; ALT Grade 3 to 4 (>5.0 x ULN) 2%, 2%; AST Grade 2 (>2.5-5.0 x ULN) 5%, 3%; AST Grade 3 to 4 (>5.0 x ULN) 3%, 2%; Total Bilirubin Grade 2 (1.6-2.5 x ULN) 3%, 2%; Total Bilirubin Grade 3 to 4 (>2.5 x ULN) <1%, <1%; Creatine kinase Grade 2 (6.0-9.9 x ULN) 2%, 5%; Creatine kinase Grade 3 to 4 (≥10.0 x ULN) 7%, 4%; Hyperglycemia Grade 2 (126-250 mg/dL) 6%, 6%, Hyperglycemia Grade 3 (>250 mg/dL) <1%, 2%; Lipase Grade 2 (>1.5-3.0 x ULN) 7%, 7%; Lipase Grade 3 to 4 (>3.0 ULN) 2%, 5%; Total neutrophils Grade 2 (0.75-0.99 x 109) 4%, 3%; Total neutrophils Grade 3 to 4 (<0.75 x 109) 2%, 2%. • SINGLE (Week 144 Analysis) were – TIVICAY + EPZICOM vs ATRIPLA, respectively: ALT Grade 2 (>2.5-5.0 x [ULN]) 3%, 5%; ALT Grade 3 to 4 (>5.0 x ULN) 1%, <1%; AST Grade 2 (>2.5-5.0 x ULN) 3%, 4%; AST Grade 3 to 4 (>5.0 x ULN) 1%, 3%; Total Bilirubin Grade 2 (1.6-2.5 x ULN) <1%, <1%; Total Bilirubin Grade 3 to 4 (>2.5 x ULN) <1%, <1%; Creatine kinase Grade 2 (6.0-9.9 x ULN) 5%, 3%; Creatine kinase Grade 3 to 4 (≥10.0 x ULN) 7%, 8%; Hyperglycemia Grade 2 (126-250 mg/dL) 9%, 6%; Hyperglycemia Grade 3 (>250 mg/dL) 2%, <1%; Lipase Grade 2 (>1.5-3.0 x ULN) 11%, 11%; Lipase Grade 3 to 4 (>3.0 ULN) 5%, 4%; Total neutrophils Grade 2 (0.75-0.99 x 109) 4%, 5%; Total neutrophils Grade 3 to 4 (<0.75 x 109) 3%, 3%. The mean change from baseline observed for selected lipid values (fasted) in treatment-naïve subjects from: • SPRING-2 (Week 96 Analysis) were – TIVICAY + 2 NRTIs vs raltegravir + 2 NRTIs, respectively (mg/dL): Cholesterol 8.1, 10.1; HDL cholesterol 2.0, 2.3; LDL cholesterol 5.1, 6.1; Triglycerides 6.7, 6.6. • SINGLE (Week 144 Analysis) were – TIVICAY + EPZICOM vs ATRIPLA, respectively (mg/dL): Cholesterol 24.0, 26.7; HDL cholesterol 5.4, 7.2; LDL cholesterol 16.0, 14.6; Triglycerides 13.6, 31.9. Subjects on lipid-lowering agents at baseline were excluded from these analyses (19 subjects in each arm in SPRING-2, and in SINGLE: TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Ninety-four subjects initiated a lipid-lowering agent postbaseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (SPRING-2: TIVICAY n = 9, raltegravir n = 13; SINGLE: TIVICAY + EPZICOM n = 36 and ATRIPLA: n = 36). Direct comparisons across trials should not be made due to differing trial designs. Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatmentnaïve (SPRING-2 and SINGLE) trials. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: The most common treatment-emergent laboratory abnormalities (>5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported. Virologically Suppressed Adults: Laboratory abnormalities observed in SWORD-1 and SWORD-2 were generally similar compared with observations seen in the other Phase 3 trials. Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase 3 trials, subjects with hepatitis B and/or C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving TIVICAY were observed in 18% vs. 3% with the 50-mg once-daily dose and 13% vs. 8% with the 50-mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C at the start of therapy with TIVICAY, particularly in the setting where anti-hepatitis therapy was withdrawn. Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per dL (range: -0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced subjects. Clinical Trials Experience in Pediatric Subjects: IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV-1-infected pediatric subjects aged 4 weeks to less

than 18 years, of which 46 treatment-experienced, INSTI-naïve subjects aged 6 to less than 18 years have been enrolled. The adverse reaction profile was similar to that for adults. Grade 2 ARs reported by more than one subject were decreased neutrophil count (n = 3) and diarrhea (n = 2). There were no Grade 3 or 4 drugrelated ARs reported. No ARs led to discontinuation. The Grade 3 or 4 laboratory abnormalities reported in more than one subject were elevated total bilirubin (n = 3) and decreased neutrophil count (n = 2). The changes in mean serum creatinine were similar to those observed in adults. Postmarketing Experience: In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. 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. Hepatobiliary Disorders: Acute liver failure, hepatotoxicity. Investigations: Weight increased. Musculoskeletal: Arthralgia, myalgia. Psychiatric: Anxiety. DRUG INTERACTIONS Effect of Dolutegravir on the Pharmacokinetics of Other Agents: In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin). In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3. In vitro, dolutegravir did not inhibit (IC50 >50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters. Effect of Other Agents on the Pharmacokinetics of Dolutegravir: Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir (see below). In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Established and Other Potentially Significant Drug Interactions: The recommendations below are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. Alterations in dose or regimen may be recommended based on drug interaction trials or predicted interactions for the following drugs when coadministered with TIVICAY: • Non-nucleoside reverse transcriptase inhibitor: etravirine – use of TIVICAY with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended. • Non-nucleoside reverse transcriptase inhibitor: efavirenz – adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily. Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.* • Non-nucleoside reverse transcriptase inhibitor: nevirapine – avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations. • Protease Inhibitor: fosamprenavir/ritonavir, tipranavir/ritonavir – adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (see Table 2 of the full Prescribing Information). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.* • Dofetilide - coadministration is contraindicated with TIVICAY. • Carbamazepine* – adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (see Table 2 of the full Prescribing Information). Use alternative combinations that do not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.* (cont’d on next page)

BRIEF SUMMARY for TIVICAY® (dolutegravir) tablets (cont’d) • Oxcarbazepine, phenytoin, phenobarbital, St. John’s wort (Hypericum perforatum) – avoid coadministration with TIVICAY because there are insufficient data to make dosing recommendations. • Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids or laxatives, sucralfate, buffered medications – administer TIVICAY 2 hours before or 6 hours after taking medications containing polyvalent cations. • Oral calcium and iron supplements, including multivitamins containing calcium or iron – administer TIVICAY 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food. • Metformin – with concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TIVICAY. When stopping TIVICAY, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TIVICAY is recommended. • Rifampin – adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (see Table 2 of the full Prescribing Information). Use alternative combinations that do not include rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.* * The lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) upon coadministration with certain inducers may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. Consult full Prescribing Information for potential drug interactions; this list is not all-inclusive. Drugs without Clinically Significant Interactions with Dolutegravir: Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, darunavir/ritonavir, daclatasvir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, sofosbuvir/velpatasvir, and tenofovir. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TIVICAY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Preliminary data from an observational study has identified a possible increased risk of neural tube defects when TIVICAY is administered at the time of conception compared with non-dolutegravir-containing antiretroviral regimens. As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk. In addition, 2 of the 4 birth defects (encephalocele and iniencephaly), which have been observed with dolutegravir use, although often termed neural tube defects, may occur post-neural tube closure, the time period of which may be later than 6 weeks of gestation, but within the first trimester. Due to the limited understanding of the types of reported neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, avoid use of TIVICAY at the time of conception through the first trimester of pregnancy. No neural tube defects have been reported in infants born to mothers who have started TIVICAY after the first trimester of pregnancy. If there are plans to become pregnant or if pregnancy is confirmed while on TIVICAY during the first trimester, if possible, switch to an alternative regimen. Advise pregnant adolescents and adults of the potential risk to the embryo exposed to TIVICAY from the time of conception through the first trimester of pregnancy. There are insufficient human data on the use of TIVICAY during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. Lactation: The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known whether TIVICAY is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, dolutegravir was present in milk. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TIVICAY. Females and Males of Reproductive Potential: Perform pregnancy testing in adolescents and adults of childbearing potential before initiation of TIVICAY. Adolescents and adults of childbearing potential should avoid use of TIVICAY at the time of conception through the first trimester of pregnancy because of the potential risk of neural tube defects. Advise adolescents and adults of childbearing potential who are taking TIVICAY to consistently use effective contraception. Pediatric Use: The safety, virologic, and immunologic responses in subjects who received TIVICAY were evaluated in 46 treatment-experienced, INSTI-naïve, HIV-1–infected subjects aged 6 to less than 18 years in an open-label, multicenter,

dose-finding clinical trial, IMPAACT P1093. Frequency, type, and severity of adverse drug reactions among the 46 pediatric subjects were comparable to those observed in adults. In 17 subjects weighing at least 30 kg, pharmacokinetic parameters of dolutegravir were comparable to adults receiving 50 mg once daily. Safety and efficacy of TIVICAY have not been established in pediatric patients weighing less than 30 kg or in any pediatric patients who are INSTI-experienced. Geriatric Use: Clinical trials of TIVICAY did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TIVICAY in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment: No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment. Renal Impairment: Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls. However, no dosage adjustment is necessary for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. Dolutegravir has not been studied in patients on dialysis. OVERDOSAGE There is no known specific treatment for overdose with TIVICAY. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

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Revista Puertorriqueña de Medicina y Salúd Pública

Levantarse a las cuatro de la madrugada para una cita médica que finalmente se produce a las dos de la tarde, recibir el rechazo del plan médico al tratamiento que se le recomienda, que no se le apruebe un medicamento porque es excesivamente caro o no conseguir cita con un especialista en meses porque quedan muy pocos en Puerto Rico, es parte de la normalidad del sistema de salud que los pacientes asumen con estoicismo. Analizar pues lo que pasó en ese sistema en el año 2018 y lo que podemos esperar para el año 2019, tiene necesariamente que partir de esa desmoralizadora realidad. Nos espera más de lo mismo y las víctimas del sistema tendrán que aguantarse. Partimos de ahí para analizar tres cosas: (1) el estado de situación al cerrar el 2018 y sus motivos, (2) las posibilidades de cambio a la luz de los que pueda producir la metrópolis que controla económicamente el sistema desde el Congreso de Estados Unidos y (3) las posibilidades de cambios a nivel nacional para sobrellevar mejor el peso de la crisis de la salud. En cuanto a la primera, sin duda ya se reconoce que la raíz de la crisis del sistema de salud de Puerto Rico es el cambio de política pública de la salud como derecho, a política pública de la salud como negocio. Puerto Rico no es el único país que ha sufrido ese cambio, pero ciertamente nuestro empobrecimiento intencional ha hecho más difícil que acojamos esa transformación. A modo de explicación: a nivel mundial se reconocen dos razonamientos sobre la salud a nivel internacional: Que la destrucción del ecosistema es una de las causas principales de buena parte de los problemas de salud del planeta Que la medicina de hoy responde al negocio de las ciencias y no al altruismo sobre la salud como derecho humano. Un negocio que comienza con el desarrollo y formación de las profesiones de la salud, la administración de las facilidades de salud, el lucro de multimillonarias empresas farmacéuticas y las ganancias de las compañías aseguradoras, hasta la rentabilidad de las funerarias. Un negocio que se beneficia y especula sobre la enfermedad y la muerte. Esos dos razonamientos son acogidos por diferentes países desde dos puntos de vista de política pública: el salubrista (seguro de salud universal) o el comercial (el negocio de la salud). Desafortunadamente Puerto Rico, como colonia de un país administrador que ocupa la peor posición mundial en prestación de servicios de salud, se ubica precariamente en el segundo sector. Sobre el primer razonamiento no entramos en este escrito, aunque debemos destacar y no descartar que Revista Puertorriqueña de Medicina y Salúd Pública

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también sufrimos pertenecer a un país cuyo gobierno no reconoce el cambio climático y la destrucción del ecosistema. Sobre el segundo, no podemos pasar por alto que en 1993, ante la realidad de unos problemas económicos y de acceso poblacional al sistema que teníamos, el gobierno lo abandonó para imponer uno nuevo. Abandonó el sistema público salubrista (el Sistema Arbona) que aún con sus dificultades sirvió de ejemplo para muchos países, por la privatización del sistema. (El Sistema Arbona, diseñado por el doctor Guillermo Arbona en 1956 surgió a partir del sistema de seguro universal de salud británico de 1948 en el que los proveedores brindan servicios a toda la población sin intermediarios entre ellos y el gobierno responsable de la salud de los ciudadanos. La salud como derecho. Nuestro sistema nunca fue extensivo a toda la población y en 1993 fue sustituido por la privatización favorecida por la Reforma Rosselló. Desde entonces, el sistema de salud de Puerto Rico es uno de los más caros del mundo, arrastra un problema deficitario mucho más serio que el que nunca enfrentó antes y ha sido en buena medida responsable de toda la crisis económica del país.) Desde 1993, el sistema privatizado ha cambiado tres veces de nombre para tratar de mitigar su fracaso, ya que su incapacidad para sostenerlo económicamente es reconocida. Se estima que para el 2019 la inversión en el sistema de salud de Puerto Rico sea de unos $11.4 mil millones, dependiendo mayormente de fondos federales de Medicare y Medicaid (unos $7 mil millones) que actualmente se debaten en el Congreso por la desigualdad en asignaciones proporcionales a Puerto Rico por ser colonia. El resto se desglosa de una aportación del gobierno de $1.7 mil millones y $2.6 mil millones de patronos y ciudadanos en planes médicos privados. En otras palabras, Puerto Rico no puede sostener el gasto del sistema de salud que tiene, aún con la reducción poblacional que ha sufrido. El fallo más grande de este sistema es la falta de control del Estado sobre la salud de los ciudadanos. Ese control fue entregado a las compañías aseguradoras como intermediarias entre los proveedores de la salud y el gobierno. Esas aseguradoras son las que mantienen el sistema de racionamiento de tratamiento y medicamentos a los pacientes y las bajas tarifas a los proveedores para poder mantener sus ganancias que se estiman en sobre $200 millones para el 2019. Al entregarle la salud de los pobres a intermediarios para su lucro, el gobierno no solo ha burlado el principio 124

Revista Puertorriqueña de Medicina y Salúd Pública

fundamental de la salud como derecho declarado por la Organización Mundial de la Salud desde 1946, sino que ha perdido el control sobre la salud del país. La guerra económica contra las aseguradoras, por otro lado, también la han perdido los proveedores creando el tercer gran problema del sistema: la fuga de médicos. En los últimos años miles de médicos se han ido del país. De hecho, en la actualidad hay un déficit de médicos de todas las especialidades en Puerto Rico, a excepción de oftalmólogos y psiquiatras. Se calcula que en los últimos tres años se han ido del país seis de cada diez médicos generalistas y más de ocho mil especialistas. No es de extrañar cuando también se calcula que en los últimos tres años más de dos mil médicos han quedado fuera de los planes médicos por cancelación unilateral de sus contratos por parte de las compañías aseguradoras. El Colegio de Médicos Cirujanos ha advertido que en la actualidad Puerto Rico solo cuenta con un galeno especializado en medicina deportiva, cuatro cirujanos de colon y recto, dos dermopatólogos, dos cirujanos de cabeza y cuello, tres cirujanos de trauma, tres endocrinólogos pediátricos, tres nefrólogos pediátricos y dos radiólogos pediátricos. Como si fuera poco, sabiendo que Puerto Rico tiene una de las prevalencias más altas de cáncer y diabetes, solo contamos con veintiún oncólogos, veintisiete hematólogos, ocho hematólogos-oncólogos y treinta y tres endocrinólogos. Para colmo, en un país donde la población es cada día más vieja, apenas se cuenta con diez geriatras. La fuga de médicos se hace razonable si enumeramos sus razones: • Falta de control y fiscalización del gobierno sobre las aseguradoras • Decisiones unilaterales de las aseguradores en cuanto a procedimientos y medicamentos prescritos a sus pacientes • Pagos tardíos • Cancelación unilateral de sus contratos por parte de las compañías aseguradoras. • Diferencia en salarios médicos entre Puerto Rico y estados de Estados Unidos donde los nuestros pueden ejercer ( Diferencia por la falta de paridad en los programas federales Medicare y Medicaid.) • Médicos que se gradúan fuera de Puerto Rico y no regresan a ejercer al país donde saben de las dificultades que enfrentarían.

• Médicos que salen a completar sus especialidades

y no regresan porque su especialidad es codiciada y mejor pagada fuera de aquí. A lo anterior hay que añadir otra realidad: la edad mediana de la clase médica en Puerto Rico es de sesenta años. Los jóvenes se van o no regresan. Quedan en el país unos 9.500 médicos y una fracción de ellos son médicos retirados que continúan dentro del registro del Colegio. Visto el panorama local, lo segundo que hay que analizar es lo que ocurriría en el Congreso de Estados Unidos para el 2019. Dado que el sistema de salud de Puerto Rico depende casi en su totalidad de fondos federales, es preciso saber que esperar del nuevo Congreso.El optimismo sobre la ganancia demócrata en la Cámara de Representantes choca contra la realidad de que cualquier proyecto a favor de un sistema más favorable puede enredarse y colapsar en el Senado que controlan los republicanos. Ciertamente entre la población de Estados Unidos ha ganado terreno la propuesta de un seguro de salud universal de la mano de los elementos más liberales – y socialistas – del Partido Demócrata. El Partido Republicano, sin embargo, se sostiene precisamente sobre el principio de la mínima intervención del gobierno en la vida de sus ciudadanos y contra lo que se conoce como el Estado de Bienestar (“Welfare State”) que ha sido precisamente la base del sistema de salud universal de otros países como el Reino Unido que celebró en julio de 2018 los setenta años de sus sistema salubrista. La oposición republicana al Obamacare y todo el daño que le han infligido al programa de salud de la administración anterior surge precisamente de ese principio republicano de menos reglamentación gubernamental. Un sistema salubrista – que presupone la salud como derecho público, solidaridad y colaboración entre todos los elementos del sistema, acceso ilimitado a servicios de calidad, costos razonables, medicina preventiva y cuidado primario como clave esencial de un sistema que no esté sujeto a la competencia económica comercial – requiere de una visión política que los republicanos no tienen. El tranque legislativo entre demócratas y republicanos frente al sistema de salud que prevalezca para la metrópolis y la colonia continuará. Sin embargo, hay optimismo en la realidad de que los demócratas llegan con nuevos bríos – y más mujeres - al Congreso y que los republicanos se van a ver obligados a negociar muchas de sus posturas intransigentes si

quieren acumular puntos hacia las elecciones del 2020. Siendo así, el optimismo nuestro reside en que entre esas negociaciones avancen en alguna medida los pedidos de igualdad y paridad en los programas de Medicare y Medicaid para Puerto Rico. La resonancia del tratamiento nefasto de la administración Trump hacia Puerto Rico durante el episodio del Huracán María alimenta el optimismo de que los demócratas logren paliativos en el trato congresional para con Puerto Rico. Los republicanos saben de su desventaja emocional cuando se toca el tema relacionado con nuestro país. La asignación de fondos federales para corregir su actitud miserable no va a ser suficiente para la historia de ese capítulo de la historia. Podría sin embargo mitigar el trato desigual en algunos renglones. Esa es la esperanza de los que sostienen la visión de la salud como negocio. Más fondos para alimentar la codicia de los intermediarios, los contratistas del gobierno. Entretanto, hay quienes realmente están considerando medidas paralelas al margen de la pugna político partidista de demócratas y republicanos, para enderezar de alguna manera el sistema que ha hecho descender a Estados Unidos aparatosamente en las escalas de salud y educación a nivel mundial. Entre los años de 1990 a 2016, Estados Unidos bajó 21 puestos en esas escalas según el último estudio publicado por el Instituto de Métricas y Evaluación de la Salud de la Universidad de Washington. Ese estudio mide, entre otras cosas, la salud funcional de los ciudadanos para establecer escalas sobre su “capital humano”. Desde 1990, cuando ocupaba el lugar número 6 a nivel mundial, Estados Unidos ha descendido al lugar número 27. Lógico que eso no sea aceptable para una nación que quiere seguir viviendo de la ilusión de que es cuna de democracia y calidad de vida. A los que les importa les preocupa buscar nuevas avenidas para corregir ese desfase. Lo que parece que ganará terreno en el Congreso en el 2019 es trasladar a los estados, jurisdicción y facultad para manejar aspectos fundamentales del sistema de salud para sus ciudadanos. Hecho que estaría pensado para que unos estados logren antes que otros un sistema de salud salubrista sin intermediarios. De ser así, y de hacerse extensiva esa potestad a los territorios, estaríamos entrando en una nueva discusión en Puerto Rico. El tercer punto en el análisis sería entonces sobre lo que puede hacer Puerto Rico a nivel nacional para mejorar su sistema.Desafortunadamente, no vemos en el Revista Puertorriqueña de Medicina y Salúd Pública

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panorama ningún indicio a cambiar la visión gubernamental sobre el sistema de salud como negocio, un sistema privatizado en manos de las aseguradoras. A corto plazo entonces – hablamos de 2019 – veremos más de lo mismo: insistir en que el Plan Rosselló es el mejor y cabildear en el Congreso por fondos federales adicionales para sostenerlo manteniendo el rol protagónico de las aseguradoras como intermediarias entre los proveedores de la salud y el gobierno. Frente a eso la insistencia de lo contrario: un sistema de pagador único que abarate los costos y concentre en métodos salubristas de camino a un sistema de salud universal. Un sistema a tono con la economía real del país y el estado de salud de una población envejeciente y pobre. Al no ver cambios para el 2019 en la política pública del gobierno colonial en manos del partido que impuso en principio el sistema de salud deficiente y deficitario que tenemos, parece inminente que los cambios – si alguno en 2019 – sigan siendo eco de lo que produzca la metrópolis. En ese sentido, debemos entonces destacar una ruta que ya se viene trazando sin mucha fanfarria. Un método paralelo de trabajar por el regreso de una política salubrista donde el cuidado directo y preventivo prevalezcan. Ese podría ser el resultado favorable del Programa de Adherencia a Medicamentos impuesto por Medicare hace un par de años. Se trata del monitoreo efectivo de la adhesión – compromiso y cumplimiento - del paciente a su tratamiento, al uso adecuado y 126

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consistente de los medicamentos que le han sido recetados. Medicare Advantage obliga a las compañías aseguradoras a establecer medidas para garantizar la continuidad de los pacientes con lo recetado y las aseguradoras han recurrido a las farmacias de la comunidad para poner en marcha el programa. A hora, si n proponér selo, o sin anunciarlo, el sistema está descansando la dura pero imprescindible tarea del cuidado primario y la prevención en las farmacias de la comunidad. Y eso puede ser muy bueno. A propósito o por inercia, el sistema de salud de Puerto Rico comienza a colocar su aspecto primario y de prevención en las farmacias de las comunidades. No en las grandes cadenas sino en las farmacias de las comunidades que tienen una relación directa y constante con el sector poblacional más pobre y necesitado del país. La farmacia de comunidad y el farmacéutico siempre han sido de las instituciones más confiables de nuestra cultura. Eso se dislocó con la introducción de las grandes cadenas de mercados que incluyen un recetario en su oferta comercial. Aunque quebró a muchas, no las desplazó. De hecho, han regresado en conceptos híbridos mejorados. Eso es lo que reconoce esta nueva tendencia del sistema para utilizar las farmacias de comunidad como lo que han sido tradicionalmente centro de salud y centro comunal en sus vecindarios. La nueva tendencia es que la farmacia de comunidad se conv ierta en centro de información y educación en salud, consultorio, centro de referidos, centro de vacunación y sistema de seguimiento de tratamiento médico

y monitoreo de condiciones crónicas como hipertensión y diabetes. A eso le llaman terapia colaborat iva entre méd ico farmacéutico y paciente y es una iniciativa tan lógica como prometedora para reducir el caos en el sistema. En esta nota optimista nos gusta concluir y empezar el análisis de la crisis. Una nota optimista que descansa en la calidad de los seres humanos que integran el sistema, no en el sistema. Éste, por su parte, sigue en crisis y continuará en crisis mientras los principios que lo definen sean el de la salud como negocio y no como derecho. La alternativa reside en buscar maneras de burlar el caos con ingenio y solidaridad hasta que logremos regresar al sistema salubrista que corresponde a nuestra cultura y nuestra economía de pueblo empobrecido. Cuando la crisis es lo ordinario, tenemos que apostar a lo extraordinario. La autora es considerada la Decana y la conciencia del periodismo puertorriqueño. Periodista en medios de comunicación escrita, radial y televisiva. Comenzó en el periódico El Mundo. Miembro de la plantilla original de El Nuevo Día donde fungió como reportera en La Fortaleza, corresponsal en Estados Unidos y Jefa de Información del diario. Fue directora de noticias de Radio WADO en Nueva York, y columnista de El Diario/La Prensa. Productora, libretista y conductora de programas de radio y televisión. Consultora de medios en Puerto Rico y Estados Unidos.

Agenda 2018 Médica

www.medicinaysaludpublica.com

MSP Somos Ciencia

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

Revista Puertorriqueña de Medicina y Salúd Pública Sandra Berríos 787-236-6344 CONGRESO 787-630-5740

787-608-1477 ahomprgq@gmail.com

CONFERENCIA

CURSO

CONVENCIÓN

SIMPOSIO

CONVENCIÓN

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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

128

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 heh@hehpr.com

5 al 6 de abril Pulmonary and Critical Care Congress Título deFecha 2019 2019-Sociedad Puertorriqueña de Neumología

Ponce Hilton LugarPR Ponce,

Merna morales Business Planners o Contacto 787-706-0442 Coordinador bplanner21@gmail.com

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

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

CONGRESO CURSOS

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

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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.

Enfermedades infantiles crónicas: nueva realidad en la pediatría puertorriqueña La decimocuarta versión de la Asociación de Médicos Pediatras Región Este (AMPRE) se llevó a cabo a inicios de noviembre. Este año, las conferencias de los especialistas se orientaron hacia los nuevos retos que deben enfrentar los pediatras ante el aumento de ciertas condiciones en la población infantil y las estrategias del manejo del dolor crónico en el paciente pediátrico.

Dr. José J. Berdecía Rosa, Presidente de AMPRE

Más información:

Patólogos se educan en las nuevas tendencias del cáncer de mama Más información:

130

Conozca a la primera mujer presidente de la Sociedad Puertorriqueña de Neumología Más información:

José L. Pérez Berenger, presidente de APML

Dra. Daphne Delgado, presidenta de la Sociedad Puertorriqueña de Neumología

La Academia de Patología y Medicina de Laboratorio de Puerto Rico (APML) llevó a cabo un seminario sobre los conceptos patológicos del cáncer de seno. Entre los temas mayormente tratados se encuentran las lesiones papilares, lesión de células fusiformes del seno, el sistema de estadificación por el American Joint Committe on Cancer (AJCC) para conocer la progresividad en los pacientes con cáncer.

Durante la pasada convención organizada por la Sociedad Puertorriqueña de Neumología, se presentó a la nueva presidenta de la sociedad. Se trata de la Dra. Daphne Delgado, médica graduada de la Escuela de Medicina en Ponce y especializada en Neumología en Estados Unidos. Desde que inició formalmente las labores de su cargo, ha llevado a cabo iniciativas para dar la conocer la sociedad no solo a los especialistas sino también a los pacientes.

Revista Puertorriqueña de Medicina y Salúd Pública

Revista

Exitosa convención del Colegio de Médicos Cirujanos de Puerto Rico La convención más grande de los médicos cirujanos en la isla se llevó a cabo durante el primer fin de semana de diciembre. En esta ocasión, 3.600 médicos participaron en múltiples conferencias sobre el zika, chikungunya, dengue, técnicas especiales en el manejo del dolor y el uso apropiado de antibióticos. De esta manera, los especialistas buscan mejorar la atención y la obtención del diagnóstico de los pacientes. Vale destacar que el gobernador Ricardo Roselló también hizo parte de esta convención con una ponencia de calidad científica sobre la importancia de las células madre para la medicina actual.

Educan para la prevención de la diabetes en la convención de la Sociedad Puertorriqueña de Endocrinología y Diabetología Más información:

Más información:

Dr. Víctor Ramos presidente del Colegio de Médicos de Puerto Rico.

Cumbre sobre el VIH/ Sida enfocada en pacientes transgénero y al manejo clínico de la enfermedad Más información:

Dr. Luis Raúl Ruiz Rivera, presidente de SPED Doctor Iván Meléndez Rivera

La convención anual de la Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED) se llevó a cabo durante los primeros días de diciembre. En esta ocasión, los temas tratados se orientaron al cuidado de la mujer y su esperanza de vida tras el diagnóstico de diabetes o de ciertas condiciones endocrinas, ya que la mitad de mujeres en la isla sufren de estos males sin ninguna causa común conocida.

Con el fin de visualizar y dar a conocer los avances sobre el tratamiento del VIH, se llevó a cabo la Cumbre sobre el VIH/SIDA para el Cuidado Primario de la Excelencia. Un evento que contó con el apoyo del gobierno de la isla y de varias entidades privadas. En esta actividad se realizaron varias conferencias, dictadas por especialistas en cuidado, tratamientos, recursos y estrategias de prevención de la enfermedad. Revista Puertorriqueña de Medicina y Salúd Pública

131

Revista

Alergistas se unen para educar sobre esta condición en Puerto Rico Más información:

Salud firma acuerdo con ASES para ampliar beneficios a pacientes que viven con VIH

Más información:

Doctor Rafael Zaragoza, presidente de la Asociación Puertorriqueña de Médicos Alergistas.Rodríguez Mercado

Secretario de Salud de República Dominicana, Dr. Rafael Rodríguez Mercado

Antes de finalizar el año, se llevó a cabo el Congreso Anual de Alergia e Inmunología de la Asociación Puertorriqueña de Médicos Alergistas. En el evento, diez especialistas y profesores de la salud lideraron ponencias sobre las nuevas tendencias en esta rama de la medicina y educar en los hallazgos para tratar y prevenir las comorbilidades ocasionadas por esta enfermedad. Se destaca la participación de 150 médicos, quienes en calidad de asistentes conocieron aspectos de primera mano sobre las alergias y el sistema inmune.

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. La enmienda firmada, incluye tres medicamentos adicionales que fueron aprobados recientemente por la Administración de Drogas y Alimentos (FDA, por sus siglas en inglés) para tratar la condición de VIH.

Lilly ilumina a Puerto Rico para crear conciencia sobre la diabetes

Merck conmemora 70 años en la industria farmacéutica de Puerto Rico Más información:

Eli Lilly and Company (NYSE: LLY) Puerto Rico conmemoró el Día Mundial de la Diabetes, 14 de noviembre, iluminando con una luz azul brillante el edificio de la empresa cerca de la carretera PR #3. La exhibición es parte de los esfuerzos anuales de Lilly cada noviembre para crear conciencia sobre una condición que afecta a más de 420 millones de personas en todo el mundo. Además de ello, el personal de Lilly proporciona con estas actividades, recursos educativos a profesionales de la salud para apoyar a sus pacientes durante su trayectoria. 132

Revista Puertorriqueña de Medicina y Salúd Pública

Comité Ejecutivo de Merck La biofarmacéutica Merck conmemoró 70 años de trabajo en Puerto Rico. Durante ese tiempo, ha estado innovando, descubriendo medicinas y vacunas para atender los retos de salud pública más complejos en las comunidades de la isla. Entre estos, se destacan los 30 centros de investigación clínica, en áreas terapéuticas como la diabetes, oncología, enfermedades infecciosas y vacunas, manejados por un equipo de investigadores y desarrolladores locales.De esta manera, se asegura el acceso a los pacientes para mejorar su calidad de vida.

Revista

Exitosa labor de la Unidad de Rehabilitación del Hospital Auxilio Mutuo

Más información:

Reumatólogos de Puerto Rico a la vanguardia de nuevos tratamientos

Más información:

Dr. Luis Espinoza, dermatólogo y expresidente de la Sociedad Dermatológica de Puerto Rico.

Melisa Martínez, presidenta de la Asociación de Reumatólogos de Puerto Rico

La recién inaugurada Unidad Especializada en Rehabilitación del Hospital Auxilio Mutuo atiende -por ahora- más de 15 pacientes con complicaciones médicas que les han afectado su diario vivir. Además, los pacientes se educan sobre nuevas maneras de realizar tareas, uso de equipo adaptativo y prevención de futuras complicaciones.

La Asociación de Reumatólogos de Puerto Rico ofrece -de forma constante- conferencias educativas para los especialistas en esta rama de la medicina. Como parte de esta iniciativa, llevó a cabo una actividad de actualización sobre la miositis y el manejo del dolor donde alrededor de 50 expertos aprovecharon la oportunidad. Se estima que en Puerto Rico existen más de 70 profesionales en este campo en el país y más de 12 mil pacientes.

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

Nuevo método para reconocer a los pacientes en coma que reaccionan ante las palabras

Dr. Alexis Cruz Chacón, Director del Centro de Trasplante de Médula Osea del Hospital Auxilio Mutuo

Dr. Amílcar Rodríguez y Dra. Aileen Santos, ambos dermatólogos.

El primer trasplante de médula ósea alogénico en paciente con un cáncer tipo linfoma periférico de células T en Puerto Rico, se realizó a inicios de noviembre. El procedimiento estuvo a cargo del Dr. Alexis Cruz Chacón, director del Centro de Trasplante de Médula Ósea del Hospital Auxilio Mutuo. Nunca se había realizado y de ahora en adelante serviría como una nueva alternativa para pacientes con cáncer de linfoma tipo agresivo que muchas veces no responden a quimioterapi

Investigadores de varios centros estadounidenses han desarrollado un nuevo método para evaluar a las personas en estado profundo de inconsciencia y distinguir a los pacientes que, aunque no pueden hablar, mantienen su capacidad cognitiva a pleno rendimiento. La técnica, basada en el uso de la electroencefalografía (EEG), se publicó el pasado mes de noviembre en la revista Current Biology.

Más información:

Revista Puertorriqueña de Medicina y Salúd Pública

133

Los genetistas en Puerto Rico: testimonio de entrega total a la investigación científica

Santiago Cornier, MD, PhD

El propósito de los médicos puertorriqueños especialistas en genética va más allá de comprender enfermedades y trastornos poco comunes. Desde sus investigaciones y laboratorios, estos galenos buscan mejorar la calidad de vida de los afectados con enfermedades raras, a través de la constante búsqueda de tratamientos que garanticen su calidad de vida. De esta manera, los doctores Juan Santiago Cornier y Simón Carlo Torres y las doctoras Myrna Borges - ya fallecida - y María del Carmen González, han labrado su nombre como los únicos en Puerto Rico y por ser destacados especialistas en esta área de la medicina, no solamente en la isla sino también a nivel internacional. A cada uno de ellos, se deben importantes triunfos relacionados con el estudio de anomalías y síndromes de origen genético, hallazgos que permiten un significativo avance no solamente para los médicos tratantes sino para la población afectada. Entre ellos, destacamos los hallazgos de los Dres. Cornier y Carlo sobre el síndrome de Jarcho - Levin, condición en la que la isla lidera las estadísticas y que se diagnostica en la infancia, el trabajo de la Dra. Myrna Borges en 134

Revista Puertorriqueña de Medicina y Salúd Pública

Simón Carlo, MD

el tratamiento de condiciones genéticas en la población infantil y la Dra. María del Carmen González, cuyo trabajo profesional se centra en la investigación de anomalías genéticas. Todos ellos realizan un trabajo tan exigente como gratificante. Tras sus valiosos esfuerzos, se encuentran horas y días que no pasan inadvertidos a los ojos de sus pacientes y colegas. No en vano existe la Fundación Ser de Puerto Rico, una institución creada con la misión de ayudar a la población con discapacidad y autismo, en la que también prestan sus servicios desinteresadamente dos de los únicos genetistas de la isla. Una realidad que -para estos escasos especialistas- es imprescindible cambiar. Hoy la genética en Puerto Rico -a pesar de sus falencias-, no sería igualmente eficaz sin su arduo trabajo, recompensado por los descubrimientos, avances y posibilidades que abren en el mundo de la medicina para asegurar el progreso de una área que necesita más profesionales adeptos. Mientras tanto, entregamos un merecido reconocimiento y el deseo de miles de éxitos más en el ejercicio de su profesión.

Trabajamos con múltiples

terapias de medicamentos para

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Llama 787-892-8700 Fax:787-264-5800 Centro de Despacho de Recetas:

San Germán Medical Plaza Suite 107 San German, PR 00683

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