Pregunte a su equipo del cuidado de la salud si EMEND es adecuado para usted.

Visite emend.com para conocer ms.

Las marcas mencionadas son marcas de sus respectivos dueos.

2011 Merck Sharp & Dohme Corp., una subsidiaria de Merck & Co., Inc. Derechos reservados. ONCO-1010177-0000 emend.com

No acepte las nuseas y los vmitos de la quimioterapiaPrevngalos con la ayuda de EMEND.EMEND, en combinacin con otras medicinas, ayuda a prevenir las nuseas y los vmitos inducidos por la quimioterapia (NVIQ).Informacin importante acerca de EMENDEMEND se utiliza en adultos para prevenir las nauseas y los vmitos causados por ciertas medicinas contra el cncer. EMEND siempre se usa con otras medicinas para tratar las nuseas y los vmitos.

EMEND no se usa para tratar las nauseas y los vmitos existentes.

EMEND no debe usarse de forma continua por tiempo prolongado (uso crnico).

No tome EMEND si est tomando Orap (pimozide), Seldane (terfenadina), Hismanal (astemizol) o Propulsid (cisapride). Tomar EMEND con cualquiera de estas medicinas pudiera causar problemas graves o potencialmente mortales. No tome EMEND si usted es alrgico a cualquiera de los ingredientes de EMEND.

Antes de tomar EMEND, informe a su mdico si tiene problemas del hgado.

Antes de tomar EMEND, informe a su mdico si est embarazada o planea quedar embarazada porque se desconoce si EMEND puede hacer dao a su beb por nacer. Las mujeres que usan medicinas para el control de la natalidad que contienen hormonas (pldoras anticonceptivas, parches para la piel, implantes y ciertos DIU) deben tambin usar un mtodo de respaldo para el control de la natalidad durante el tratamiento con EMEND y hasta por 1 mes despus de usar EMEND para prevenir el embarazo.

Antes de tomar EMEND, informe a su mdico si est lactando porque se desconoce si EMEND pasa a la

leche y si puede causar dao a su beb.

EMEND puede afectar cmo otras medicinas trabajan, incluida la quimioterapia. Otras medicinas pueden afectar cmo trabaja EMEND. Informe a su mdico acerca de todas las medicinas que est usando o planea usar, incluidas las medicinas con receta y las que no requieren receta mdica, vitaminas y suplementos naturales.

Si toma la medicina warfarina sdica (Coumadin o Jantoven) para hacer fluida la sangre, su mdico puede hacerle pruebas de sangre despus de tomar EMEND para verificar la coagulacin de su sangre.

EMEND puede causar efectos secundarios graves, incluidas reacciones alrgicas como ronchas, erupcin, picor y dificultad para respirar o tragar. Deje de tomar EMEND y llame a su mdico de inmediato si tiene cualquiera de estas seales o sntomas de una reaccin alrgica.

Los efectos secundarios ms comunes de EMEND son cansancio, nuseas, hipo, estreimiento,diarrea, prdida de apetito, dolor de cabeza y prdida de cabello.Estos no son todos los efectos secundarios posibles de EMEND.

Se le exhorta a informar los efectos secundarios negativos de los medicamentos recetados a la FDA. Visite www.fda.gov/medwatch o llame al 1-800-FDA-1088.

EMEND est disponible con receta mdica solamente. Por favor, lea la Informacin para el paciente para EMEND en la siguiente pgina y disctala con su mdico.

Merck Oncology

Informacin para el pacienteEMEND (EE mend)

(aprepitant)Cpsulas

Lea la Informacin para el paciente que viene con EMEND antes de comenzar a tomarlo y cada vez que repita su receta. Puede haber informacin nueva. Este folleto no sustituye una conversacin con su mdico sobre su condicin mdica o tratamiento.

Qu es EMEND?

EMEND es un medicamento recetado usado en adultos para prevenir nuseas y vmitos: causados por ciertas medicinas contra el cncer (quimioterapia). Cuando se usa para este propsito, EMEND siempre se usa con otras medicinas. despus de ciruga.

EMEND no se usa para tratar las nuseas y los vmitos existentes.EMEND no debe usarse de forma continua por tiempo prolongado (uso crnico).

Se desconoce si EMEND es seguro y efectivo en nios.

Quin no debe tomar EMEND?

No tome EMEND si:

est tomando cualquiera de las siguientes medicinas: ORAP (pimozide) SELDANE (terfenadina) HISMANAL (astemizol) PROPULSID (cisapride)

Tomar EMEND con cualquiera de estas medicinas pudiera causar problemas graves o potencialmente mortales.

es alrgico a cualquiera de los ingredientes de EMEND. Vea al nal de este folleto una lista de los ingredientes de EMEND.

Qu debo decirle a mi mdico antes y durante el tratamiento con EMEND?

Antes de tomar EMEND, informe a su mdico si:

tiene problemas del hgado

est embarazada o planea quedar embarazada. No se conoce si EMEND puede hacerle dao a su beb por nacer.

Las mujeres que usan medicinas para controlar la natalidad que contienen hormonas para prevenir el embarazo (pastillas anticonceptivas, parches de la piel, implantes y ciertos DIU) tambin deben usar un mtodo de respaldo para el control de la natalidad durante el tratamiento con EMEND y hasta por 1 mes despus de tomar EMEND para prevenir el embarazo. est lactando. Se desconoce si EMEND pasa a la leche y si puede hacerle dao a su beb.

Informe a su mdico sobre todas las medicinas que est usando o planea usar, incluidas las medicinas con receta y las que no requieren receta mdica, vitaminas y suplementos naturales.

EMEND puede causar reacciones graves potencial-mente mortales si se usa con ciertas medicinas. Vea la seccin Quin no debe tomar EMEND?

EMEND puede afectar cmo otras medicinas trabajan, y otras medicinas pueden afectar cmo EMEND trabaja. Pregunte a su mdico o farmacutico antes de usar cualquier medicina nueva. Ellos pueden decirle si es seguro tomar la medicina con EMEND.

Conozca las medicinas que usa. Tenga una lista de estas para mostrarla a su mdico o farmacutico cuando obtenga una medicina nueva.

Cmo debo tomar EMEND?

Tome EMEND tal como se lo recetaron. Si toma demasiado EMEND, llame a su mdico, departamento de emergencia local o al centro de control de envenenamientos de inmediato.

Si recibe quimioterapia para el cncer, EMEND se toma en 3 dosis durante 3 das - comenzando el da que recibe la quimioterapia, y los dos das despus de la quimioterapia. Hay dos maneras en que su mdico puede recetarle EMEND:

1. Cpsulas de EMEND por va oral para las 3 dosis:

Debe recibir un paquete con tres cpsulas de EMEND. Da 1 (el da de la quimioterapia): Tome una cpsula de 125 mg de EMEND (blanca y rosada) por boca 1 hora antes de comenzar la quimioterapia; Da 2 y Da 3 (los dos das despus de la quimioterapia): Tomar una cpsula de 80 mg de EMEND (blanca) por va oral, cada maana durante los 2 das despus de su quimioterapia.

,

2. Inyeccin intravenosa (IV) en una vena el primer da, luego cpsulas por va oral los dos das despus de la quimioterapia:

Da 1 (el da de la quimioterapia): recibir EMEND en inyeccin intravenosa (IV) por la vena 30 minutos antes de comenzar su quimioterapia. Debe recibir un paquete con dos cpsulas de EMEND. Da 2 y Da 3 (los dos das despus de la quimioterapia): Tome una cpsula de 80 mg de EMEND (blanca) por boca, cada maana durante los 2 das despus de su quimioterapia.

Si est recibiendo quimioterapia, puede tomar EMEND con o sin alimentos.

9988902

Si se va a someter a ciruga:

Su mdico le recetar una cpsula de 40 mg de EMEND antes de la ciruga. Tomar EMEND tres horas antes de la ciruga. Siga las instrucciones de su mdico en cuanto a las restricciones de comidas y bebidas antes de la ciruga.

Si toma la medicina warfarina sdica (Coumadin o Jantoven) para hacer fluida la sangre, su mdico puede hacerle pruebas de sangre despus de tomar EMEND para verificar la coagulacin de su sangre.

Cules son los posibles efectos secundarios de EMEND?

EMEND puede causar efectos secundarios graves, que incluyen:

Reacciones alrgicas graves. Reacciones alrgicas pueden ocurrir con EMEND y pueden ser graves. Deje de usar EMEND y llame a su mdico de inmediato si tiene cualquiera de estas seales o sntomas de una reaccin alrgica: ronchas erupcin picor dificultad para respirar o tragar. Rara vez pueden ocurrir reacciones severas de la piel.

En personas que usan EMEND para prevenir las nuseas y los vmitos causados por la quimioterapia, los efectos secundarios ms comunes de EMEND incluyen:

cansancio nuseas hipo estreimiento diarrea prdida de apetito dolor de cabeza prdida del cabello

En personas que toman EMEND para prevenir nauseas y vmitos despus de una ciruga, losefectos secundarios ms comunes son: estreimiento nuseas picor fiebre presin arterial baja dolor de cabeza

Informe a su mdico si tiene algn efecto secundario que le molesta o que no desaparece. Estos no son todos los efectos secundarios posibles de EMEND. Para ms informacin, pregunte a su mdico o farmacutico.

Llame a su mdico para obtener consejo mdico en cuanto a los efectos secundarios. Puede notificar los efectos secundarios a la FDA al 1-800-FDA-1088.

Cmo debo almacenar EMEND? Almacene EMEND a temperatura ambiente, entre 68F y 77F (20C y 25C). Mantenga EMEND y todas las medicinas fuera del alcance de los nios.

Informacin general acerca de EMEND

A veces, las medicinas se recetan para condiciones que no se mencionan en los folletos de informacin para el paciente. No use EMEND para una condicin para la cual no fue recetada. No d EMEND a otras personas, aunque tengan los mismos sntomas que usted. Pudiera causarles dao.

Este folleto de Informacin para el Paciente resume la informacin ms importante de EMEND. Si quisiera saber ms informacin, hable con su mdico. Puede solicitar a su mdico o farmacutico informacin acera de EMEND que est escrita para profesionales de la salud. Para ms informacin acerca de EMEND llame al 1-800-622-4477 o visite www.emend.com.

Cules son los ingredientes de EMEND?

Ingrediente activo: aprepitant

Ingredientes inactivos: sucrosa, celulosa microcris-talina, hidroxipropil celulosa y lauril sulfato sdico. Los excipientes de la capa de la cpsula son gelatina, dixido de titanio y puede contener lauril sulfato sdico y dixido de silicona. La capa de la cpsula de 125 mg tambin contiene xido frrico rojo y xido frrico amarillo. La capa de la cpsula de 40 mg tambin contiene xido frrico amarillo.

Patente de los EE.UU Nm.: 5,145,684; 5,719,147; 6,048,859; 6,096,742; 6,235,735

Las marcas mencionadas en las secciones anteriores Quin no debe tomar EMEND? y Qu debo decirle a mi mdico antes y durante el tratamiento con EMEND? son marcas registradas de sus respec-tivos dueos y no son marcas de Merck Sharp & Dohme Corp., una subsidiaria de Merck & Co., Inc.

EMEND es una marca registrada de Merck Sharp & Dohme Corp., una subsidiaria de Merck & Co., Inc.

Derechos reservados 2003, 2005, 2006Merck Sharp & Dohme Corp., una subsidiaria de Merck & Co., Inc.

Derechos reservados.

Emitido en Marzo 2011

Merck Sharp & Dohme Corp.,una subsidiaria de Merck & Co., Inc.Whitehouse Station, NJ 08889, USA

ONCO-1010177-0000

9988902

EnsureClinical StrengthEl mo es...

Nutre tu Cuerpo. Toma

Endosado por:

Nutricin Completa y Balanceada para tu Salud.

Hay uno para ti.

Anita Gregorio es sobreviviente de cncer.El Ensure de ella es Clinical Strengthcon REVIGOR (una fuente de HMB),que ayuda a proteger, preservar y promoverla masa magra corporal.

Tambin tiene IMMUNE BALANCE, una mezcla nica de fibra prebitica y antioxidantes* para ayudar a apoyar el sistema inmunolgico.

Adems, tiene Calcio y ms caloras que Ensure Nutrition Shake, para ayudarla a

mantener su energa durante el proceso de recuperacin.

Anita GregorioRelacionista Profesional,sobreviviente de cncery usuaria de Ensure

www.Ensure.com

*Vitamina C, E y Selenio.

BoneHealth

Immune

Health

NutritionShake

MuscleHealth

Plus

ClinicalStrength

ClinicalStrength

2011 Abbott Laboratories, Inc. APR-110123 LITHO IN P.R.

FP Ad y Ed Ensure Clinical MED Y SALUD PUb.indd 2 9/20/11 4:42 PM

*Clnicamente probado que minimiza los picos de glucosa en sangre comparado con otros productos nutricionales de uso general.Use los productos Glucerna bajo supervisin mdica como parte de su plan de alimentacin para la diabetes.

www.miglucerna.com

Cuando tienes diabetes, mantener el control en la vida es difcily a veces no tienes tiempo para comer lo que debes.

Los productos Glucerna, contienen una mezcla nica de hidratos de carbono que ayuda a disminuir los picos en el nivel de glucosa en sangre*. Al disminuirlos, con

el tiempo pueden ayudar a reducir los niveles de A1C.

2010 Abbott Laboratories, Inc. APR-100378 LITHO IN PR

Programa Socios Saludables Glucernanete y recibirs consejos, descuentos y muchos otros beneficios exclusivos para socios. Para inscribirte hoy, llama al: 1-888-991-9116 o accede www.tomacontrolpr.com

PUEDEAYUDAR A

REDUCIR EL

A1C*

Endosado por:

20AOS

CON DIABETES POR

MEJ

ORAN

DO

LAS VIDAS DE LAS PERSONAS

Ayudando a las Personascon Diabetes a Tomar Control

NUEVOEMPAQUEMISMO GRAN SAB

OR!

IMPORTANT SAFETY INFORMATIONSERIOUS INFECTIONSPatients treated with ENBREL 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 or were predisposed to infection because of their underlying disease. ENBREL should not be initiated in the presence of sepsis, active infections, or allergy to ENBREL or its components. ENBREL should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: 1) Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before ENBREL use and periodically during therapy. Treatment for latent infection should be initiated prior to ENBREL use, 2) Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric antifungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness, and 3) Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with ENBREL should be carefully considered prior to initiating therapy in patients 1) with chronic or recurrent infection, 2) who have been exposed to TB, 3) who have resided or traveled in areas of endemic TB or endemic mycoses, or 4) with underlying conditions that may predispose them to infections such as advanced or poorly controlled diabetes. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ENBREL, including the possible development of TB in patients who tested negative for latent TB prior to initiating therapy.

MALIGNANCIESLymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including ENBREL.

In adult clinical trials of all TNF blockers, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA and psoriasis patients. The role of TNF blocker therapy in the development of malignancies is unknown.

Cases of acute and chronic leukemia have been reported in association with postmarketing TNF blocker use in RA and other indications. The risk of leukemia may be higher in patients with RA (approximately 2-fold) than the general population.

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF blockers, including ENBREL. Periodic skin examinations should be considered for all patients at increased risk for skin cancer.

Pediatric PatientsIn patients who initiated therapy at 18 years of age, approximately half of the reported malignancies were lymphomas (Hodgkins and non-Hodgkins lymphoma). Other cases included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.

NEUROLOGIC EVENTSTreatment with TNF-blocking agents, including ENBREL, has been associated with rare (< 0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barr syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with ENBREL therapy. Prescribers should exercise caution in considering the use of ENBREL in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.

CONGESTIVE HEART FAILURECases of worsening congestive heart failure (CHF) and, rarely, new-onset cases have been reported in patients taking ENBREL. Caution should be used when using ENBREL in patients with CHF. These patients should be carefully monitored.

HEMATOLOGIC EVENTSRare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. The causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL in patients who have a previous history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. Consider discontinuing ENBREL if significant hematologic abnormalities are confirmed.

HEPATITIS B VIRUS REACTIVATIONUse of TNF blockers, including ENBREL, has been associated with reactivation of hepatitis B virus (HBV) in chronic carriers of this virus. The majority of these reports occurred in patients on concomitant immunosuppressive agents, which may also contribute to HBV reactivation. Exercise caution when considering ENBREL in patients identified as carriers of HBV.

ALLERGIC REACTIONSAllergic reactions have been reported in < 2% of patients in clinical trials of ENBREL.

IMMUNIZATIONSLive vaccines should not be administered to patients on ENBREL. JIA patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, consider temporary discontinuation of ENBREL and prophylactic treatment with Varicella Zoster Immune Globulin.

AUTOIMMUNITYAutoantibodies may develop with ENBREL, and rarely lupus-like syndrome or autoimmune hepatitis may occur. These may resolve upon withdrawal of ENBREL. Stop ENBREL if lupus-like syndrome or autoimmune hepatitis develops.

WEGENERS GRANULOMATOSIS PATIENTSThe use of ENBREL in patients with Wegeners granulomatosis receiving immunosuppressive agents (e.g., cyclophosphamide) is not recommended.

MODERATE TO SEVERE ALCOHOLIC HEPATITISBased on a study of patients treated for alcoholic hepatitis, exercise caution when using ENBREL in patients with moderate to severe alcoholic hepatitis.

ADVERSE EVENTSThe most commonly reported adverse events in RA clinical trials were injection site reaction, infection, and headache. In clinical trials of all other adult indications, adverse events were similar to those reported in RA clinical trials.

DRUG INTERACTIONSThe use of ENBREL in patients receiving concurrent cyclophosphamide therapy is not recommended. The risk of serious infection may increase with concomitant use of abatacept therapy. Concurrent therapy with ENBREL and anakinra is not recommended. Hypoglycemia has been reported following initiation of ENBREL therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

References: 1. Data on file, Amgen. 2. Enbrel (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks, Calif. September 2011. 3. Gordon KB, Gottlieb AB, Leonardi CL, et al; for the Etanercept Psoriasis Study Group. Clinical response in psoriasis patients discontinued from and then reinitiated on etanercept therapy. J Dermatol Treat. 2006;17:9-17. 4. Weinblatt ME, Bathon JM, Kremer JM, et al. Safety and efficacy of etanercept beyond 10 years of therapy in North American patients with early and long-standing rheumatoid arthritis [published online ahead of print October 18, 2010]. Arthritis Care Res (Hoboken). doi: 10.1002/acr.20372.

Please see Brief Summary of Prescribing Information on following pages.

Show off the long-term

Since 2006 Since 2008 Since 2005 Since 2002* Since 2005

Give your moderate to severe plaque psoriasis patients the chance to

Long-term, recapturable efficacy Rapid and sustained efficacy for up to 2.5 years1 In clinical trials, nearly half of patients saw significant improvement

in their moderate to severe plaque psoriasis by week 12 with ENBREL. Overall, 3 out of 4 patients saw improvement1,2

ENBREL recaptured almost all of its initial response following suspension of treatment for up to 5 months1-3

Please see Important Safety Information on previous page.

Long-term safety profile 3 years of continuous safety data in moderate to severe plaque psoriasis1 10 years of continuous safety data in moderate to severe rheumatoid

arthritis (RA)1,4

Long-term experience 18 years of clinical experience in RA1,2 More than 13 years of postmarketing experience since approval for

moderate to severe RA in 1998 More than 7 years of postmarketing experience since approval for

moderate to severe plaque psoriasis in 2004 More than 2.8 million patient-years of worldwide postmarketing experience1

These actual ENBREL patients can get back to doing many of the things they love

TTTTTTTRRRRUUUSSTT YYYYOOOUUURRRTTTTTT

RRRRRUUSSTT YYOO

EEEEEEEXXXXX PPPPPPPPPPEEEEEEE RRRRRR IIIIII EEEEEE NNNNNNNN CCCCCCCCCCCC EEEEEEEEEEEEEE

experience of ENBREL

Since 2002* Since 2004 Since 2008 Since 2003*

Important Safety Considerations: ENBREL has been associated with serious and sometimes fatal infections, including opportunistic infections and TB. Malignancies, neurologic events, hematologic events, and hepatitis B reactivation have also been reported. Common adverse reactions: headache, infection, and injection site reaction.

Prescription ENBREL is administered by injection.

ENBREL is indicated for: The treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis. ENBREL can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

* Clinical trial patient; ENBREL approved for adult chronic moderate to severe plaque psoriasis in May 2004. Initial clinical research in RA patients began in 1993. ENBREL approved for psoriatic arthritis in 2002 and for adult chronic moderate to severe plaque psoriasis in 2004. Based on estimated number of patient-years from 1998 through May 2011. As of May 2011, estimated patient-years is 2,845,000. Estimated number of patient-years

is calculated by region based on the number of ENBREL units distributed and an estimated average dose. Based on year of FDA approval.

62597-R1-V1

Los Bebs Fuertes Empiezan Aqu.

LUTENA& DHA

APOYO

INMUNOLGICO

CE

RE

BR

O Y O

JOS HU

ESO

S FU

ER

TES

Similac con EarlyShieldTM, es la nica frmula infantil que tiene lutena, nutriente especial que ayuda a apoyar la salud de los ojos de tu beb.

Adems, estudios recientes sugieren que la lutena puede ayudar a proteger los cidos grasos omega; como el DHA que es un nutriente importante para el desarrollo de los ojos y cerebro de tu beb.

La lutena puede encontrarse solamente en la leche materna o en Similac con EarlyShield.

Tu beb aprende con sussentidos, incluyendo la visin. Su buena nutricin juega un papel importante en el desarrollo de su cerebro y ojos.

AUTORIZADASEN EL PROGRAMA

WIC*

EarlyShieldTM esta presente en:

Accede: www.STRONGMOMS.COM Encontrars un mundo de herramientas, consejos y guas para el cuidado de tu beb desde su etapa prenatal. Tambin podrs bajar la nueva aplicacin BABY JOURNAL para que lo lleves contigo siempre (disponible para IPhone o Ipod touch)

Con exclusin de todas las fuentes inherentes. Antes de comenzar alimentos slidos.* Autorizada en el Programa WIC de Puerto Rico. WIC es una marca registrada del Departamento de Agricultura de los Estados Unidos y con la abreviacin de un programa especial para mujeres, infantes y nios. 2011 Abbott Laboratories, Inc. APR-110045 ( April 2011) LITHO in Puerto Rico

Medicina y Salud Publica APR-110045.indd 1 4/14/11 10:44 AM

POWERFUL

PAIN MANAGEMENT

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

For the management of moderate to severe chronic pain

in adults when a continuous, around-the-clock opioid analgesic is

needed for an extended period of time

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

An 11-point pain intensity scale. A score of 0 being no pain; a score of 10 being pain as bad as you can imagine. Clinical trials were conducted with controlled-release oxycodone, which is the opioid ingredient in OxyContin. Intent-to-treat population included all randomized subjects who received at least one dose of study drug. II Safety population included all subjects who received at least one dose of study drug (N=965). Patients had a mean baseline pain intensity score of 7.5. Incidence is based on the number of

subjects experiencing at least one adverse event, not the number of events. OxyContin is a registered trademark of Purdue Pharma Inc.

* In a double-blind study, eligible patients were randomized 1:1:1 (N=981) to receive NUCYNTA ER, oxycodone CR, or placebo. The intent-to-treat population included 958 patients. Primary ef cacy analysis is based on the last observation carried forward (LOCF) imputation method. Treatment comparisons used ANCOVA model and were based on least squares mean difference from placebo.

Primary ef cacy endpoint was change from baseline of the mean pain intensity scores at Week 12 based on NRS1 Patients had an overall mean pain intensity score of 7.5 at baseline1 Oxycodone CR was included in the study for assay sensitivity2

NUCYNTA ER DEMONSTRATED POWERFUL EFFICACY IN LOW BACK PAIN

TOLERABILITY PROFILE

IIn aan ddodouble-blind study elieligibgiblee patients were randomized 1:1:1 (N=981) to receive NUCYNTA ER oxycodone CR or placebo The intent-to-treat population

NUCYNTA ER DEMONSTRATED POWERFUL EFFICACY IN LOW BACK PAIN

*I*I**In an an an a ddodododo blblbublubl bbbe bliliililinddd sd ddtuddy elileligibgiblele patients were randomized 1:1:1 (N=981) to receive NUCYNTA ER oxycodone CR or placebo The intent to treat population

NUCYNTA ER DEMONSTRATED POWERFUL EFFICACY IN LOW BACK PAIN

Mean change in pain intensity at Week 12 from baseline as measured by Numerical Rating Scale (NRS)1

-1.0-1.5-2.0-2.5

-0.5

-3.0-3.5

0

Mea

n C

hang

e in

Pai

n In

tens

ityFr

om B

asel

ine

Placebo

-2.1

NUCYNTA ER Oxycodone CR

-2.9 -2.9P

References: 1. Buynak R, Shapiro DY, Okamoto A, et al. Ef cacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother. 2010;11(11):1787-1804. 2. Data on le. Johnson & Johnson Pharmaceutical Research & Development, LLC.

IMPORTANT SAFETY INFORMATION

WARNING: POTENTIAL FOR ABUSE, PROPER PATIENT SELECTION, AND LIMITATIONS OF USEPotential for Abuse

NUCYNTA ER contains tapentadol, a mu-opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics.

NUCYNTA ER can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when prescribing or dispensing NUCYNTA ER in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Schedule II opioid substances, which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone, and methadone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Proper Patient Selection

NUCYNTA ER is an extended-release formulation of tapentadol indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Limitations of Use NUCYNTA ER is not intended for use as an as-needed analgesic. NUCYNTA ER is not intended for the management of acute or postoperative pain. NUCYNTA ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed.

Taking split, broken, chewed, dissolved, or crushed NUCYNTA ER tablets could lead to rapid release and absorption of a potentially fatal dose of tapentadol.

Patients must not consume alcoholic beverages, or prescription or nonprescription medications containing alcohol. Co-ingestion of alcohol with NUCYNTA ER may result in a potentially fatal overdose of tapentadol.

CONTRAINDICATIONS NUCYNTA ER is contraindicated in patients with signi cant respiratory depression, acute or severe bronchial asthma or

hypercapnia in unmonitored settings or in the absence of resuscitative equipment. NUCYNTA ER is contraindicated in any patient who has or is suspected of having a paralytic ileus. NUCYNTA ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or who have

taken them within the last 14 days due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.

NUCYNTA ER is contraindicated in patients with a known hypersensitivity to the active substance, tapentadol, or any component of the product. Angioedema has been reported in association with use of tapentadol.

WARNINGS and PRECAUTIONS NUCYNTA ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed.

Taking split, broken, chewed, crushed, or dissolved NUCYNTA ER tablets leads to the rapid release and absorption of a potentially fatal dose of tapentadol.

NUCYNTA ER tablets must be kept in a secure place out of the reach of children. Accidental consumption of NUCYNTAER, especially in children, can result in a fatal overdose of tapentadol.

Respiratory depression is the primary risk of mu-opioid agonists. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may signi cantly decrease pulmonary ventilation.

Use NUCYNTA ER with caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve, such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, central nervous system (CNS) depression, or coma. In such patients, even usual therapeutic doses of NUCYNTA ER may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative nonmu-opioid agonist analgesics should be considered, and NUCYNTA ER should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid agonist-induced respiratory depression.

IMPORTANT SAFETY INFORMATION (cont) Patients receiving other opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives,

hypnotics, centrally acting muscle relaxants, or other CNS depressants (including alcohol) concomitantly with NUCYNTAER may exhibit additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, coma, or death may result if these drugs are taken in combination with NUCYNTA ER. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.

Opioid analgesics can raise cerebrospinal uid pressure as a result of respiratory depression with carbon dioxide retention. Therefore, NUCYNTA ER should not be used in patients who may be susceptible to the effects of raised cerebrospinal uid pressure, such as those with evidence of head injury and increased intracranial pressure. Opioid analgesics may obscure the clinical course of patients with head injury due to effects on pupillary response and consciousness. NUCYNTAER should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.

Tapentadol is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. NUCYNTA ER can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when

prescribing or dispensing NUCYNTA ER in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction, since use of mu-opioid agonist analgesic products carries the risk of addiction even under appropriate medical use.

Drug abusers may attempt to abuse NUCYNTA ER by crushing, chewing, snorting, or injecting the product. These practices may result in the uncontrolled delivery of NUCYNTA ER and pose a signi cant risk to the abuser that could result in overdose and death.

NUCYNTA ER may cause severe hypotension. Patients at higher risk of hypotension include those with hypovolemia or those taking concurrent products that compromise vasomotor tone (eg, phenothiazines, general anesthetics).

Patients should be cautioned that NUCYNTA ER may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. This is to be expected, especially at the beginning of treatment, at any change of dosage, as well as in combination with alcohol or tranquilizers.

NUCYNTA ER may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause CNS depression, because respiratory depression, hypotension, hypertension, and profound sedation, coma, or death may result.

NUCYNTA ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. As with other opioids, NUCYNTA ER should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures.

Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (eg,mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg,hyperre exia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea), and can be fatal.

Withdrawal symptoms may occur if NUCYNTA ER is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be reduced by tapering NUCYNTA ER.

A study with the immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Tapentadol should be used with caution in patients with moderate hepatic impairment.

NUCYNTA ER has not been studied in patients with severe hepatic impairment, and use in this population is not recommended.

Like other drugs with mu-opioid agonist activity, NUCYNTA ER may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.

NUCYNTA ER should be used with caution in the following conditions: adrenocortical insuf ciency (eg, Addisons disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis.

Pregnancy Category C. There are no adequate and well-controlled studies of NUCYNTA ER in pregnant women. NUCYNTA ER should be used during pregnancy ONLY if the potential bene t justi es the potential risk to the fetus.

ADVERSE REACTIONS The most common (10%) adverse reactions were nausea, constipation, headache, dizziness, and somnolence.

Please see Important Safety Information, including Boxed WARNING on adjacent page and above and Brief Summary of Prescribing Information on the following pages.

Evolving anticoagulation in patients with NVAF, including those at increased stroke risk...

HELP INTERCEPT STROKE RISK

...combining proven protection, a demonstrated safety profi le, and convenient once-daily dosing

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fi brillation (NVAF).

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

IMPORTANT SAFETY INFORMATIONWARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMAA. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATIONDiscontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fi brillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (contd)WARNINGS (contd):B. SPINAL/EPIDURAL HEMATOMAEpidural 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 non-steroidal anti-infl ammatory 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

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.Consider the benefi ts and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS Active pathological bleeding Severe hypersensitivity reaction to XARELTO

WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing

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 fi brillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

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. Discontinue XARELTO in patients with active pathological hemorrhage.

A specifi c antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifi brinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientifi c rationale for benefi t nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fi brinolytic therapy, and NSAIDs.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy, event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1

Defi ned as clinically overt bleeding associated with a decrease in hemoglobin of 2 g/dL, transfusion of 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and effi cacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO and 2.9 for warfarin per 100 patient-years.

The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Once-daily XARELTO delivers... Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism*

Results achieved in NVAF patients with multiple comorbidities refl ecting increased risk of stroke

A demonstrated safety profi le Comparable major bleed rates versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years

In bleeding categories of great concern, such as bleeding into a critical organ and fatal bleeding, fewer events were observed with XARELTO

In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO

Convenient once-daily dosing and administration Oral 20-mg fi xed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min)

No routine monitoring of INR or other coagulation parameters is required1

If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as possible on the same day

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

IMPORTANT SAFETY INFORMATION (contd) Concomitant use of drugs that are combined

P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

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. An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO for 24 hours if traumatic puncture occurs.

Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefi t justifi es the potential risk to the mother and fetus. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C

Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO.

DOSING AND ADMINISTRATION For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal.

Missed Dose: If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as possible on the same day.

Instructions for Patient Use Remind patients to not discontinue XARELTO

without fi rst talking to their healthcare professional to minimize the risk of post-discontinuation thrombotic events.

Advise patients with atrial fi brillation to take XARELTO once daily with the evening meal.

Learn more at www.XARELTOhcp.com

Event rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of 2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

Janssen Pharmaceuticals, Inc.

XARELTO is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. Janssen Pharmaceuticals, Inc. 2012 January 2012 02X11227R1

Reference: 1. 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 fi brillation. N Engl J Med. 2011;365(10):883-891.

IMPORTANT SAFETY INFORMATION (contd)DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause signifi cant increases in rivaroxaban exposure that may increase bleeding risk.

Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. Johns wort) due to decreases in rivaroxaban exposure that may decrease effi cacy.

NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefi t justifi es the potential risk (eg, amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, azithromycin, chloramphenicol, and cimetidine).

USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother.

Geriatric Use: In clinical trials the effi cacy 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-benefi t profi le was favorable in all age groups.

Renal Impairment Patients with renal impairment taking P-gp and

weak to moderate CYP3A4 inhibitors may have signifi cant increases in exposure, which may increase bleeding risk.

For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO is 15 mg once daily with the evening meal. Avoid use in patients with CrCl 50 mg due to limited absorption. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. 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 expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications.

The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO- versus warfarin-treated patients, respectively, major bleeding events were 5.6% versus 5.4%.

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.

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Brief Summary of Prescribing Information for XARELTO (rivaroxaban) XARELTO (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information

WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE,

(B) SPINAL/EPIDURAL HEMATOMAA. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL

FIBRILLATIONDiscontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. Ifanti coagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].B. SPINAL/EPIDURAL HEMATOMAEpidural 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 non-steroidal

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[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 USAGEReduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) 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].CONTRAINDICATIONSXARELTO is contraindicated in patients with: activepathologicalbleeding[see Warnings and Precautions] severehypersensitivityreactiontoXARELTO[see Warnings and Precautions]WARNINGS AND PRECAUTIONSIncreased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing 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 must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) 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. Discontinue XARELTO in patients with active pathological hemorrhage.A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].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].An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing

nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypo tension, or fetal distress).Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions].ADVERSE REACTIONSClinical 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, 11598 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) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups. Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.Table 1: Bleeding Events in ROCKET AF*

Parameter XARELTON = 7111

n (%)

Event Rate (per 100 Pt-yrs)

WarfarinN = 7125

n (%)

Event Rate (per 100 Pt-yrs)

Major bleeding 395 (5.6) 3.6 386 (5.4) 3.5Bleeding into a critical organ 91 (1.3) 0.8 133 (1.9) 1.2Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5Bleeding resulting in transfusion of 2 units of whole blood or packed red blood cells

183 (2.6) 1.7 149 (2.1) 1.3

Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2* For all sub-types of major bleeding, single events may be represented in more

than one row, and individual patients may have more than one event. Defined as clinically overt bleeding associated with a decrease in hemoglobin of 2 g/dL, transfusion of 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin.

The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. 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: agranulocytosisGastrointestinal disorders: retroperitoneal hemorrhageHepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitisImmune system disorders: hypersensitivity, anaphylactic reaction, anaphy lactic shockNervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesisSkin and subcutaneous tissue disorders: Stevens-Johnson syndromeDRUG INTERACTIONSRivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmaco-dynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. Significant increases in rivaroxaban exposure may increase bleeding risk. Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state

rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.

Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.

Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.

Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.

Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/

XARELTO (rivaroxaban) tablets

ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In a drug interaction study, co-administration of XARELTO (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmaco dynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. Johns wort).Anticoagulants: In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetics of rivaroxaban.NSAIDs/Aspirin: In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concom itantly with XARELTO. In a single-dose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with XARELTO. 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].Clopidogrel: In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were co-administered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel [see Warnings and Precautions]. Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose XARELTO in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to 75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% 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].Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.Renal Impairment: The safety and pharmacokinetics of single-dose XARELTO (10mg) were evaluated in a study in healthy subjects [CrCl 80mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Table 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.Table2: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in

Subjects with Renal Insufficiency from a Dedicated Renal Impairment Study

Parameter

Renal Impairment Class[CrCl (mL/min)]

Mild[50 to 79]

N=8

Moderate[30 to 49]

N=8

Severe[15 to 29]

N=8Exposure AUC 44 52 64

(% increase relative to normal) Cmax 28 12 26FXa Inhibition AUC 50 86 100

(% increase relative to normal) Emax 9 10 12PT Prolongation AUC 33 116 144

(% increase relative to normal) Emax 4 17 20PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl=creatinine clearancePatients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk [see Drug Interactions].Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.1) in full Prescribing Information].Hepatic Impairment: The safety and pharmacokinetics of single-dose XARELTO (10mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 3). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmaco-dynamic effects were also observed.Table3: Percent Increase of Rivaroxaban PK and PD Parameters from Normal

in Subjects with Hepatic Insufficiency from a Dedicated Hepatic Impairment Study

Parameter

Hepatic Impairment Class(Child-Pugh Class)

Mild(Child-Pugh A)

N=8

Moderate(Child-Pugh B)

N=8Exposure AUC 15 127

(% increase relative to normal) Cmax 0 27FXa Inhibition AUC 8 159

(% increase relative to normal) Emax 0 24PT Prolongation AUC 6 114

(% increase relative to normal) Emax 2 41PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concen tration or effect curve; Cmax = maximum concentration; Emax = maximum effectAvoid 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 [see Dosage and Administration (2.3) in full Prescribing Information and Warnings and Precautions].OVERDOSAGEOverdose of XARELTO may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. 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 expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].Active Ingredient Made in GermanyFinished Product Manufactured for: Licensed from: Manufactured by: Janssen Pharmaceuticals, Inc. Bayer HealthCare AGJanssen Ortho, LLC Titusville, NJ 08560 51368 Leverkusen, GermanyGurabo, PR 00778 Janssen Pharmaceuticals, Inc. 2011 10185201 02X11309BBAR1

XARELTO (rivaroxaban) tablets XARELTO (rivaroxaban) tablets

iPro Continuous Glucose Monitoring (CGM) can help you discover glycemic excursions not revealed by self-monitoring of blood glucose (SMBG) alone

The American Diabetes Association recommends that patients with diabetes using multiple insulin injections perform SMBG three or more times daily1

iPro CGM provides up to 12 glucose values per hour and up to 288 values per day,2 a rate unrealistic for patients to achieve with SMBG alone

Get the insights you need to make informed treatment decisions

Continuous Glucose Monitoring aided identi cation of unrecognized hypoglycemia in patients with type 1 diabetes3

Continuous Glucose Monitoring assisted in determining insulin therapy modi cations3

Indications for Use

iPro CGM is intended to continuously record interstitial glucose levels in persons with diabetes mellitus

This information is intended to supplement, not replace, blood glucose information obtained using standard home glucose monitoring devices

Please see Important Safety Information on adjacent page or request a copy of the iPro CGM user guides from your Medtronic sales representative.

For more information, please contact Medtronic at 1-888-350-3245.

45133_elhmlp_HI66161_mph_ad_fa.indd 145133_elhmlp_HI66161_mph_ad_fa.indd 1 1/28/11 11:05:46 AM1/28/11 11:05:46 AM

Indications for Use

The CGMS iPro Digital Recorder is intended to continuously record interstitial glucose levels in persons with diabetes mellitus. This information is intended to supplement, not replace, blood glucose information obtained using standard home glucose monitoring devices. The information collected by the digital recorder may be downloaded and displayed on a computer and reviewed by healthcare professionals.

This information may allow identi cation of patterns of glucose-level excursions above or below the desired range, facilitating therapy adjustments which may minimize these excursions.

The CGMS iPro Digital Recorder:

Is intended for prescription use only.

Will not allow readings to be made available directly to patients in real time.

Provides readings that will be available for review by physicians after the recording interval (72 hours).

Is currently intended for occasional rather than everyday use.

Is to be used only as a supplement to, and not a replacement for, standard invasive measurement.

Is not intended to change patient management based on the numbers generated, but to guide future management of the patient based on response to trends noticed. That is, these trends or patterns may be used to suggest when to take ngerstick glucose measurements to better manage the patient.

The glucose sensor, tester, charger, and CGMS iProWand are intended for use with the CGMS iPro Digital Recorder. The Sen-serter device is indicated only for insertion of the Medtronic MiniMed glucose sensor.

Important Safety Information

Contraindication

Do not use magnetic mattress pads while wearing the CGMS iPro Digital Recorder.

Warning

Product contains small parts and may pose a choking hazard for young children.

Important Safety Information, continued

Sensor

The glucose sensor should be removed if redness, bleeding, pain, tenderness, irritation, or in ammation develops at insertion site, or if you experience unexplained fever. An optional occlusive dressing should be removed if irritation or reaction to the tape develops.

The glucose sensor may create special needs regarding your patients medical conditions or medications. Healthcare professionals should discuss this with their patients before they use the glucose sensor.

Wait 5 minutes after glucose sensor insertion before setting up the CGMS iPro Digital Recorder with Solutions CGMS iPro.

Make sure that the site is not bleeding before connection.

If bleeding occurs, apply steady pressure with a sterile gauze or clean cloth at the insertion site until bleeding stops. After bleeding stops, attach the digital recorder to the glucose sensor.

If bleeding persists after 3 minutes, remove the glucose sensor and discard. Insert a new glucose sensor in a different location.

Contact the 24 Hour HelpLine if you experience any adverse reactions associated with the digital recorder or glucose sensor.

Precautions

If performing multiple CGMS iPro Digital Recorder studies on the same patient, establish a rotation schedule for choosing new glucose sensor sites. Avoid sites that are constrained by clothing, have scar tissue, or are subject to rigorous movement during exercise.

For additional information, please consult the iPro CGM user guides.

iPro is a trademark of Medtronic MiniMed, Inc.Sen-serter is a registered trademark of Medtronic MiniMed, Inc.

References

1. American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61.

2. Solutions Software for CGMS iPro Continuous Glucose Recorder User Guide.

3. Chico A, Vidal-Rios P, Subira M, Novials A. Diabetes Care. 2003;26:1153-1157.

9403750-011 20100708 Medtronic MiniMed, Inc. 2010. All rights reserved. HI66161 0810 PRINTED IN USA 2010, LILLY USA, LLC. ALL RIGHTS RESERVED.

45133_elhmlp_HI66161_mph_ad_fa.indd 245133_elhmlp_HI66161_mph_ad_fa.indd 2 1/28/11 11:05:47 AM1/28/11 11:05:47 AM

STELARA is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy

STELARA, available as 45 mg and 90 mg, is a subcutaneous injection that should only be administered by a healthcare provider to patients who have regular follow-up with a physician.1

Please see related and other Important Safety Information for STELARA within this advertisement.

Selected Safety Information

STELARA is an immunosuppressant and may increase the risk of infections, reactivation of latent infections, and malignancies. Serious adverse reactions have been reported in STELARA-treated patients, including bacterial, fungal, and viral infections, malignancies, serious allergic reactions and one case of Reversible Posterior Leukoencephalopathy Syndrome (RPLS).

STELARA should not be given to patients with any clinically important active infection. Patients should be evaluated for tuberculosis prior to initiating treatment with STELARA. Live vaccines should not be given to patients receiving STELARA. If RPLS is suspected, discontinue STELARA.

PROSTATE TUMOR TISSUE

ADRENALS

TESTES

Janssen Biotech, Inc. Janssen Biotech, Inc. 2011 10/11 08A11090

ZYTIGA (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate

cancer (CRPC) who have received prior chemotherapy containing docetaxel.

ORALTHERAPY

ContraindicationsZY TIGA may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid ExcessUse with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)AI has been reported inclinical trials in patients receiving ZYTIGA in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. Perform appropriate tests, if indicated to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

HepatotoxicityIncreases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patients baseline should prompt more frequent monitoring. If at any

time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Food EffectZY TIGA must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0- (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Use in Specific PopulationsThe safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA.

Drug InteractionsZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Adverse ReactionsThe most common adverse reactions ( 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection.

* Study Design: ZYTIGA, in combination with prednisone, was evaluated in a Phase 3, randomized, double-blind, placebo-controlled, multicenter study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone 50 ng/dL).1 The primary efficacy endpoint was overall survival.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information. www.zytiga.com

Mechanism of action Abiraterone is an androgen biosynthesis inhibitor (ABI) that directly affects the androgen biosynthesis pathway by inhibiting CYP17 (17-hydroxylase/C17,20-lyase) Consequently, androgen biosynthesis is inhibited at 3 sources of testosterone

production: the testes, adrenal glands, and prostate tumor tissue

Androgen biosynthesis inhibition with ZYTIGA results in decreased levels of serum testosterone and other androgens

At the interim analysis of the pivotal phase 3 study, ZYTIGA + prednisone showed a statistically significant improvement in median overall survival (OS) compared with the control arm* Median OS: 14.8 months vs 10.9 months (hazard ratio = 0.646; 95% confidence interval:

0.543, 0.768, P < 0.0001)

Important Safety Information

www.Excedrin.com

Excedrin Extra Strength:Contiene acetaminophen, aspirina y cafena. Los mdicos opinan que esta combinacin de ingredientes ofrecen ventajas importantes, incluyendo un mayor efecto analgsico. Para algunos, Excedrin Extra Strength comienza a aliviar el dolor en 15 minutos.

Excedrin Menstrual:Tiene tres ingredientes para aliviar cinco de sus sntomas principales, todo ello a velocidad exprs. Excedrin Menstrual tiene una triple combinacin de ingredientes que alivia la hinchazn, los calambres, los dolores musculares, el dolor de cabeza y la fatiga.

Excedrin Back & Body: Para un rpido alivio de los dolores de cuerpo. Con una frmula de doble accin que trabaja de dos maneras: aliviando y bloqueando el dolor exactamente donde duele. Contiene acetaminophen y aspirina buffered que cae suave al estmago.

Excedrin Migraine:El primer medicamento de venta libre aprobado por la FDA para tratar todos los sntomas de lamigraa. Excedrin Migraa comienza a alviarla en slo 30 minutos. Quienes la padecen saben cuan rpido es eso. Excedrin Migraa contiene acetaminophen, aspirina y cafena. El medicamento OTC #1 recomendado para la migraa por los neurlogos en Estados Unidos.

Excedrin PM:Contiene acetaminophen y difenhidramina, un ingrediente no adictivo que promueve el sueo reparador. Excedrin PM no contiene aspirina y cae suave al estmago. Excedrin PM alivia el dolor acompaado de insomnio y ayuda a conseguir el sueo que necesita para despertarse alerta, fresco y bien descansado a la maana siguiente.

Excedrin Tension:Proporciona un alivio rpido al dolor de cabeza, el cuello y dolor en el hombro, sntomas asociados a la tensin. Contiene acetaminophenformulado con cafena, una formulacin confiable para el tratamiento de dolores de cabeza causados por estrs. Y es 100% libre de aspirina ideal para quienes no pueden consumir aspirina.

Excedrin Sinus:Alivia el dolor de cabeza, congestin nasal y la presin, y ayuda a despejar los conductos nasales. Excedrin Sinus contiene acetaminophen para aliviar el dolor y el phenileprina, descongestionante nasal. El dolor de cabeza causado por sinusitis consiste en un dolor profundo y constante en los pmulos, la frente o el puente de la nariz.

CUANDO NECESITES ALIVIO RPIDO... EL DOLOR SE DETIENE,

USTED NO.

PR.11.EXC.012

Conozca ms de EXCEDRIN:

Para los dolores de cabeza de la vida.www.Excedrin.com

*El medicamento OTC #1 recomendado para la migraa por los neurlogos. Wolters Kluwer Health 2009.

PR.11.EXC.012

EL DOLOR SE DETIENE,USTED NO.CUL DOLOR?