OPM October 2014 by Value-Based Cancer Care

www.OncPracticeManagement.com

OCTOBER 2014

VOLUME 4 • NUMBER 6

Oncology Practice Management ™

FOR ONCOLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

Connecting Patients to Resources

Community–Hospital Relationships: Working Together to Define What Is Right for Patients

By Sheryl Riley, RN, OCN, CMCN

By Dawn Holcombe, MBA, FACMPE, ACHE; President, DGH Consulting, South Windsor, CT; Editor-in-Chief, Oncology Practice Management

nce upon a time, there existed a town–gown divide in healthcare: a large academic center in one part of the state sought referrals from physicians in surrounding com-

munities, but the physicians were reluctant to send too many referrals because often they would not get the patients back. The academic center would denContinued on page 6

Disaster Planning for the Oncology Office, Part 2 By Mariana S-B Lamb, MS, with contributions from Richard Levine, MD

hanges in our economy and healthcare system (ie, the Affordable Care Act, accountable care organizations, evolving reimbursement models) have given birth to a new member of the healthcare team: the financial advocate. Although many hospitals and large clinics have some form of patient advocates and Continued on page 14

very medical practice is at risk for a natural or man-made disaster. Those who have worked through a disaster will share their relief at having had a plan in place to get through it, or they may share, unfortunately, how much they wish they had developed a plan ahead of time. Crises such as a fire or weather event have the potential to be a major disruption to your business, and, should disaster strike, many

will turn to the practice manager for a plan. Since you never know when a crisis may strike, the best time to prepare is now. We hope this series of articles will guide you in your ongoing preparations, or perhaps will inspire you to start developing a plan. The first article in this series (“Bringing the Future into the Present: Disaster Planning for the Continued on page 20

From the publishers of

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

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Table of Contents

October 2014 • Volume 4 • Number 6

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Directors, Client Services Lou Lesperance llesperance@the-lynx-group.com Zach Ceretelle zceretelle@the-lynx-group.com Editorial Directors Dalia Buffery dbuffery@the-lynx-group.com Anne Cooper acooper@the-lynx-group.com Associate Editor Lara J. Lorton Copyeditor Jessica Cheng Editorial Assistant Cara Guglielmon Production Manager Cara Nicolini The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Oncology Practice Management ™

FOR ONCOLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

FROM THE EDITOR Community–Hospital Relationships: Working Together to Define What Is Right for Patients......................1 By Dawn Holcombe, MBA, FACMPE, ACHE

FEATURES Disaster Planning Disaster Planning for the Oncology Office, Part 2..............................1 By Mariana S-B Lamb, MS, with contributions from Richard Levine, MD

Financial Advocacy Connecting Patients to Resources........................................................1 By Sheryl Riley, RN, OCN, CMCN

Insurance and Benefits CMS Takes Stock of Federal Health Insurance Marketplace Benefits............................................................................ 12 By Rosemary Frei, MSc

Testing and Diagnostics FDA to Regulate Laboratory-Developed Tests................................. 24

By Rosemary Frei, MSc

Physician–Hospital Alignment Series Do’s and Don’ts in Physician–Hospital Alignment, Part 2............... 30 By Max Reiboldt, CPA

Continued on page 4

MISSION STATEMENT Oncology healthcare requires providers to focus attention on financial concerns and strategic decisions that affect the bottom line. To continue to provide the high-quality care that patients with cancer deserve, providers must master the ever-changing business of oncology. Oncology Practice Management offers process solutions for members of the cancer care team—medical, surgical, and radiation oncologists, as well as executives, administrators, and coders/billers—to assist them in reimbursment, staffing, electronic health records, REMS, and compliance with state and federal regulations. POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Oncology Practice Management™, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

October 2014

www.OncPracticeManagement.com

Table of Contents

October 2014 • Volume 4 • Number 6

Oncology Practice Management™, ISSN 2164-4403 (print), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Oncology Practice Management™ is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Oncology Practice Management™ do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Oncology Practice Management ™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Oncology Practice Management ™

FOR ONCOLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

Continued from page 3

DEPARTMENTS Clinical Trial Tracker New Clinical Trials Under Way............................................................. 34 Patient Assistance Programs Commitment to Access Supports Patients Prescribed Arzerra, Other Medications.............................................. 37 Drug Update Arzerra (Ofatumumab) Receives FDA Approval for Patients with Previously Untreated Chronic Lymphocytic Leukemia for Use in Combination with Chlorambucil....................................... 38 By Lisa A. Raedler, PhD, RPh

Drug Coding FDA-Approved Medications Used for the Treatment of Breast Cancer......................................................... 45

EDITORIAL ADVISORY BOARD Editor-in-Chief Dawn Holcombe, MBA, FACMPE, ACHE President DGH Consulting South Windsor, CT Carla Balch CEO, Altos Solutions, a Division of Flatiron Health, Inc New York, NY Peggy Barton, RN Practice Manager Toledo, OH Risë Marie Cleland President Oplinc, Inc Portland, OR

Ruth Linné Lander, FACMPE Practice Administrator Columbus Oncology & Hematology Associates, Inc Columbus, OH

Robert D. Orzechowski, MBA, SPHR Chief Operating Officer Lancaster Cancer Center Lancaster, PA

Teri U. Guidi, MBA, FAAMA President and CEO Oncology Management Consulting Group Pipersville, PA

Bonnie J. Miller, RN, BSN, OCN, FAAMA Administrative Director Women’s Cancer Center Fox Chase Cancer Center Philadelphia, PA

Sheryl A. Riley, RN, OCN, CMCN Director of Clinical Services SAI Systems Shelton, CT

Mariana Lamb, MS Executive Director Medical Oncology Association of Southern California Upland, CA

Karna W. Morrow, CPC, RCC, CCS-P, PCS Senior Consultant CSI Coding Strategies, Inc Powder Springs, GA

Patrick A. Grusenmeyer, ScD, FACHE President Christiana Care Health Initiatives Newark, DE

ONCOLOGY PRACTICE MANAGEMENT

I October 2014

Mary Pat Whaley, FACMPE, CPC Physician Advocate and Consultant www.managemypractice.com Durham, NC

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US-CELG140179

From the Editor

Community–Hospital Relationships…Continued from the cover igrate the private physicians as not having adequate resources to handle complex cancers, and the private physicians would denigrate the academic center as being caught up in an ivory tower, out of touch with the daily practice of diverse community medicine. In current times, academic or hospital systems are likely to have acquired many of the private practices in their market—mostly primary care—but in doing so they may also have gained control of referrals to specialty care (eg, oncology) or acquired specialty oncology practices to fill out niche markets.

The Great Divide The divide has grown sharper between community-based private practices that are still standing and hospital-based centers with an expanding footprint of commu nity- located, but hospital-owned, practices. Hospitals may question the ability of stand-alone practices to provide truly comprehensive care for patients with cancer. Communitybased practices and private payers have not been shy about noting the higher costs for cancer treatments in hospital-owned practice settings. Concerns often are raised about the same patient receiving the same care from the same doctor in a facility that was acquired by a hospital, and yet the patient may be billed at substantially higher rates by the hospital that acquired that practice than they were before the acquisition, thus increasing both patient and payer costs. Is the care really the same in these environments, or is it different, and do the differences justify the costs? There may indeed be short-term and long-term answers to this not-so-simple question: • Hospitals by nature are subject to intense scrutiny and oversight, and

probably have developed checklists and processes for reduction of variation and risk in provided care • Hospitals have certification and accreditation options not available to the general oncology practice, with detailed cross-disciplinary processes and operational standards that drive consistency and attention to quality

Dawn Holcombe, MBA, FACMPE, ACHE

The divide has grown sharper between community-based private practices that are still standing and hospital-based centers with an expanding footprint.

• Hospitals, by design, have a wide range of departments and specialties, facilitating multidisciplinary programs and rounding, which increases joint attention to patients, the facilitation of both upstream and downstream consensus treatment decisions, and communication focused on the patient, potentially raising quality and outcomes • Hospitals have more overhead

ONCOLOGY PRACTICE MANAGEMENT

I October 2014

and are able to charge facility fees; they also often have different contract prices for reimbursement of line items (eg, cancer drugs), which explains why payers see increased prices for care when a private physician is acquired by a hospital • Private practices may be more flexible and able to focus more closely on patient attention and engagement without multiple departments and disparate facilities to separate care providers • Private practices may provide innovative, patient-focused services and schedules to accommodate patients in a local community setting • Private practices have less facility and staff overhead than hospital services, which could provide a more cost-efficient site for services • Value-based reimbursement is a moving target, and we do not yet know how these transformative years will play out in the future; we may need the protection of a widely diverse and robust organization to absorb financial risk and provide a cushion to healthcare providers under a fully value- based system • As an alternative, we may need smaller, focused service models to expand and become flexible, aligned components of care within diverse settings, working together to balance care delivery in the right setting at the right time. We now have states where the majority of cancer care providers are hospital-based, others that are still predominantly private, and some states where almost all private groups have been acquired. The acquisition fever that gripped some hospital systems seems to be abating somewhat. We have been left with a medical community that is divided even more so now than in days gone by, and that is not good

From the Editor

for our physicians, cancer centers, or patients. We are who we are, and we need not only to embrace and learn from our differences, but also to use our collective voices—private or hospital-based—to speak up for our patients in the face of changes being made to external policy and oncology management. During my travels across the country, I have had the pleasure of visiting a wide variety of cancer centers and meeting the many groups who comprise the oncology providers of the United States. There are definitely different nuances and blends that work better in some markets than others. Sometimes the cards have already been dealt, and payers, physicians, and hospitals have to play them out as they stand. In other markets, there is greater fluidity to the physician–hospital mix, and payers, physicians, and hospitals have more of an opportunity to craft a final solution that works well in that area. There are even some markets that have, while watching and worrying, experienced little real change thus far. The devil is definitely in the details. Like most diverse markets, there is clearly a bell curve shaking out, and there are good and notas-good aspects to both private and hospital- based options. There are many hospital-based programs that prominently exemplify the power of a deeply aligned, multidisciplinary entity that can leverage its resources for its patients. There are strong community and private programs that may—or may not—be enhanced by strategic affiliations rather than acquisitions, and still serve their patients in a comprehensive manner.

Privilege and Responsibility When we lose sight of ourselves as a full medical community, we lose

our voice to speak for our patients in the greater healthcare policy discussion. There is a common saying, “With great privilege comes great responsibility.” We are privileged with our ability to care for patients with cancer, whether that care is packaged in a private practice or a hospital-based cancer center. We also have an obligation to those patients to stand up for them and enter into the debate of “value”-based reimbursement and “evidence”-based care. If a proposed policy or program does not make sense, or needs to be tweaked to better serve the spirit of value and evidence rather than some other twist or interpretation,

definition of appropriate oncology management. These are common issues that can be addressed collaboratively between private and hospital-based medical providers, taking a stance on appropriate evidence and value standards, as well as measures within the treatment of patients with cancer.

Next Steps Tomorrow when you wake up, pick up the phone and call your counterparts in your local market, no matter where they are based. Start a dialogue about setting the bar for clinical evidence and decision- making in your market; even if you have different technology and service solutions, there often will be common end points. Sometimes the cards Each of you will report and deliver on those standards at different have already been times and in different ways, but dealt, and payers, you will have collectively created physicians, and hospitals the parameters within which you feel it is most appropriate to move have to play them out forward. Then you can individualas they stand. ly or collectively introduce these parameters to your employers and payers in the market, and begin we need to engage and advocate more focused discussions on oncolfor such changes. Unfortunately, if ogy management. we are too busy battling each other We are a diverse medical comwithin the medical community over munity, with changing delivery site of service, we may lose the war models. Together we can still be with others over evidence-based on- strong for our patients, and recogcology management. nize the common threads of similar There will still be opportunities values and expectations for evito learn and shift site-of-service dence, which will not vary because mixes in specific markets, and we of our own diversity. There are should continue to review those advantages and disadvantages to opportunities, but we should also any delivery model. Let us recogincrease our efforts to work col- nize the differences, embrace the lectively with our local payers and good, and spend more time workpurchasers on defining libraries of ing together with our payers and evidence, expectations for clini- purchasers to define evidence and cal pathways, utilization of exter- value as we, the treating providers nal prior authorization portals and regardless of site of service, see as resultant utilization review, and appropriate for our patients. l

October 2014

www.OncPracticeManagement.com

For patients with bone metastases from solid tumors

Prevent bone complications longer In a prespecified integrated analysis of 3 pivotal trials (N = 5,723),

8.2

XGEVA® was proven to delay the median time to first bone complication by

months longer vs zoledronic acid1

XGEVA® is a convenient 120 mg subcutaneous injection administered once every 4 weeks.2

Bone complications, or skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2,3 Median Time to First Bone Complication1 27.7

months

XGEVA VA® 120 mg Q4W (n = 2,862) VA

Data from a prespecified integrated analysis of three international, phase 3, double-blind, double-dummy, active-controlled trials comparing XGEVA® with zoledronic acid for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma.1

19.5

months

zoledronic acid 4 mg Q4W (n = 2,861) 1 YEAR

HR* = 0.83 (95% CI: 0.76-0.90)

2 YEARS

P < 0.001†

IMPORTANT SAFETY INFORMATION Hypocalcemia • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®. XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. • An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake. Hypersensitivity • XGEVA® is contraindicated in patients with known clinically significant hypersensitivity to XGEVA®, including anaphylaxis that has been reported with use of XGEVA®. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA® therapy permanently.

*Hazard ratio (HR) is defined as the increase or decrease in likelihood of an event of interest (in this case a bone complication) for one group relative to that in a comparator group. P value for superiority.

†

Drug Products with Same Active Ingredient • Patients receiving XGEVA® should not take Prolia® (denosumab). Osteonecrosis of the Jaw • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. • Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. • RANK Ligand (RANKL) is produced by bone cells in the skeleton and is a key mediator of bone resorption4 • RANKL production is increased at sites of bone metastases, and stimulates osteoclasts to destroy bone4 • XGEVA® acts precisely to bind RANKL and inhibits osteoclast formation, function, and survival2 • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®2

Learn more at XGEVA.com

• Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA® treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA® therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Embryo-Fetal Toxicity • XGEVA® can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA® is expected to result in adverse reproductive effects.

• Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. Please see brief summary of Prescribing Information on the following page. REFERENCES: 1. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48:30823092. 2. XGEVA® (denosumab) prescribing information, Amgen. 3. Brodowicz T, O’Byrne K, Manegold C. Bone matters in lung cancer. Ann Oncol. 2012;23:22152222. 4. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.

www.XGEVA.com

S:6.875”

Brief Summary: Consult package insert for complete Prescribing Information

DOUS14CDNY4736_A_XGEVA_Asize_BS_V10_8pt_r10.indd 1

8/11/14 11:56 AM

S:9.875”

INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia. Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way. Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva. Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva. WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia. Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently. Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake. Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions). Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should

receive care by a dentist or an oral surgeon. In these on-study was 13 months (range: 0.1 – 41). Of patients patients, extensive dental surgery to treat ONJ may who received Xgeva, 46% were female. Eighty-five exacerbate the condition. percent were White, 5% Hispanic/Latino, 6% Asian, and Atypical Subtrochanteric and Diaphyseal Femoral 3% Black. The median age was 63 years (range: 18 – 93). Fracture. Atypical femoral fracture has been reported Seventy-five percent of patients who received Xgeva with Xgeva. These fractures can occur anywhere in the received concomitant chemotherapy. femoral shaft from just below the lesser trochanter to Table 1. Per-patient Incidence of Selecteda Adverse above the supracondylar flare and are transverse or short Reactions of Any Severity (Trials 1, 2, and 3) oblique in orientation without evidence of comminution. Zoledronic Atypical femoral fractures most commonly occur with Xgeva Acid minimal or no trauma to the affected area. They may Body System n = 2841 n = 2836 % be bilateral and many patients report prodromal pain % in the affected area, usually presenting as dull, aching GASTROINTESTINAL thigh pain, weeks to months before a complete fracture 32 31 Nausea occurs. A number of reports note that patients were also 19 20 Diarrhea receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients GENERAL should be advised to report new or unusual thigh, hip, or Fatigue/ Asthenia 45 46 groin pain. Any patient who presents with thigh or groin IN VESTIGATIONS pain should be suspected of having an atypical fracture Hypocalcemiab 9 18 and should be evaluated to rule out an incomplete femur 20 32 Hypophosphatemiab fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and NEUROLOGICAL signs of fracture in the contralateral limb. Interruption Headache 13 14 of Xgeva therapy should be considered, pending a risk/ RESPIRATORY benefit assessment, on an individual basis. 18 21 Dyspnea EMBRYO-FETAL TOXICITY: Xgeva can cause fetal harm 15 15 Cough when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse a Adverse reactions reported in at least 10% of patients reproductive effects. In utero denosumab exposure in receiving Xgeva in Trials 1, 2, and 3, and meeting one cynomolgus monkeys resulted in increased fetal loss, of the following criteria: stillbirths, and postnatal mortality, along with evidence of • At least 1% greater incidence in Xgeva-treated absent peripheral lymph nodes, abnormal bone growth, patients, or and decreased neonatal growth (see Use in Specific • Between-group difference (either direction) of less than Populations). Advise females of reproductive potential 1% and more than 5% greater incidence in patients to use highly effective contraception during therapy, treated with zoledronic acid compared to placebo (US and for at least 5 months after with the last dose of Prescribing Information for zoledronic acid) Xgeva. Apprise the patient of the potential hazard to a b Laboratory-derived and below the central laboratory lower fetus if Xgeva is used during pregnancy or if the patient limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) becomes pregnant while patients are exposed to Xgeva. for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) Advise patients to contact their healthcare provider for phosphorus] if they become pregnant or a pregnancy is suspected Severe Mineral/Electrolyte Abnormalities during this time. • Severe hypocalcemia (corrected serum calcium less ADVERSE REACTIONS: The following adverse reactions than 7 mg/dL or less than 1.75 mmol/L) occurred are discussed below and elsewhere in the labeling: in 3.1% of patients treated with Xgeva and 1.3% of • Hypocalcemia patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced • Osteonecrosis of the Jaw The most common adverse reactions in patients receiving 2 or more episodes of severe hypocalcemia and 16% Xgeva (per-patient incidence greater than or equal to 25%) experienced 3 or more episodes. were fatigue/asthenia, hypophosphatemia, and nausea • Severe hypophosphatemia (serum phosphorus less (see Table 1). The most common serious adverse reaction than 2 mg/dL or less than 0.6 mmol/L) occurred in in patients receiving Xgeva was dyspnea. The most 15.4% of patients treated with Xgeva and 7.4% of common adverse reactions resulting in discontinuation of patients treated with zoledronic acid. Xgeva were osteonecrosis and hypocalcemia. Osteonecrosis of the Jaw Clinical Trials Experience. Because clinical trials are In the primary treatment phases of Trials 1, 2, and 3, conducted under widely varying conditions, adverse ONJ was confirmed in 1.8% of patients in the Xgeva group reaction rates observed in the clinical trials of a drug (median exposure of 12.0 months; range 0.1 – 40.5) cannot be directly compared to rates in other clinical and 1.3% of patients in the zoledronic acid group. The trials and may not reflect the rates observed in practice. trials in patients with breast (Trial 1) or prostate (Trial The safety of Xgeva was evaluated in three randomized, 3) cancer included an Xgeva open label extension double-blind, double-dummy trials in which a total treatment phase where patients were offered Xgeva 120 of 2841 patients with bone metastasis from prostate mg once every 4 weeks (median overall exposure of 14.9 cancer, breast cancer, or other solid tumors, or lytic bony months; range 0.1 – 67.2). The patient-year adjusted lesions from multiple myeloma received at least one dose incidence of confirmed ONJ was 1.1% during the first of Xgeva. In Trials 1, 2, and 3, patients were randomized year of treatment and 4.1% thereafter. The median time to receive either 120 mg of Xgeva every 4 weeks as to ONJ was 20.6 months (range: 4 – 53). a subcutaneous injection or 4 mg (dose adjusted for Atypical Subtrochanteric and Diaphyseal Fracture reduced renal function) of zoledronic acid every 4 weeks Atypical femoral fracture has been reported with Xgeva. by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to Postmarketing Experience. Because postmarketing 2.9 mmol/L) and creatinine clearance 30 mL/min or reactions are reported voluntarily from a population greater. Patients who had received IV bisphosphonates of uncertain size, it is not always possible to reliably were excluded, as were patients with prior history of estimate their frequency or establish a causal relationship ONJ or osteomyelitis of the jaw, an active dental or jaw to drug exposure. condition requiring oral surgery, non-healed dental/ The following adverse reactions have been identified oral surgery, or any planned invasive dental procedure. during post approval use of Xgeva: During the study, serum chemistries including calcium • Hypocalcemia: Severe symptomatic hypocalcemia, and phosphorus were monitored every 4 weeks. Calcium including fatal cases. and vitamin D supplementation was recommended but • Hypersensitivity, including anaphylactic reactions. not required. The median duration of exposure to Xgeva • Musculoskeletal pain, including severe musculoskeletal was 12 months (range: 0.1 – 41) and median duration pain. Positive rechallenge has been reported.

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to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation. Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/ RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated. Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth. Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Renal Impairment. Two clinical trials were conducted in patients without cancer and with varying degrees of renal function. In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/ no calcium supplementation. Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and, calcium and vitamin D intake.

DOUS14CDNY4736_A_XGEVA_Asize_BS_V10_8pt_r10.indd 2

Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk. OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth • Persistent pain or slow healing of the mouth or jaw after dental surgery • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain • Pregnancy or nursing Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia.

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Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cellbased in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result 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 antibodies to denosumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy. USE IN SPECIFIC POPULATIONS: Pregnancy: Category D. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva. Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned

Insurance and Benefits

CMS Takes Stock of Federal Health Insurance Marketplace Benefits By Rosemary Frei, MSc

s the Centers for Medicare & Medicaid Services (CMS) continues its efforts to ensure that those who are enrolled in the Federal Health Insurance Marketplace (FHIM) meet eligibility requirements, the ripple effects of these efforts may be felt at medical practices nationwide. In a news release issued on September 15, 2014, the agency stated that 115,000 people who had not submitted sufficient information to clear up data inconsistency issues relating to their citizenship or immigration status “will be receiving notices saying their last day of Federal Marketplace coverage is September 30, 2014.”1 The potential revoking of FHIM benefits to more than 100,000 Americans may make insurance-verification processes at practices even more complex than they already are. The statement also states that “there are still about 279,000 households with unresolved income-related data-matching issues that haven’t sent in supporting information [to reconcile differences between the households’ applications and those the CMS has on file], representing 363,000 individuals. CMS will send letters starting today to individuals who, if they do not send in supporting documents by September 30, may see their costs change.…For instance, this may impact the cost of their monthly premium, deductibles, copays, and co-insurance, and even their tax bill or refund during filing season.”1 These moves are part of CMS’s preparations for the next Marketplace open enrollment period beginning on November 15, 2014. “[CMS] is resolving data-matching issues that occurred during the first year so that its records are accurate before the

renewal process begins, and so that consumers have the information they need about their coverage,”1 the news release states. John V. Cox, DO, Medical Oncologist, Methodist Hospitals of Dallas, TX, and a medical director at Texas Oncology PA, Dallas, said he hopes it will be easy for practices to find out whether their patients’ FHIM coverage remains in place. “Many plans now have patient coverage information on their computerized systems so you can confirm it right away. So as long as that mechanism remains in place, then practices can use their routine mechanisms to be able to confirm whether a given patient is covered by the FHIM or not,” said Dr Cox in a phone interview. “I guess we’re always concerned— oncology, urology, and some other practice types that have high-dollar therapeutics that patients are given in their offices—that we’re not going to be told one day that a patient has coverage, then we provide treatment, and then found out on day 2 or day 3 that that coverage doesn’t exist. No practice can suffer the nonreimbursement for these expensive therapeutics. There’s no margin for error.” Rick Rutherford, Director, Practice Management, American Urological Association, is also hoping for the best for urology practice managers. “Because the health exchange insurance policies have the 90-day grace period for unpaid premiums already in place, this new development—the termination of coverage for lack of citizenship or income- verification documentation—is just another administrative hassle,” Mr Rutherford wrote in an e-mail. CMS announced on August 12, 2014, that its staff had sent out reminder notices

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I October 2014

to 310,000 people2—including 93,800 to Florida addresses and 52,700 to Texas residents3—who had inconsistencies in their citizenship and/or immigration information. These individuals had not responded to 5 to 7 previous requests via e-mail, phone, and regular mail about inconsistencies. There was a September 5 deadline for submitting information to clear up the data-matching issues, and a September 30 FHIM-benefit cutoff date for people whose submissions had not cleared up the inconsistencies. September 30 was also the date that costs could change for people who had not cleared up income inconsistencies; CMS also said it had made “numerous previous attempts” to reach these individuals since May 30.1 The news release stated that individuals still can clear up inconsistencies in several ways: by logging into their HealthCare.gov account and selecting their current application to upload their documents, mailing their information to the CMS’s consumer center, or calling the CMS’s call center at 800-318-2596 to see what documents they need to submit and check whether the Federal Marketplace has received their information. l

References

1. Centers for Medicare & Medicaid Services. News release September 15, 2014. CMS update on consumers who have data matching issues. http://cms. gov/Newsroom/MediaReleaseDatabase/Press-releases/ 2014-Press-releases-items/2014-09-15.html. Accessed September 16, 2014. 2. Centers for Medicare & Medicaid Services. News release August 12, 2014. Federal Health Insurance Marketplace: Send in requested documents now to keep marketplace coverage. www.cms.gov/Newsroom/ MediaReleaseDatabase/Press-releases/2014-Pressreleases-items/2014-08-12.html. Accessed September 15, 2014. 3. Centers for Medicare & Medicaid Services. Warning notices generated for citizenship/immigration data matching issues (Individual Level) by State Data as of 8/10/14. www.hhs.gov/healthcare/facts/factsheets/2014/08/datamatching-map.pdf. Accessed September 16, 2014.

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Financial Advocacy

Connecting Patients to Resources Continued from the cover nurse navigators, not all of these professionals are trained in the complex financial issues inherent to the care of treating a patient with cancer. Furthermore, many professionals are too thinly spread, and see too many patients to develop an expertise in advising on any single disease type. Cancer is one of those disease processes that is particularly challenging and requires specialized knowledge of the complex nature of diagnosis, copayment, coinsurance, drug assistance, and financial assistance. Most facilities have only one advocate who serves many purposes, which again creates difficulty in being an expert in financial assistance options for patients with one disease type. I recently attended a conference about financial advocacy. I was delighted to see so many people from all over the country in attendance. It afforded me the opportunity to speak with as many professionals as possible, and augment my knowledge on the specifics of what they do and how they do it. I had the assumption before attending that financial advocates would be mostly nurses and social workers, but I was mistaken; it was a diverse group. Some of the advocates were laypersons who got involved due to a personal experience and decided to make it a career, while others were nurses and social workers. Some had degrees in education, finance, or communications. Regardless of everyoneâ&#x20AC;&#x2122;s backgrounds, their common goal was to advocate for patients. During the presentation, the speakers acknowledged that the bulk of financial advocacy work is done by laypersons with little or no college education. The highest level of education of the majori-

ty of the people employed in this job is a high school diploma; this was both fascinating and reassuring. The mix of clinical, psychosocial, and nonclinical professionals working together in concert provides the best combination for patients and their families. I had a chance to speak with some of the advocates and was delighted to see how they have embraced the role to become experts in finding resources, reimbursement, and supportive services for patients, providers, and families. These advocates were particularly engaging, possessed a wealth of knowledge, and were extremely passionate about their work.

Cancer is one of those disease processes that is particularly challenging and requires specialized knowledge of the complex nature of diagnosis, copayment, coinsurance, drug assistance, and financial assistance.

In my conversations, I discovered some important information about the number of patients they service and how their services are supported. Advocates were not limited to hospitals and clinics, as large physician practices were jumping on board as well. One aspect that I found particularly fascinating was that some facilities have disease-specific and drug assistance advocates. Only a handful

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I October 2014

had specific advocates for nonmedical-related expenses and issues. Through these conversations, combined with further research I did after the conference, I discovered that regardless of who is performing the job, there are never enough financial advocates to meet the needs of our patients.

Realities of Patients with Cancer Comprehending a cancer diagnosis is not something anyone wants to deal with, and the cost of care is the last thing that most patients want to wrap their mind around. The cost of having cancer and/or surviving cancer presents many challenges for the patients, caregivers, families, and providers. Skyrocketing healthcare costs, the price of drugs, plus physician fees and other commodities, such as time off from work, healthcare premiums, copay and coinsurance, possible loss of income, meals, transportation, and other services, can be overwhelming to a person newly diagnosed with cancer. A survey conducted in 2012 by the Association of Community Cancer Centers, â&#x20AC;&#x153;Cancer Care Trends in Community Cancer Centers,â&#x20AC;? demonstrated that nearly all of respondents reported that they were seeing more patients who needed help with copays and/or coinsurance. Community cancer centers were spending increased time assisting patients with identifying resources to help with costs for medications, missed work hours, transportation, and more. A survey conducted by the Association of Oncology Social Work (AOSW) revealed that for more than one half of patients with cancer, treatment costs negatively impact their focus on recovery. According to the sur-

Financial Advocacy

vey, 66% of patients with major financial challenges suffer with depression or anxiety, 29% delay filling prescriptions due to financial pressures, and 22% skip doses. Sixty-three percent of surveyed oncology social workers said financial issues reduce compliance with treatment, and 55% of patients surveyed said the stress of dealing with costs impaired their ability to focus on their recovery. In addition, 40% of patients surveyed had depleted their savings, nearly 30% reported dealing with bill collectors, 54% of those handling a major financial burden said it had become more difficult in the past year to afford treatment, and 68% of responses reported that patients experience financial hardship from the medical bills. Only 36% of patients have discussed treatment costs with their oncologist, and only 16% of patients and caregivers report that they believe their oncologists even think about the financial implications of the treatments they prescribe. In fact, only about one half of patients feel comfortable speaking with health professionals about financial issues. Too often the physician does not address cost with the patient until after treatment is under way and the patient receives the first bill. This can be devastating to the patient, and hinder the success of treatment by causing incredible stress, anxiety, and depression. Findings show that at initial diagnosis, nearly all cancer patients consider treatment effectiveness before all other factors when determining their therapy, ranking the cost of treatment last in their decision-making process. The physicians can supply the knowledge and expertise of care, and financial advisors will help patients navigate through the nonclinical, which is just as significant

in the patient’s success in fighting, beating, and surviving this complex disease. Data show that the stress related to finances can impact compliance and potentially present serious consequences. Consider these statistics from the AOSW survey:

relocated due to the financial stress, and 3% experienced a home foreclosure. • 56% of patients were not at all prepared to handle the financial burden of cancer, while only 7% indicated they were completely prepared for it.

Value of Financial Advisors These numbers tell the story as to why this new emerging profession is so important to the success of cancer treatment. Physicians are faced with many challenges regarding diagnosis, treatment, and care for their patients with cancer, but many do not realize the impact that finances play in patients’ decisions and how it can hinder care. Acknowledgment of this other component to oncology care should assist oncology practices in making the decision to create a position for a financial advocate within their office. It is another salary to pay, but the return on investment is a decrease in the burden on current staff. Current staff members do not have adequate time or resources to provide financial assistance services or reimbursement reduction with the recent increase in underinsured patients. Physician practices are then faced with balancing a good patient experience with financial concerns. The financial advocate knows how to speak with patients and their families about all the difficult topics, and assist the oncology practice in meeting the growing financial concerns of their patients, streamlining the billing, appeals, denial, verification, and drug assistance or replacement programs. Easing financial concerns have been proven to decrease stress, anxiety, and depression, and help the patient focus on recovery. Financial advocates pay for themselves by giving the oncologist, the patient, and their families peace of mind during a difficult and frightening time. l

Sheryl Riley, RN, OCN, CMCN

Findings show that at initial diagnosis, nearly all cancer patients consider treatment effectiveness before all other factors. • Treatment costs negatively impact the ability to focus on recovery for 87% of patients with catastrophic or major financial burdens due to cancer treatment, and 75% of these patients constantly worry about financial issues due to cancer treatment. • Almost one half (46%) of patients who have experienced a financial burden from their cancer have cut back on necessary expenses such as food to pay for cancer treatment. • 24% of respondents indicated they suffered a relationship issue in their efforts to afford treatment for cancer. • 6% of patients sold a home or

October 2014

www.OncPracticeManagement.com

Kyprolis速 (carfilzomib) for Injection Now Has a Permanent J Code: J9047 For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma. Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment. Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline. Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.

KYPROLIS is engineered for selective inhibition1 • Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma. • Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%) *Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria. References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391. 2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated. Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently. Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of the full Prescribing Information on adjacent pages.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2013 Onyx Pharmaceuticals, Inc., South San Francisco, CA 0512-CARF-243R1 December 2013

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%. Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS No 20 20 20 No 20 20 No No 20 (20 mg/m2): Dosing Dosing Dosing Dosing a Cycles 2 and Beyond Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS 27 No 27 27 No 27 27 No No 27 2 Dosing Dosing Dosing Dosing (27 mg/m ): a If

previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2. Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity • Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

Recommended Action • Withhold dose. • If fully recovered before next scheduled dose, continue at same dose level. • If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. Non-Hematologic Toxicity Recommended Action • Withhold until resolved or returned to baseline. Cardiac Toxicity Grade 3 or 4, new onset or worsening of: • After resolution, consider if restarting KYPROLIS at a reduced dose is appropriate (from 27 mg/m2 to • congestive heart failure; 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • decreased left ventricular • If tolerated, the reduced dose may be escalated to the function; previous dose at the discretion of the physician. • or myocardial ischemia [see Warnings and Precautions] Pulmonary Hypertension • Withhold until resolved or returned to baseline. • Restart at the dose used prior to the event or reduced [see Warnings and Precautions] dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Pulmonary Complications • Consider restarting at the next scheduled treatment • Grade 3 or 4 with one dose level reduction (from 27 mg/m2 to [see Warnings and Precautions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Hepatic Toxicity • After resolution, consider if restarting KYPROLIS is • Grade 3 or 4 elevation of appropriate; may be reinitiated at a reduced dose (from transaminases, bilirubin or other 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) liver abnormalities with frequent monitoring of liver function. [see Warnings and Precautions)] • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. (continued)

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function. • Serum creatinine equal to or • If attributable to KYPROLIS, restart at the next scheduled greater than 2 × baseline treatment at a reduced dose (from 27 mg/m2 to [see Adverse Reactions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If not attributable to KYPROLIS, restart at the dose used prior to the event. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 [see Adverse Reactions] to 15 mg/m2), at the discretion of the physician. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Other • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to toxicities 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag. 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3. Table 3: Stability of Reconstituted KYPROLIS Storage Conditions of Reconstituted KYPROLIS

Stabilitya per Container Vial

Syringe

IV Bag (D5Wb)

Refrigerated (2°C to 8°C; 36°F to 46°F)

24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F)

4 hours

Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently [see Dosage and Administration and Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] • Pulmonary Hypertension [see Warnings and Precautions] • Pulmonary Complications [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] • Thrombocytopenia [see Warnings and Precautions] • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. Clinical Trials Safety 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 the clinical trials of another drug, and may not reflect the rates observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes. Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). Adverse reactions occurring at a rate of 10% or greater are presented in Table 4. Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS

Event Fatigue Anemia Nausea Thrombocytopenia Dyspnea Diarrhea Pyrexia Upper respiratory tract infection Headache Cough Blood creatinine increased Lymphopenia Edema peripheral Vomiting Constipation Neutropenia Back pain Insomnia Chills Arthralgia Muscle spasms Hypertension Asthenia Hypokalemia Hypomagnesemia Leukopenia Pain in extremity Pneumonia Aspartate aminotransferase increased Dizziness Hypoesthesia Anorexia Pain Hyperglycemia Chest wall pain Hypercalcemia Hypophosphatemia Hyponatremia

All Gradesa 292 (55.5) 246 (46.8) 236 (44.9) 191 (36.3) 182 (34.6) 172 (32.7) 160 (30.4) 149 (28.3) 145 (27.6) 137 (26.0) 127 (24.1) 126 (24.0) 126 (24.0) 117 (22.2) 110 (20.9) 109 (20.7) 106 (20.2) 94 (17.9) 84 (16.0) 83 (15.8) 76 (14.4) 75 (14.3) 73 (13.9) 72 (13.7) 71 (13.5) 71 (13.5) 70 (13.3) 67 (12.7) 66 (12.5) 66 (12.5) 64 (12.2) 63 (12.0) 63 (12.0) 62 (11.8) 60 (11.4) 58 (11.0) 55 (10.5) 54 (10.3)

Patients (N = 526) [n (%)] Grade 3 Events 38 (7.2) 111 (21.1) 7 (1.3) 69 (13.1) 25 (4.8) 4 (0.8) 7 (1.3) 17 (3.2) 7 (1.3) 1 (0.2) 13 (2.5) 84 (16.0) 3 (0.6) 5 (1.0) 1 (0.2) 50 (9.5) 15 (2.9) 0 1 (0.2) 7 (1.3) 2 (0.4) 15 (2.9) 12 (2.3) 14 (2.7) 2 (0.4) 27 (5.1) 7 (1.3) 52 (9.9) 15 (2.9) 5 (1.0) 3 (0.6) 1 (0.2) 12 (2.3) 16 (3.0) 3 (0.6) 13 (2.5) 24 (4.6) 31 (5.9)

Grade 4 Events 2 (0.4) 7 (1.3) 0 54 (10.3) 1 (0.2)b 1 (0.2) 2 (0.4) 0 0 0 1 (0.2) 11 (2.1) 0 0 0 4 (0.8) 0 0 0 0 0 2 (0.4) 1 (0.2) 3 (0.6) 0 1 (0.2) 0 3 (0.6)b 1 (0.2) 1 (0.2) 0 0 0 3 (0.6) 0 8 (1.5) 3 (0.6) 3 (0.6)

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. One event was Grade 5 severity.

Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection. DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Clinical Pharmacology section of full PI]. USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre‑implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area. Nursing Mothers. It is not known whether KYPROLIS is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and effectiveness of KYPROLIS in pediatric patients have not been established. Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond. The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac Impairment. Patients with New York Heart Association Class III and IV heart failure were not eligible for the clinical trials. Safety in this population has not been evaluated. OVERDOSAGE: There is no known specific antidote for KYPROLIS overdosage. In the event of an overdosage, monitor the patient and provide appropriate supportive care. NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility. Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area. PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms. Advise patients that they may experience shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath. Counsel patients to avoid dehydration, since patients receiving KYPROLIS therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take KYPROLIS treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. Advise patients to discuss with their physician any medication they are currently taking prior to starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS.

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012

Disaster Planning

Disaster Planning for the Oncology Office…Continued from the cover Oncology Office,” Oncology Practice Management, Volume 4, Number 5) addressed how to get started with your disaster planning as well as steps to take before a disaster strikes. This second article provides insights on how to involve patients in emergency planning, and what to do when a disaster is imminent, as well as before and after it strikes.

their wallet. Further, as a backup, patients are encouraged to mail a copy of their card to a friend or family member who lives in a different area. Then, even if patients do not have their card, they will be able to retrieve their record of treatment from their backup contact person. Aside from emergency planning, the OPEN card has helped patients even in day-to-day settings. One Involving Patients in doctor shared that recently one of Emergency Planning, his oncology patients received treatthe OPEN Way ment one morning, then found himRecognizing that disasters are self in the emergency department prone to occur—earthquakes in that very afternoon. He was unable California, hurricanes along the to communicate to the emergency East Coast, and floods in the department physician the names of Midwest—the Medical Oncology the drugs he had been given that Association of Southern California day. Fortunately, he was able to pro(MOASC) launched the Oncolo vide the OPEN card that had been gy Patient Emergency Network updated by staff at his oncology visit. (OPEN) in 2007. Key to that plan is the creation of wallet-sized cards When a Disaster Is on Its Way If you are fortunate enough to that patients carry with them; these cards contain critical and updated receive 24 hours or more advanced information such as their diagnosis, warning of a pending disaster, you treatment, medications, and insur- will have a chance to attend to some ance carrier’s contact information. specific tasks to protect your pracStaff members update the patient’s tice. It is important, however, to be card after each treatment. If there is practical. Do what you can without ever a need, the patient will then be jeopardizing your life or the lives able to access continuity of care with of others. Stay in touch with the alternate health providers. Even in authorities to know when you must an emergency, most people will grab evacuate the building. Here are some tips to secure the their wallet or purse as they run out the door, and their OPEN card is in building and equipment when a disasTable 1 Contact Information for Government Agencies Centers for Medicare & Medicaid Services: www.cms.gov Federal Emergency Management Agency: www.fema.gov Department of Health & Human Services: www.dhhs.gov/emergency/index.shtml Centers for Disease Control and Prevention: www.bt.cdc.gov Pandemic flu: www.pandemic.flu.gov Agency for Healthcare Research and Quality: www.ahrq.gov/plep Food and Drug Administration: www.fda.gov IRB (if patients are in clinical trials): www.hhs.gov/ohrp/assurances/irb/ IRB indicates Institutional Review Board.

ter is on its way: (1) close window blinds and coverings, and remove flammable candles and lamps from the building; (2) move all furniture and medical equipment (if feasible) away from windows, and place them on counters or cabinets (off of the floor), covered in plastic sheeting tied or taped in place, if possible; (3) unplug all electrical equipment; (4) close and secure all doors and windows, evaluate the risk of vandalism, and barricade windows and doors with sandbags if possible or required; (5) clean out the breakroom refrigerator, remove all personal items, and remove all trash from premises.

If you are involved in ongoing research, you will want to ensure that you are also prepared to maintain the integrity of that research in the event of a disaster. To protect the business, you should secure business documents, equipment, and inventory. This includes securing both perishable and nonperishable inventory and removing and storing medication inventory offsite at a generator-serviced site or a site with secure power. Inventory should be reported to the office manager. Finally, to coordinate patient continuity of care, contact patients and alternative physicians or hospitals to arrange referrals for potential future care of patients if needed, print out 2 weeks of patient schedules, maintain compliance with the Health Insurance Portability and Accountability Act, and provide patients with a copy of salient medical records. These should also be Continued on page 22

ONCOLOGY PRACTICE MANAGEMENT

I October 2014

Now enrolling: MURANO study Investigating the Selective BCL-2 Inhibitor GDC-0199/ABT-199 in Chronic Lymphocytic Leukemia GDC-0199/ABT-199 is an investigational agent that has not been approved by regulatory agencies.

A Phase III Study of GDC-0199/ABT-199 Plus Rituximab Compared With Bendamustine Plus Rituximab in Patients With Relapsed or Resistant Chronic Lymphocytic Leukemia (CLL)

GDC-0199/ABT-199 + rituximab

Phase III Relapsed or resistant CLL (N=370)

GDC-0199/ABT-199 continued for 2 years or until disease progression

Bendamustine + rituximab Randomize Primary Endpoint

Secondary Endpoints

• Investigator-assessed progression-free survival, defined as time from randomization until disease progression or death from any cause

• Overall response rate • Incidence of adverse events

Key Inclusion Criteria

Key Exclusion Criteria

• Adult patients ≥18 years of age • Diagnosis of CLL per diagnostic criteria and relapsed or refractory CLL per the iwCLL guidelines • Previously treated with 1-3 lines of therapy (eg, completed ≥2 treatment cycles per therapy), including ≥1 standard chemotherapy-containing regimen • Previously treated with bendamustine, only if duration of response was ≥24 months • ECOG performance status of 0-1 • Adequate bone marrow function • Adequate renal and hepatic function

• Transformation of CLL to aggressive non-Hodgkin lymphoma or CNS involvement by CLL • Undergone an allogenic stem-cell transplant • A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease • Hepatitis B, hepatitis C, or known HIV-positive • Receiving warfarin treatment • Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug • Received any anticancer or investigational therapy within 14 days prior to the first dose of study drug or has not recovered from previous therapy • Received CYP3A4 inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamezapine, phenytoin, St John’s Wort) within 7 days prior to the first dose of GDC-0199/ABT-199 • Prior GDC-0199/ABT-199 treatment

To learn more about this study, please visit www.ClinicalTrials.gov (NCT02005471, GO28667) or call the Trial Information Support Line at 1-888-662-6728.

GDC-0199/ABT-199 is being codeveloped by AbbVie and Genentech, a member of the Roche Group.

Reference: ClinicalTrials.gov, as of 5/2014. A2396579

Disaster Planning

Disaster Planning for the Oncology Office…Continued from page 20 forwarded to previously identified alternative providers. Include treatment plans, a treatment summary, and follow-up plan documents, as well as a current medication list. It is also important to get up-todate information and maintain contact with local and county medical societies, your state medical society, and state professional societies during an emergency. Keep a list of these in your disaster plan. Table 1 features some important contacts to get your list started.

When a Disaster Strikes When a disaster does hit, stay calm. Now is when you will appreciate the time you put into advanced planning. In addition to the items addressed in our first article, be ready to perform the following steps: • Contact media on closing and opening of office • Evaluate the disaster site for any personnel injuries or deaths; confirm evacuation of the office by all individuals • Evaluate the need for containment and disposal of biohazard waste, as well as decontamination and radioactive fallout potential

• Determine mobility (car, bus, train, airplane, fuel availability), and determine availability of water, food, electricity, communication, and shelters • Maintain contact with public service communication sources (weather stations, news stations, and security such as the police department, fire department, or highway patrol), as well as the American Cancer Society (800ACS-2345 or www.cancer.org) and the American Red Cross (800-7332767 or www.redcross.org).

Conducting Research in Emergency Situations If you are involved in ongoing research, you will want to ensure that you are also prepared to maintain the integrity of that research in the event of a disaster. Refer to the Belmont Report1 for guidance on implications related to basic ethical principles of respect for persons (individual autonomy, protection of individuals with reduced autonomy), beneficence (maximize benefits and minimize harms), and justice (equitable distribution of research risks and benefits).

Table 2 Reopening the Practice After Disaster Strikes Determine status of security and of power supply Contact all vendors, banks, insurance companies, construction contractors, and cleaning companies to inform them to resume supply deliveries and services Assess and document any damage with photographs and videotape; make a list of lost and damaged items and their replacement or repair costs Contact insurance company representatives for appraisals, as needed Restock inventory of medical supplies, office supplies, and equipment; prioritize retrievals from offsite locations (medication that requires refrigeration, computer servers and equipment, medical equipment, and furniture) Contact patients to reschedule appointments onsite, offsite, or with alternative providers Reorder and restock chemotherapy and medication supplies Evaluate and reestablish computer network, telephone, and security systems Evaluate functionality of equipment, recalibrate, and perform quality-control test

ONCOLOGY PRACTICE MANAGEMENT

I October 2014

In the midst of emergency situations, your goals remain the same, and are perhaps even more intensely highlighted: (1) to protect continuity in FDA-regulated studies; (2) to protect communication with regulatory authorities; (3) to keep patients informed about what to do; and (4) to ensure that the principal investigator maintains compliant with 45 CFR 46, the Department of Health & Human Services regulatory code regarding the protection of human subjects in research, specifically relating to unanticipated problems involving risk to patients or others, suspension of trials, and termination of trials.

After a Disaster: Returning to Office Operations The Disaster Plan Coordinator will maintain communication with area emergency teams and notify staff when it is safe to reopen the office. Staff will initiate responsibilities to reestablish the practice. The list in Table 2 should serve as a guide to facilitate an organized, wellplanned reopening of the practice. Conclusion We hope this 2-part series has helped you consider preparations to make for a potential disaster. While we cannot predict when or if a dis aster will strike, we can put steps and processes in place now to help plan for one and ensure continuity of care. As practice managers, our staff members and the patients we serve will turn to us for answers in the event of a dis aster. With proper planning, we can offer our team members and patients the answers, guidance, and reassurance they need in a time of turmoil. l Reference

1. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. www. hhs.gov/ohrp/humansubjects/guidance/belmont.html. Published April 18, 1979. Accessed October 10, 2014.

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Testing and Diagnostics

FDA to Regulate Laboratory-Developed Tests By Rosemary Frei, MSc

he US Food and Drug Ad ministration (FDA) recently took initial steps toward regulating laboratory-developed tests (LDTs). Used to select appropriate treatment for individual patients, LDTs are designed, made, and used within a single laboratory,1 and include genetic tests and tests used by clinicians to guide their patients’ treatment. On July 31, 2014, the FDA announced it would take “impor tant steps to ensure that certain tests used by healthcare professionals to

standards for good laboratory practices under the Clinical Laboratory Improvement Amendments,3 and also state laws and accreditation requirements by relevant authorities. However, with its announcement in mid-July, the FDA indicated it will publish a proposed risk-based oversight framework for LDTs.4 The framework was written, in part, because “the agency has serious concerns regarding the lack of independent review of the evidence of clinical validity of LDTs. Clinical validity is the ability of a diagnostic

“Failure of such tests to perform as intended can lead to patients receiving an inappropriate and potentially harmful treatment or, alternatively, not receiving a treatment that has the potential to benefit them.” —Richard L. Schilsky, MD

help diagnose and treat patients provide accurate, consistent, and reliable results” by developing a framework for regulation of LDTs.2 Until now, the FDA has opted to “exercise enforcement discretion.”3 LDTs differ from tests sold to users such as hospitals and doctors’ offices; the latter are regulated as medical devices. There are approximately 2000 laboratories that produce LDTs in the United States. The only standards that laboratories using LDTs have had to comply with are generally accepted

device to measure or detect the clinical condition for which the device is intended. LDTs that have not been properly clinically validated for their intended use and are used to make critical clinical decisions potentially put patients at risk of missed or incorrect diagnosis, failure to administer appropriate treatment, or administration of potentially harmful treatment with no benefit.”3 The FDA will phase in the requirements over 9 years, beginning with high-risk tests—including those used in the decisions of

ONCOLOGY PRACTICE MANAGEMENT

I October 2014

which therapy is best for individual patients or to screen for serious conditions such as malignant cancer3—that have the same intended use as an FDA-approved or cleared companion diagnostic test that is already on the market.3 The FDA will continue to exercise enforcement discretion for low-risk tests; these are tests with very few or no possible deleterious consequences of inaccurate results to patients; those aimed at diagnosing rare diseases; those that have no FDAapproved or cleared alternative; or those that are made for laboratories that are within healthcare facilities in which the patients who are being tested are also being treated.3 “Phasing in the requirements is a way not only to give the labs time to come into compliance, but [also so that] we can then adjust, based upon our resources, to provide the appropriate level of oversight,” said Jeffrey Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, in a media teleconference on the day of the midsummer announcement.3 A few days earlier, a group of 23 pathologists and heads of diagnostic laboratories wrote to the head of the Office of Management and Budget.5 They urged that the FDA “refrain from issuing any draft, proposed, or final guidance document or rule that would purport to regulate LDTs as medical devices.” They expressed concern that, among other points, “FDA regulation of LDTs would stifle innovation, [and] be contrary to public health” due in part to the probable slowdown of test approval “under the rigid, inflexible, and duplicative [proposed] FDA regulatory scheme.” Richard L. Schilsky, MD, chief

Testing and Diagnostics

medical officer, American Society of Clinical Oncology (ASCO), said the society supports the FDA’s approach, particularly with respect to genomic tests used to guide cancer treatment. “Failure of such tests to perform as intended can lead to patients receiving an inappropriate and potentially harmful treatment or, alternatively, not receiving a treatment that has the potential to benefit them,” Dr Schilsky wrote in an e-mail. “In contemporary oncology practice, a patient’s treatment options are increasingly driven by detection of molecular abnormalities in the tumor that drive treatment selection. ASCO believes that tests used to detect those

or be harmed by treatment with a particular drug.2 l

abnormalities must be of the highest quality and thoroughly validated before being offered to doctors and patients. Our patients depend on high-quality tests as much as they depend on carefully studied, safe, and effective drugs to achieve the best possible outcomes.” On July 31, the FDA also provided to Congress with a draft proposal on its LDT regulation. It also intends to publish a draft version of the LDT guidance this fall,1 and then to gather public comments for 90 days.1 Meanwhile, it has also produced a final guidance on the development, review, and approval or clearance of companion diagnostics, which are all types of tests used to identify patients who will benefit

References

1. US Food and Drug Administration. Laboratory developed tests. www.fda.gov/MedicalDevices/ ProductsandMedicalProcedures/InVitroDiagnostics/ ucm407296.htm. Accessed September 11, 2014. 2. US Food and Drug Administration. FDA takes steps to help ensure the reliability of certain diagnostic tests. News release. July 31, 2014. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ ucm407321.htm. Accessed September 11, 2014. 3. US Food and Drug Administration. Framework for regulatory oversight of laboratory developed tests (LDTs). July 31, 2014. www.fda.gov/downloads/ MedicalDevices/ProductsandMedicalProcedures/ InVitroDiagnostics/UCM407409.pdf. Accessed September 11, 2014. 4. US Food and Drug Administration. Transcript of media briefing on companion diagnostic final guidance and proposed risk-based oversight framework for laboratory developed tests. www.fda.gov/down loads/NewsEvents/Newsroom/MediaTranscripts/ UCM408370.pdf. Accessed September 11, 2014. 5. American Clinical Laboratory Association. July 16, 2014. www.acla.com/wp-content/uploads/2014/ 07/Letter-to-OMB-from-Lab-Leaders.pdf. Accessed September 11, 2014.

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Your Patients, Your Practice… Helping Your Practice This comprehensive financial assistance program offers ongoing support across the reimbursement spectrum to help you help your patients. Complete Provider Assistance Benefits verification Prior authorization tracking Regionally dedicated case managers Local access and reimbursement specialists Denied claims assistance Indication XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Important Safety Information Contraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. Warnings and Precautions In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. Adverse Reactions The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/ vertigo. Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI

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(0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). • Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. • Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas. • Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients. Drug Interactions • Effect of Other Drugs on XTANDI – Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided,

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reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible. • Effect of XTANDI on Other Drugs – XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. PLEASE SEE BRIEF SUMMARY OF COMPLETE PRESCRIBING INFORMATION ON FOLLOWING PAGES.

XTANDI Support SolutionsSM, a component of Astellas Access ServicesSM 1-855-8XTANDI (1-855-898-2634); Fax 1-855-982-6341; XTANDISupportSolutions.com ©2014 Astellas Pharma US, Inc. All rights reserved. 076-0329-PM 9/14 Printed in USA XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma, Inc.

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information. INDICATIONS AND USAGE

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in Study 1 (cont.) Respiratory Disorders

Table 1. Adverse Reactions in Study 1

Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDItreated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

XTANDI N = 800

XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Grade 1-4a (%)

CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)]. WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience readministering XTANDI to patients who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

General Disorders Asthenic Conditionsb Peripheral Edema

Placebo N = 399

Grade Grade Grade 3-4 1-4 3-4 (%) (%) (%)

50.6

9.0

44.4

9.3

15.4

1.0

13.3

0.8

Musculoskeletal And Connective Tissue Disorders Back Pain

26.4

5.3

24.3

4.0

Arthralgia 20.5 Musculoskeletal 15.0 Pain Muscular 9.8 Weakness Musculoskeletal 2.6 Stiffness Gastrointestinal Disorders

2.5

17.3

1.8

1.3

11.5

0.3

1.5

6.8

1.8

0.3

0.0

21.8

1.1

17.5

0.3

Hot Flush

20.3

0.0

10.3

0.0

Hypertension

6.4

2.1

2.8

1.3

Diarrhea Vascular Disorders

Nervous System Disorders Headache

12.1

0.9

5.5

0.0

Dizzinessc Spinal Cord Compression and Cauda Equina Syndrome Paresthesia Mental Impairment Disordersd Hypoesthesia

9.5

0.5

7.5

0.5

Epistaxis

3.3

0.1

1.3

0.3

a CTCAE v4 b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Table 2. Adverse Reactions in Study 2 XTANDI N = 871 Grade 1-4a (%)

Grade 3-4 (%)

Placebo N = 844 Grade 1-4 (%)

Grade 3-4 (%)

General Disorders Asthenic 46.9 3.4 33.0 2.8 Conditionsb Peripheral 11.5 0.2 8.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders Back Pain

28.6

2.5

22.4

3.0

Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders 7.4

6.6

4.5

3.8

6.6

0.0

4.5

0.0

4.3

0.3

1.8

0.0

4.0

0.3

1.8

0.0

6.5

0.3

Infections And Infestations Upper Respiratory Tract 10.9 Infectione Lower Respiratory 8.5 Tract And Lung Infectionf Psychiatric Disorders

2.4

4.8

1.3

Insomnia

8.8

0.0

6.0

0.5

Anxiety

6.5

0.3

4.0

0.0

Renal And Urinary Disorders Hematuria

6.9

1.8

4.5

1.0

Pollakiuria

4.8

0.0

2.5

0.0

Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 Non-pathologic 4.0 1.4 0.8 Fractures Skin And Subcutaneous Tissue Disorders

0.0 0.3

Pruritus

3.8

0.0

1.3

0.0

Dry Skin

3.5

0.0

1.3

0.0

Constipation

23.2

0.7

17.3

0.4

Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders Hot Flush

18.0

0.1

7.8

0.0

Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders Dizzinessc

11.3

0.3

7.1

0.0

Headache

11.0

0.2

7.0

0.4

Dysgeusia

7.6

0.1

3.7

0.0

5.7

0.0

1.3

0.1

2.1

0.1

0.4

0.0

0.6

8.5

0.6

0.0

10.5

0.0

1.5

4.7

1.1

0.1

5.7

0.0

Mental Impairment Disordersd Restless Legs Syndrome

Respiratory Disorders Dyspneae

11.0

Infections And Infestations Upper Respiratory 16.4 Tract Infectionf Lower Respiratory Tract And 7.9 Lung g Infection Psychiatric Disorders Insomnia

8.2

Table 2. Adverse Reactions in Study 2 (cont.) Renal And Urinary Disorders Hematuria

8.8

1.3

5.8

1.3

Injury, Poisoning And Procedural Complications Fall

12.7

1.6

NonPathological 8.8 2.1 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 Appetite

5.3

0.7

3.0

1.1

16.4

0.7

8.5

0.2

Investigations Weight Decreased

12.4

0.8

Reproductive System and Breast Disorders Gynecomastia

3.4

0.0

1.4

0.0

a b c d

CTCAE v4 Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)]. Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl

enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)]. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)]. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category X [see Contraindications (4)]. Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryofetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical

experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)]. OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC). Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: September 2014 14B006-XTA-BRFS Rx Only © 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-0472-PM

Physician–Hospital Alignment Series

Do’s and Don’ts in Physician–Hospital Alignment, Part 2 By Max Reiboldt, CPA, President/CEO, Coker Group, Alpharetta, GA

s today’s healthcare climate evolves, physicians and hospitals continue to explore options for alignment between private practices and healthcare systems. Interest in alignment perseveres despite a challenging healthcare environment, and economic, leadership, and structural issues should all be explored with due diligence prior to agreeing on a final arrangement. In this article, the issues of governance and compensation plans are explored as key elements for hospitals and physicians to consider as they work toward developing successful alignment plans.

Governance One of the major hurdles to overcome within any alignment structure is the definition and understanding of governance and leadership responTable 1

sibilities. This can be divided into several components. A major part of this discussion relates to operational decision-making. Often, when they align with hospitals, physicians are challenged to give up day-to-day decision-making responsibilities. In this instance, we are not considering clinical decision-making (discussed below), but the decisions that relate to the day- to-day management and operation of their businesses. In fact, in many instances physicians still do a better job of this than hospitals do, a premise that many hospitals are starting to concede. Thus, they are allowing physicians to have a great deal more input than they have had in the past. The structure of the alignment model will affect the ability for operational decision-making. A professional service agreement (PSA) model, for exam-

Alignment Model–Limited

Strategy

Basic concept

Compensation framework

Managed care networks (IPAs, PHOs)

Loosely formed alliances

No true impact on pay unless through improved payer contracts

Primarily for contracting purposes Limited in ability unless clinically integrated Being used as a platform for ACO development

If used as a platform for ACO, could result in distribution of incentives received

Call coverage stipends

Compensation for the personal, financial, and risk burden associated with ED coverage

Payment can come in the form of a daily stipend, fee-for-service payment, or hybrid payment

Medical directorships

Payment for defined administrative services

Typically paid via a marketbased hourly rate

Must be a true need for the services Recruitment/incubation

Traditional style of a hospital financially supporting a new recruit

Allows existing physicians in practice to not see a decrease in their pay as a new physician comes on board

ACO indicates accountable care organization; ED, emergency department; IPA, independent practice association; PHO, physician–hospital organization. Source: Coker Group.

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ple, allows physicians to have much decision-making ability on day-to-day operations. The issues surrounding day-to-day decision-making often involve staff supervision, which physicians usually can handle best. Ultimately, however, the hospital, as the employer, must have control and overall responsibility. Clinical decision-making is also an important part of the governance and leadership structure and definition. While physicians certainly are allowed to practice medicine as they choose (even under full employment models), certain clinical decision protocols must be considered. For example, when a practice becomes a part of a large hospital network, the implicit understanding and expectation is that they will primarily consider referring to other physicians within that aligned network, although they are not legally and contractually bound to do this. Other clinical decision-making should continue to rest with the physicians, though the utilization of ancillary services and rehabilitation should be directed toward the aligned hospital network. There is absolutely no requirement under any aligned model (Tables 1-3) for hospitals to direct physicians on how best to practice medicine. While there is much more decision-making allowance within the typical governance and leadership structures, ultimately the hospital (under a fully aligned model) should have certain reserve powers. These are usually “big picture” rights, entailing major decisions or expenditures. They could, however, be drilled down into detailed decisions, such as the hospital’s ultimate approval for any staff and for adding providers. Continued on page 32

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Physician–Hospital Alignment Series

Do’s and Don’ts in Physician–Hospital…Continued from page 30 The purpose of the reserve powers is to provide the hospital with the ultimate check and balance, knowing that under a fully aligned model it is in control of most major decisions. Under a PSA model where the practice does retain its responsibility for managing the practice, ultimately certain decisions that rest with that management structure would still be those of the practice and not subject to the reserve powers. Also, organizational chart protocols are a consideration of leadership and governance, as in the structure of the entity and how the management processes are carried out. Certain practices, for example, could be structured as a group practice subsidiary, or, if not officially and legally, this would be organized (at least in substance) as a stand-alone subset of the overall hospital’s employed physician Table 2

network entity. Some hospitals will establish an institute model wherein the aligned practice(s) are separated into a major service line structure. Within that institute, there are individual governance, organizational, and operational understandings and protocols—again, within the definition of being a part of the overall hospital/health system organization. Many decisions must be considered within the leadership and governance structure as the alignment process unfolds. We recommend that a checklist of all the key derivatives be considered.

Compensation Plan Physician compensation is a major part of any transaction concerning physicians and hospitals. This does not have to be under an employment setting, though it is often the case. If not

Alignment Model–Moderate

Strategy

Basic concept

Compensation framework

Management services organization

Services such as revenue cycle, human resources, or IT

Can provide an additional revenue stream

Can be hospital-owned, joint venture, or private practice– owned Equity model assimilation

Ties all entities via legal agreements Can jointly contract with payers

Can result in increased profitability through better payer contracts and other efficiencies

May be with a hospital partner; may be with a private group Target cost objectives

Focus to ensure delivery of cost-effective care while still maintaining quality

Savings shared with providers • Percentage • Hourly fee • Fixed fee

Provider equity (joint ventures, investments)

Joint ventures such as specialty hospitals or surgery centers

Can provide an additional revenue stream to private practice physicians

Clinical comanagement/service line management

Provision of administrative services and work toward certain strategic initiatives within a service line

Involves hourly payment for administrative time and incentive payment for achieving established metrics

May include pay-for-call or medical directorships IT indicates information technology. Source: Coker Group.

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I October 2014

employment, one of the fuller forms of alignment (such as a PSA) is often applicable. As such, there are several model alternatives (Tables 1-3). These vary from heavily productivity-based incentive plan models to nonproductivity-based incentives. Often and particularly as accountable care and changing reimbursement paradigms start to apply in many instances, the compensation model is truly a hybrid (ie, a combination of several of these incentives, both productivity- and nonproductivity-based). From the productivity side, the most prominent form of incentive is through a relative value unit (RVU) format. Often, RVUs are used because they are relatively easy to understand and they tend to be payer blind. Thus, physicians can work diligently within a practice and not worry about the actual reimbursement that is involved, as RVUs do not differen tiate from one payer to another. Typically, their compensation plan involves being paid a certain amount per work RVU (wRVU), and as the RVUs accumulate, the total dollars of compensation do, as well. Other productivity-based models can be tied to encounters, charges, and actual payments. There is no particular right or wrong way; it requires a concerted effort of analysis and deliberation (even some negotiations) to determine the most acceptable structure. Nonproductivity-based incentives are typically tied to patient satisfaction, quality outcomes, cost-savings, and overall conduct. These incentives can be structured in a variety of ways and can be set up so that (1) productivity thresholds must be met, and (2) a portion of what would oth erwise be paid from the productiv ity measurement would have to be earned through meeting certain nonproductivity-based performance thresholds. Thus, the models can have a wide range of variations, and,

Physician–Hospital Alignment Series

as long as genuine incentives to perform and meet the expectations of the criteria are present, the chances are good that the compensation model will be successful. Many employed physicians expect a base or guaranteed rate of pay. This is negotiable but is often the case, at least for a limited period of time. Ancillary services are also key to the compensation structure, if those services remain within the practice after alignment. If they do, the physician may be able to share in a portion of the profits from those ancillary services (just as they do today in private practice). If not, the ancillary services cannot be paid to the physicians and may be a reason why overall productivity and profit margins are less after the transaction. There are ways to mitigate this issue through calibrating an appropriate rate per wRVU that is still within legally permissible/fair market value parameters, but possibly better than the practice realizes in actuality prior to the alignment transaction. Quality and shared savings incentives are increasingly popular as accountable care forms of reimbursement (ie, reimbursement that is not based strictly on productivity and a fee-for-service payment) gain ground. Realizing that it is important to measure overall performance based on the quality of the outcomes and the cost to incur the services, more compensation plans are mirroring these forms of reimbursement, which is certain to continue to be the case in the future. Finally, here is a word of caution relative to the overall compliance standards that must be met whenever physicians are compensated by a hospital. The term fair market value is a readily used concept, which entails the determination that the rate of compensation is consistent with market standards and norms. This is often reviewed and opined upon by an expert independent party that is not directly involved in establishing the rates or

Table 3

Alignment Model–Full

Strategy

Basic concept

Compensation framework

Employment light–PSA model

Allows practice to remain private, but hedge payer risk

Hospital provides payment, often on wRVU basis, which is intended to provide FMV compensation, benefits, and other overhead costs incurred by the practice

Hospital owns receivables Hospital owns payer contracts Contract with practice for professional services Employment–traditional

Traditional employment arrangement with a hospital

Typically includes productivity payment and potentially some other incentives for quality or cost control

Employment–group practice subsidiary

The larger single or multispecialty practice operates as a stand-alone, wholly owned subsidiary of the hospital

Entails a group income distribution plan wherein entity dynamics remain at play

FMV indicates fair market value; PSA, professional service agreement; wRVU, work relative value unit. Source: Coker Group.

the overall compensation plan. In addition, compensation must meet existing commercially reasonable standards within the particular area and specialty involved. Also, there are many compensation structures where multiple portals of pay are provided to the physicians. For example, perhaps the physician is employed and generates a compensation structure from that employment contract. In addition, he is subject to a medical directorship and is compensated. Perhaps the physician is also compensated for call responsibilities. All of these things must be considered within the compliance standard so this stacking concept does not ultimately result in a total pay package that is beyond the realm of reason (ie, that exceeds the test for fair market value/commercially reasonable rates). Thus, when the compensation plan is structured, it should be considered in totality, not just as stand-alone components. Thus, there are numerous models to consider—no matter the alignment model. Even within a PSA structure (also referred to as employment “lite”), the payments can be varied and tied to certain levels of incentives. There are other forms of

October 2014

compensation, such as payment for malpractice premiums or tail premiums, sign-on and/or retention bonuses, and other forms of pay—all of which must be considered in the broad context of physician compensation. For models that do not entail employment or other forms of full alignment, the pay structure is frequently set with fewer incentives (though some incentives could be in place within these structures). Often, a guaranteed rate per hour is applied, but that payment must be consistent with the total amount of time worked and the value for that work per hour. Usually, this varies greatly from one specialty to another. l This article is the second in a 3-part series addressing physician–hospital alignments. Part 1 focused on pretransactional due diligence and structural design processes as they pertain to these alignments. Part 2 of this series is focused on governance and compensation plans. Watch for the final installment of this series— highlighting ongoing relationships and unwind possibilities—in the November issue.

www.OncPracticeManagement.com

Clinical Trial Tracker

New Clinical Trials Under Way

he following clinical trials are currently recruiting participants with breast cancer for inclusion. Each trial description includes the NLM Identifier to use as reference with ClinicalTrials.gov.

Akt Inhibitor MK-2206 and Anastrozole with or Without Goserelin Acetate The goal of this phase 2, openlabel, single-arm clinical trial is to assess the efficacy of the Akt inhibitor MK-2206 and anastrozole with or without goserelin acetate in treating patients with stage II to stage III breast cancer. Female patients aged ≥18 years with estrogen-receptor– positive, HER2-neu, recurrent, stage II, IIIA, IIIB, or IIIC breast cancer are eligible to participate in this study. Serum estradiol levels, apoptotic index, and Ki-67 level biomarker analyses are conducted. All patients receive oral MK-2206 on days 2, 9, 16, and 23, and oral anastrozole daily on days 1 to 28. Premenopausal patients receive go serelin acetate subcutaneous injection on day 1. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Other procedures include neoadjuvant therapy and therapeutic conventional therapy. The primary outcome is the pathological complete response based on tumor Ki-67 value at a 90% confidence interval. Secondary outcomes include clinical and radiological response rate and incidence of adverse events. This clinical trial is expected to enroll 87 patients and will be conducted at multiple sites throughout the United States. For more information, contact Cynthia Ma, MD, PhD, at 314-362-9383 or cma@dom.wustl.edu. The NLM Identifier is NCT01776008.

Veliparib and Carboplatin in Patients with HER2-Negative Metastatic Breast Cancer In this phase 1, dose-escalation, open-label, single-group assignment study, investigators are evaluating the optimal dose of veliparib when given together with carboplatin in patients with metastatic HER2-neu breast cancer. Patients aged ≥18 years with histologically or cytologically confirmed metastatic or locally advanced inoperable breast cancer are eligible to participate in this clinical trial. All patients receive intravenous carboplatin for 1 hour on day 1 and veliparib orally twice daily on days 1 to 7 or on days 1 to 14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may undergo fluorothymidine positron emission tomography scan and peripheral blood cell and tumor tissue collection periodically for correlative studies. The primary objective of this clinical trial is to assess the safety, tolerability, and preliminary efficacy of this drug combination. The secondary objectives are to determine the pharmacodynamic end points of poly ADP-ribose polymerase (PARP) inhibition in the tumor and to determine the biomarkers in the primary tumor that may predict antitumor responses to PARP inhibition, such as breast cancer 1/2, early-onset protein, Fanconi anemia complementation group D2, nuclear foci formation, and expression of micro- ribonucleic acid 155. Data will be collected from a 12-week follow-up period posttreatment. This clinical trial will enroll an estimated 42 patients between Montefiore Medical Center in New York and Ohio State University Medical Center. For more information, contact Joseph A. Sparano, MD, at

ONCOLOGY PRACTICE MANAGEMENT

I October 2014

718-904-2555 or jsparano@montefiore.org. The NLM Identifier is NCT01251874.

Enzalutamide for Advanced, Androgen Receptor–Positive, Triple-Negative Breast Cancer The purpose of this phase 2 study is to determine whether enzalutamide is safe and effective in the treatment of women aged ≥18 years with advanced breast cancer that expresses only the androgen receptor. The single arm will receive enzalutamide 160 mg administered once daily as 4 soft oral gelatin capsules. The clinical benefit rate is measured at ≥16 weeks for the primary outcome and at ≥24 weeks for the secondary outcome, defined as the proportion of evaluable patients with androgen receptor–positive, triple-negative breast cancer with a best response of complete response, partial response, or stable disease. Other outcome measures include overall survival and androgen expression at ≥16 weeks. This clinical trial will enroll an estimated 95 patients and will be conducted at multiple sites across the United States. For more information, contact Amy Peterson, MD, at 415-543-3470 or amy.peterson@ medivation.com. The NLM Identi fier is NCT01889238.

NeuVax Vaccine to Prevent Breast Cancer Recurrence (PRESENT) The goal of this phase 3, randomized, double-blind study is to compare disease-free survival in patients with operable early-stage, node-positive breast cancer who receive standard-of-care multimodality therapy plus nelipepimut-S (NeuVax) vaccine as the treatment group or standard-of-care multimodality therapy plus the vaccine Continued on page 36

*The VELCADE Reimbursement Assistance Program does not file claims or appeal claims for callers, nor can it guarantee that you will be successful in obtaining reimbursement

VELCADE and Millennium are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright ÂŠ 2010, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

V-10-0196

11/10

Clinical Trial Tracker

New Clinical Trials…Continued from page 34 adjuvant sargramostim (Leukine) as the control group. The secondary outcome measures include disease-free survival and overall survival at 3, 5, and 10 years in the vaccine and control groups. Female patients aged ≥18 years with invasive adenocarcinoma are eligible to participate in this clinical trial if they previously received chemotherapy or surgery treatment to excise the cancer. Other inclusion criteria include nodepositive disease, primary tumor stage T1-T3 at initial diagnosis, and HER2-neu breast cancer. Assessments are performed at every study visit for the safety end points, adverse events, vital signs, physical examinations, and laboratory data. Yearly follow-up of survival will include imaging studies, cardiac scans, and concomitant medications. There is an estimated enrollment of 700 patients with trial locations throughout the United States. For more information, contact Elizabeth A. Mittendorf, MD, PhD, FACS, at 713-792-2362 or eamitten@mdanderson.org. The NLM Identifier is NCT01479244.

BKM120 with Paclitaxel in Patients with HER2-Negative, Locally Advanced, or Metastatic Breast Cancer In this randomized, phase 2/3, double-blind study, investigators are evaluating whether the addition of daily BKM120 to weekly paclitaxel is safe and effective in treating patients with HER2-neu locally advanced or metastatic breast cancer. Female patients aged ≥18 years with adequate bone marrow and organ function are eligible to participate in this clinical trial. PI3K biomarker activation status is collected before enrollment. The experimental arm will receive BKM120 oral capsules 100-mg daily

and paclitaxel injection 80 mg/m2 weekly, and the comparator arm will receive matching placebo and paclitaxel at the same dose. Treatment will continue until disease progression or as described in the protocol. The primary outcome of this clinical trial is progression-free survival every 8 weeks after randomization. Secondary outcomes include overall survival and response rate, duration and time to response, clinical benefit rate, and time to definitive deterioration of Eastern Cooperative Oncology Group performance status. The type, frequency, and severity of adverse events are monitored until 30 days posttreatment. This clinical trial will enroll an estimated 524 patients and will be conducted at multiple locations across the United States. For more information, contact Novartis Pharmaceuticals at 888-669-6682. The NLM Identifier is NCT01572727.

free survival (postsurgery phase), and pathological complete response rate. This study will enroll an estimated 2820 patients and will be conducted at numerous locations across the United States. For more information, contact Cynthia Ma, MD, PhD, at 314-362-9383 or cma@dom.wustl.edu. The NLM Identifier is NCT01953588.

Lapatinib Ditosylate and Radiation Therapy in Patients with Locally Advanced or Locally Recurrent Breast Cancer The objective of this phase 2, open-label clinical trial is to assess the clinical complete response rate after concurrent lapatinib ditosylate and radiotherapy in patients with locally advanced or locally recurrent breast cancer that is refractory to chemotherapy. All patients aged ≥18 years with histologically or cytologically confirmed locally advanced breast cancer with new evidence of a local recurrence, life expectancy of Fulvestrant and/or Anastrozole >3 months, and other inclusion criin Postmenopausal Patients teria are eligible for enrollment. This phase 3, randomized, Patients receive lapatinib ditoopen-label clinical trial has 2 pri- sylate orally once daily on day 1 until mary objectives: (1) to compare the completion of radiation therapy. efficacy of fulvestrant and anastro- Beginning on day 7, patients underzole, either alone or in combination go radiation therapy for 5 to 7 weeks. for 6 cycles in reducing cancer After completion of study treatment, growth before surgery; and (2) to patients are followed up at 2 to 4 evaluate whether patients who weeks and at 6 to 12 weeks. Other achieved a modified Preoperative outcomes include determining the Endocrine Prognostic Index score feasibility of using flow cytometry of 0 at surgery after 6 months of and single-cell gene expression proneoadjuvant endocrine therapy pre- filing to assess breast cancer stem dict excellent long-term outcome. cells and their change in proportion This clinical trial enrolls post- after combined modality therapy. menopausal women with Eastern This clinical trial will enroll an estiCooperative Oncology Group per- mated 22 patients and will be conformance status of 0-2 with clinical ducted at Stanford University T2-T4c, any N, M0 invasive stage Cancer Institute in California. For II to stage III breast cancer. The additional information, contact primary outcome measures of this Amanda Simmons at 650-724-4606 clinical trial include rate of endo- or amandals@stanford.edu. The crine-resistant disease, recurrence- NLM Identifier is NCT01868503. l

ONCOLOGY PRACTICE MANAGEMENT

I October 2014

Patient Assistance Programs

Commitment to Access Supports Patients Prescribed Arzerra, Other Medications

laxoSmithKline (GSK) offers support programs to patients with cancer in the United States or Puerto Rico. Through its Commitment to Access program, patients prescribed GSK medications potentially have access to free medicine, reimbursement support, or copay assistance. The programs differ in structure for federally insured, privately insured, and uninsured patients. For a complete list of oncology and oncology-supportive drugs covered through these programs as well as their indications, see the Table. For more information, visit www.gskcta.com or call 866-265-6491.

Eligibility Criteria Patients with a household income of ≤500% of the federal poverty level (FPL) may qualify for the following programs if other criteria are met: • Patient Assistance. GSK offers cancer medicines free of charge to eligiTable

ble patients in the United States and Puerto Rico who meet income and other eligibility criteria. Can didates cannot be eligible for Medi caid or Puerto Rico’s Government Health Plan or have coverage for brand name prescription drug benefits. Patients under Medicare Part D who spend ≥$600 on prescription medicines during the current calendar year are eligible to enroll. • Reimbursement Support. Patients who have private prescription drug coverage, and are in a health plan that permits member participation in copay assistance programs may be eligible if other criteria are met. Financial assistance will vary depending on the FPL percentage range at time of enrollment and specific commercial insurance coverage. • Copayment Assistance. This program is available to patients with commercial insurance coverage, in

cluding those who are enrolled in a Health Insurance Marketplace plan or exchange. GSK will determine eligibility and proportion of coverage based on income.

What Patients Will Receive • All medicines are mailed to the prescriber or directly to the pa tient’s home based on program guidelines per medication. • In order to receive the medicine by mail, send in the application, income documentation, and a prescription for the requested medicine to GSK. How to Obtain Refills •C all 866-265-6491 (8ONCOLOGY1). • Order refills ≥2 weeks before the pa tient runs out of medicine or 7 to 10 days before the next treatment. • Refills are sent at no cost for up to 12 months after enrollment in Commitment to Access. (Refills for eligible Medicare Part D patients are sent through the end of the current calendar year.) • Refills can be sent to the prescriber’s office or directly to the patient’s home based on program guidelines per medication.

O ncology and Oncology-Supportive Drugs and the Disease State Coverage

Drug name

Type of cancer

Arranon (nelarabine)

T-cell acute lymphoblastic leukemia T-cell lymphoblastic lymphoma

Arzerra (ofatumumab)

Chronic lymphocytic leukemia

Bexxar (tositumomab)

CD20-positive, relapsed or refractory, low-grade, follicular, or transferred non-Hodgkin lymphoma

Hycamtin (topotecan) capsules

Relapsed small-cell lung cancer

Hycamtin (topotecan hydrochloride) for injection

Metastatic carcinoma of the ovary Small-cell lung cancer Recurrent, or persistent carcinoma of the cervix

Leukeran (chlorambucil)

Chronic lymphatic (lymphocytic) leukemia Malignant lymphomas, including lymphosarcoma Giant follicular lymphoma Hodgkin disease

Myleran (busulfan)

Chronic myelogenous leukemia

Tykerb (lapatinib)

HER2/neu advanced or metastatic breast cancer

Votrient (pazopanib)

Advanced renal-cell carcinoma Advanced soft tissue sarcoma

Promacta (eltrombopag)

Chronic immune (idiopathic) thrombocytopenia

Enrollment An enrollment form is available at www.gskcta.com/enrollment/phoneapplication.html. Applications must be faxed to 800-750-9832 from a prescrib er’s facility or mailed to the program’s PO Box. Prescriptions must be submitted for processing with the enrollment form; up to 13 refills, if medically appropriate, can be requested at the time the prescription is submitted. A patient who is enrolling for the first time for Patient Assistance must also register a healthcare worker involved in the patient’s care as his or her patient advocate. l

Source: GlaxoSmithKline Commitment to Access. www.gskcta.com.

October 2014

www.OncPracticeManagement.com

Drug Update

Arzerra (Ofatumumab) Receives FDA Approval for Patients with Previously Untreated Chronic Lymphocytic Leukemia for Use in Combination with Chlorambucil By Lisa A. Raedler, PhD, RPh, Medical Writer

hronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is a cancer that predominantly affects the B-cell lymphocytes.1 Normal B-cell lymphocytes originate in the bone marrow, develop in the lymph nodes, and fight infection by producing an immune response.1 In CLL, excess B-cells accumulate in the bone marrow and blood, where they crowd out healthy blood cells.2 According to the Leukemia & Lymphoma Society, more than 15,600 Americans were diagnosed with CLL in 2013.3 The incidence of CLL increases significantly among people aged ≥50 years; only a small fraction of adults are diagnosed in their 30s and 40s.3 Most patients with CLL are asymptomatic and learn they have the disease as a result of a routine physical examination or a blood test.4 As CLL advances, patients can experience enlarged lymph nodes and an enlarged spleen, abnormal bleeding, and infections.5 According to the American Society of Clinical Oncology, the prognosis for patients with CLL varies significantly based on disease subtype and risk status, with survival ranging from approximately 1 year to more than 20 years.6 The 5-year overall survival rate for patients with CLL of all stages is approximately 79%.6 The cost burden associated with CLL is significant. A recent cost analysis conducted in Germany using

the direct and indirect costs of CLL calculated the total per-patient cost to be approximately $13,500 annually compared with approximately $6600 annually for patients in an age- and sex-matched control group.7 The economic burden of CLL was primarily driven by inpatient and

The FDA expanded the approved indications for ofatumumab for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. pharmaceutical costs in this study. From a societal perspective, productivity loss was the highest cost associated with a diagnosis of CLL.7 Patients with early-stage CLL are typically not treated, whereas patients with symptomatic intermediate- and high-risk CLL usually receive chemotherapy combined with a monoclonal antibody–targeting CD20.2 Studies comparing chemotherapy, such as fludarabine or the combination of fludarabine and cyclophosphamide, with immunotherapy (ie, rituximab in treatment-naïve patients with CLL) have shown that the ritux-

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I October 2014

imab-containing combinations significantly improve complete response rates, remission duration, and overall survival in CLL.2 Bendamustine is indicated as a single agent for the treatment of CLL.8 Studies of bendamustine combined with rituximab have demonstrated promising results in untreated and in previously treated patients with CLL.2 No consensus exists regarding the management of patients with relapsed or refractory CLL. Treatment decisions are based on several factors, including the timing of relapse, patient age, disease extent, overall health, and previous therapies.9 Drugs that are frequently used in the relapsed/refractory CLL setting (either alone or in combination) include bendamustine, chlor ambucil, fludarabine, ofatumumab, and rituximab.9 The development of drugs for the treatment of CLL has been fruitful, with the US Food and Drug Administration (FDA) recently approving 3 new therapies. In November 2013, the FDA approved obinutuzumab in combination with chlorambucil for the treatment of patients with previously untreated CLL.10 Obinutuzu mab is a humanized monoclonal antibody that targets CD20 on the surface of CLL cells.11 Ibrutinib was approved by the FDA in February 2014 for patients with CLL who have received at least 1 previous therapy.12 Ibrutinib is the first drug designed to target Bruton’s tyrosine kinase, a protein necessary for the growth and survival of malignant B-cells.13

Drug Update

In July 2014, the FDA approved idelalisib in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy, as well as for patients with relapsed follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma who have received at least 2 previous systemic therapies.14 Idelalisib inhibits PI3K delta, a protein that is overexpressed in many B-cell cancers. PI3K delta affects the viability, proliferation, and migration of malignant B-cells.12

FDA Approves Expanded Indication for Ofatumumab On April 17, 2014, the FDA expanded the approved indications for ofatumumab (Arzerra; Glaxo SmithKline), an anti-CD20 monoclonal antibody, for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom flu darabine-based therapy is considered inappropriate.15 Ofatumumab was initially approved in 2009 for the treatment of patients with CLL that is refractory to fludarabine or to alemtuzumab.16 The FDA approved this new indication for ofatumumab based on a multicenter, randomized, open-label, parallel-arm trial of 447 patients with CLL for whom fludarabine- based therapy was deemed inappropriate based on the patient’s age and/or comorbidities.15 The primary end point of this trial was progression-free survival (PFS) as assessed by a blinded Independent Review Committee (IRC).15 The results of this randomized clinical trial fulfilled the postmarketing requirement by the FDA for the manufacturer to verify ofatumumab’s clinical benefit in patients with CLL. Consequently, the approval of the new indication for ofatumumab was converted from accelerated approval to regular process approval.17

Table 1 Infusion Rates for Ofatumumab in Previously Untreated Patients with CLL Interval after start of infusion, min

Cycle 1, day 1,a mL/hr

Cycle 1, day 8b and cycles 2 -12,c mL/hr

0-30

31-60

61-90

100

91-120

100

200

121-150

200

400

151-180

300

400

>180

400

Cycle 1, day 1 = 300 mg; median duration of infusion = 5.2 hrs. b Cycle 1, day 8 = 1000 mg; median duration of infusion = 4.4 hrs. c Cycles 2 through 12 = 1000 mg; median durations of infusions = 4.2-4.4 hrs. CLL indicates chronic lymphocytic leukemia. Source: Arzerra (ofatumumab) injection prescribing information; April 2014. a

Mechanism of Action Ofatumumab binds to extracellular loops of the CD20 molecule, which is expressed on normal B lymphocytes and on B-cell CLL cells. After ofatumumab binds to the CD20 molecule, the Fc domain of the antibody mediates immune effector functions that result in cell lysis in vitro. Complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity are possible mechanisms of cell lysis that occurs after ofatumumab binding.16

a corticosteroid. Infusion facilities should be adequately equipped to monitor and treat infusion reactions.16 During the first infusion of ofatumumab (cycle 1, day 1, 300-mg dose), the rate of infusion should be initiated at 3.6 mg per hour (12 mL per hour). The cycle 1, day 8, and subsequent infusions (cycles 2-12, 1000-mg dose) can be initiated at a rate of 25 mg per hour.16 If no infusion-related adverse events are observed, the rate of ofatu mumab infusion can be increased every 30 minutes (Table 1).16 If a grade ≥3 infusion-related event was experienced during the previous administration of ofatumumab, the initial rate of infusion should decrease to 12 mg per hour (12 mL per hour).16

Dosing and Administration In patients with previously untreated CLL, the recommended dosage and schedule of ofatumumab is 300 mg on day 1, followed by 1000 mg on day 8 of the first 28-day cycle, followed by 1000 mg on day 1 of subsequent 28-day cycles. Treatment should be administered for a minimum of 3 cycles until best response or a maximum of 12 cycles.16 In the phase 3 study of ofatumumab in combination with chlor ambucil, the oral agent was given at a dose of 10 mg/m2 on days 1 to 7 of the 28-day cycle.16 Patients receiving ofatumumab should be premedicated with acetaminophen, an antihistamine, and

Pivotal Phase 3 Clinical Trial The safety and efficacy of ofatumumab in patients with previously untreated CLL were demonstrated in a phase 3 open-label, multicenter clinical trial known as COMPLEMENT 1. In this trial, 447 patients with CLL who were deemed unfit for fludarabine-based therapy were randomized to receive chlorambucil alone (N = 226) or ofatumumab combined with chlor Continued on page 40

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Drug Update

Arzerra (Ofatumumab) Receives…Continued from page 39 ambucil (N = 221).18 Chlorambucil was given orally at a dose of 10 mg/m2 on days 1 to 7 every 28 days in both arms of this study. Ofatumumab was administered as an intravenous infusion every month (first 28-day cycle: 300 mg on day 1 and 1000 mg on day 8; subsequent 28-day cycles: 1000 mg on day 1). In this trial, approximately 60% of the patients with CLL received 3 to 6 cycles of ofatumumab and 30% received 7 to 12 treatment cycles.18 The primary end point of this phase 3 study was PFS as assessed by a blinded IRC using the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) update of the National Cancer Institute Working Group guidelines. Secondary efficacy end points, which included overall response rate, complete response rate, and duration of response, were also assessed by the IRC using the 2008 IWCLL guidelines.18

Patient Population Patients with previously untreated CLL who enrolled in the phase 3 clinical trial comparing ofatumu

mab plus chlorambucil with chlorambucil alone were considered by the investigators to be inappropriate for fludarabine-based therapy for reasons that included advanced age and the presence of comorbidities.18 The median age of the population studied was 69 years, with the majority (69%) of patients in both arms aged ≥65 years.16,18 The study enrollees were mostly male (63%) and white (89%) and had 2 or more comorbidities (72%).15,18 A total of 48% of the patients had a creatinine clearance of <70 mL/min.16 Beta-2 microglobulin was elevated (>3500 mcg/L) in 72% of patients at baseline.18

Efficacy and Safety In this phase 3 clinical trial, the combination of ofatumumab and chlorambucil in previously untreated patients with CLL resulted in a statistically significant improvement in IRC-assessed median PFS compared with chlorambucil alone (22.4 months vs 13.1 months, respectively).18 These data and results of secondary end point analyses are summarized in Table 2.16,18 A total of 217 previously untreat-

Table 2 Ofatumumab plus Chlorambucil versus Chlorambucil Alone in Previously Untreated CLL Efficacy end points Progression-free survival, median, mo

Ofatumumab plus chlorambucil (N = 221)

Chlorambucil (N = 226)

22.4 (95% CI, 19-25.2)

13.1 (95% CI, 10.6-13.8)

Hazard ratio Stratified log rank P value Overall response, % P value

0.57 (95% CI, 0.45-0.72) P <.001 82.4 (95% CI, 76.7-87.1) 68.6 (95% CI, 62.1-74.6) P = .001

Complete response, %

Duration of response, median, mo

22.1 (95% CI, 19.1-24.6)

13.2 (95% CI, 10.8-16.4)

CI indicates confidence interval; CLL, chronic lymphocytic leukemia. Source: Arzerra (ofatumumab) injection prescribing information; April 2014.

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I October 2014

ed CLL patients received ofatumu mab combined with chlorambucil and 227 patients received chlorambucil alone.17 Overall, grade ≥3 neutropenia was observed in 26% of patients receiving the combination of ofatumumab plus chlorambucil compared with 14% in patients receiving chlorambucil alone; grade ≥3 infusion-related events were 10% in the combination group and were not available for the chemotherapy alone; grade ≥3 infections were similar between the 2 groups—15% with the combination versus 14% with chlorambucil alone.17

Adverse Reactions Infusion Reactions Overall, 67% of the patients who received ofatumumab plus chlorambucil experienced ≥1 infusion reactions, with 10% of patients experiencing reactions of grade ≥3 severity.16 None of these events was fatal.16 In the phase 3 clinical trial, the term “infusion reaction” encompassed events that occurred on the day of or within 24 hours of the end of an ofatumumab infusion and resulted in interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.16 Severe infusion reactions (grade ≥3) or infusion reactions that led to treatment interruption or discontin uation occurred most frequently during the first cycle of ofatumumab (56% on day 1 and 23% on day 8).16 The rates of reactions decreased with subsequent infusions.16 Infusion reactions led to the discontinuation of treatment in 3% of the patients.16 Cytopenia The most common grade 3 or 4 hematologic adverse reactions asso-

Drug Update

ciated with ofatumumab combined with chlorambucil included neutropenia (29%), lymphopenia (29%), and leukopenia (23%).16 Neutropenia occurring up to 60 days after the last dose of ofatumumab was reported as a serious adverse event in 3% of patients.16 One of these patients died as a result of neutropenic sepsis and agranulocytosis.16 Prolonged neutropenia was ob served in 6% of patients receiving ofatumumab plus chlorambucil versus in 4% of patients receiving chlor ambucil alone.16 Late-onset neutropenia occurred in 6% of patients receiving ofatumumab plus chlorambucil versus in 1% of patients receiving chlorambucil alone.16

Warnings and Precautions Ofatumumab has no contraindi cations. Boxed warning. Ofatumumab carries a boxed warning regarding the risk for hepatitis B virus (HBV) infection reactivation.16 High-risk patients should be screened for HBV infection before initiating ofatumumab therapy. HBV carriers should be monitored for signs of active infection during and after treatment with ofatumumab. In addition, progressive multifocal leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.16 Infusion reactions. Ofatumumab can cause serious, including fatal, infusion reactions that manifest as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia or infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid or anaphylactic reactions.16 Patients receiving ofatumumab should be premedicated with acet-

aminophen, an antihistamine, and a corticosteroid. However, infusion reactions can occur despite premedication.16 Treatment interruption or discontinuation may be required.16 The administration of ofatumumab should cease if infusion reactions of any severity are observed.16 Medical management for severe infusion reactions, including angina or other signs and symptoms of myocardial ischemia, should be instituted. If anaphylaxis occurs, ofatumumab should be discontinued immediately and permanently, and appropriate medical treatment should be initiated.16 HBV reactivation. HBV infection reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or the detection of HBV surface antigen (HBsAg) in a person who was previously HBsAg negative and hepatitis B core antibody (anti-HBc) positive. HBV reactivation is often followed by hepatitis B (ie, increased transaminase levels). Severe cases of reactivation can be followed by increased bilirubin levels, liver failure, and death.16 HBV reactivation has occurred in patients receiving ofatumumab, with some cases resulting in hepatitis, liver failure, or death.16 Cases have been reported in patients who are HBsAg positive, as well as patients who are HBsAg negative but antiHBc positive. Reactivation also has occurred in patients who appeared to have resolved HBV infection.16 All patients for whom ofatumu mab is being considered should be screened for HBV infection before the initiation of treatment.16 Patients with evidence of HBV infection should consult with physicians who have expertise in managing HBV to discuss the monitoring and potential use of HBV antiviral therapy.16 Patients with evidence of current or previous HBV infection should be evaluated for clinical and labora-

tory signs of hepatitis or HBV reactivation during and for several months after treatment with ofatumumab. HBV reactivation has been reported for at least 12 months after the completion of therapy.16 If patients develop HBV reactivation during treatment with ofatumumab, the agent (and any concomitant chemotherapy) should be discontinued. Appropriate treatment should be instituted.16 Data regarding the safety of resuming ofatu mumab in patients who develop HBV reactivation are insufficient.16 HBV infection. Fatal HBV infection has been documented with ofatumumab in patients who had not been previously infected.16 Patients with clinical and laboratory signs of hepatitis should be monitored.16 Progressive multifocal leuko encephalopathy. Death resulting from PML has occurred with ofatumumab.16 PML should be considered in any patient describing the onset of or changes in preexisting neurologic signs or symptoms. If PML is suspected, ofatu mumab should be discontin ued. Evaluation for PML, including neurology consultation, should be initiated.16 Tumor lysis syndrome. Patients receiving ofatumumab have experienced tumor lysis syndrome (TLS), which has resulted in hospitalization.16 Patients who are at greater risk of TLS include those with high tumor burden and/or high circulating lymphocyte counts (>25 × 109/L).16 Prophylaxis of TLS using antihyperuricemic agents and hy dration beginning 12 hours to 24 hours before the infusion of ofatumumab should be considered.16 The management of TLS includes aggressive intravenous hydration and antihyperuricemic agents, correction of electrolyte abnormalities, and renal function monitoring.16 Cytopenias. Severe cytopenias can occur with ofatumumab, includContinued on page 42

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Drug Update

Arzerra (Ofatumumab) Receives…Continued from page 41 ing neutropenia, thrombocytopenia, and anemia. Patients who received ofatumumab combined with chlorambucil have experienced pancytopenia, agranulocytosis, and fatal neutropenic sepsis.16 Patients receiving ofatumumab also experienced grade 3 or 4 late- onset neutropenia, occurring at least 42 days after the last dose, and/ or prolonged neutropenia that does not resolve between 24 and 42 days after the last dose.16 Complete blood count (CBC) should be monitored at regular intervals during and after the conclusion of therapy with ofatumu mab. The frequency of CBC monitoring should increase in patients who develop severe cytopenias.16 Immunizations. There are no studies evaluating the safety of immunization with live viral vaccines in association with ofatumu mab.16 Live viral vaccines should not be administered to patients who have recently received ofatumumab.

Specific Populations Ofatumumab has been assigned pregnancy Category C.16 There are no adequate or well-controlled studies of ofatumumab in pregnant women.16 Ofatumumab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.16 Caution should be exercised when administering the drug to a nursing woman.16 The safety and efficacy of ofatumumab in pediatric patients have not been established.16 In the clinical trial of previously untreated patients with CLL, 148 (68%) of the 217 patients receiving ofatumumab plus chlorambucil were

aged ≥65 years.16 Patients aged ≥65 years were more likely to experience specific grade ≥3 adverse reactions compared with young patients, especially neutropenia (30% vs 17%, respectively) and pneumonia (5% vs 1%, respectively). In patients aged ≥65 years, 29% experienced serious adverse events compared with 13% of young patients. No significant differences in the effectiveness of the combination of ofatumumab and chlorambucil were observed between older and younger patients with previously untreated CLL.16

Conclusion The addition of ofatumumab to chlorambucil represents a clinically meaningful improvement, with manageable side effects, for the treatment of previously untreated patients with CLL who are deemed inappropriate to receive fludarabine therapy. This doublet has demonstrated improved PFS in this patient population with limited therapeutic options. The safety and efficacy of ofatumumab combined with other agents for the treatment of CLL and other hematologic malignancies are being explored.19 Examples include a trial combining ofatumumab and ibrutinib for patients with relapsed or refractory CLL, and a trial combining idelalisib with ofatumumab in patients with previously untreated CLL or small lymphocytic lymphoma.19 l References

1. ASCO Answers fact sheet: chronic lymphocytic leukemia. 2013. www.cancer.net/sites/cancer.net/ files/asco_answers_cll.pdf. Accessed August 8, 2014. 2. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia. Revised 2011. www.lls.org/content/ nationalcontent/resourcecenter/freeeducationmateri als/leukemia/pdf/cll.pdf. Accessed August 8, 2014. 3. Leukemia & Lymphoma Society. CLL incidence. www.lls.org/#/diseaseinformation/leukemia/chronic lymphocyticleukemia/incidence/. Accessed August

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2014. 4. Leukemia & Lymphoma Society. CLL signs and symptoms. www.lls.org/#/diseaseinformation/leuke mia/c hroniclymphocyticleukemia/signssymptoms/. Accessed August 8, 2014. 5. Cancer.net. Leukemia—chronic lymphocytic— CLL: symptoms and signs. June 2013. www.cancer. net/cancer-types/leukemia-chronic-lymphocytic-cll/ symptoms-and-signs. Accessed August 8, 2014. 6. Cancer.net. Leukemia—chronic lymphocytic— CLL: statistics. Updated February 18, 2014. www. cancer.net/cancer-types/leukemia-chronic-lympho cytic-cll/statistics. Accessed August 8, 2014. 7. Blankart CR, Koch T, Linder R, et al. Cost of illness and economic burden of chronic lymphocytic leukemia. Orphanet J Rare Dis. 2013;8:32. 8. Treanda (bendamustine) for injection [prescribing information]. North Wales, PA: Teva Pharmaceuticals, Inc; August 2013. 9. Veliz M, Pinilla-Ibarz J. Treatment of relapsed and refractory chronic lymphocytic leukemia. Cancer Control. 2012;19:37-53. 10. US Food and Drug Administration. FDA approves Gazyva for chronic lymphocytic leukemia. Press release. November 1, 2013. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ ucm373209.htm. Accessed August 14, 2014. 11. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech; November 2013. 12. US Food and Drug Administration. Ibrutinib (Imbruvica). Updated February 13, 2014. www. fda.gov/drugs/informationondrugs/approveddrugs/ ucm385878.htm#. Accessed August 14, 2014. 13. Imbruvica (ibrutinib) capsules [prescribing information]. Sunnyvale, CA: Pharmacyclics, Inc; February 2014. 14. Business Wire. U.S. Food and Drug Administration approves Gilead’s Zydelig (idelalisib) for relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma. Press release. July 23, 2014. www.marketwatch.com/ story/us-food-and-drug-administration-approves-gil eads-zydelig-idelalisib-for-relapsed-chronic-lympho cytic-leukemia-follicular-lymphoma-and-small-lym phocytic-lymphoma-2014-07-23. Accessed August 8, 2014. 15. US Food and Drug Administration. Ofatumu mab. Updated April 17, 2014. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm393823. htm. Accessed August 8, 2014. 16. Arzerra (ofatumumab) injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; April 2014. 17. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study complement 1 (OMB110911). Abstract 528. Abstract presented at the 55th American Society of Clinical Oncology Annual Meeting and Exposition. New Orleans, LA; December 7-10, 2013. 18. National Cancer Institute. FDA approval for ofatumumab. Updated April 23, 2014. www.cancer. gov/cancertopics/druginfo/fda-ofatumumab. Accessed August 8, 2014. 19. Clinicaltrials.gov. Ofatumumab in CLL. http:// clinicaltrials.gov/ct2/results?term=Ofatumumab+ in+CLL&Search=Search. Accessed July 23, 2014.

Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40171 February 2014. Printed in USA.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 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. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40188 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

Drug Coding Supplied by RJ Health Systems

FDA-Approved Medications Used for the Treatment of Breast Cancer The following sections will assist healthcare professionals and payers by providing appropriate coding and billing information associated with the treatment of patients with breast cancer. The following sections include: • Associated ICD-9-CM codes used for the classification of breast cancer • Drugs that have been FDA approved in the treatment of breast cancer • Drugs that are Compendia-listed for off-label use for breast cancer based on clinical studies that suggest beneficial use in some cases. Please note: If a check mark appears in the FDA column it will NOT appear in the Compendia off-label use column • Corresponding HCPCS/CPT® codes and code descriptions • Drugs listed in the Compendia section have no FDA-approved uses for breast cancer. However, drugs in the FDA-approved section are FDA approved for at least 1 of the breast cancer ICD-9-CM codes but may also have Compendia-listed uses as well.

Associated ICD-9-CM codes for the treatment of breast cancer: 174

Malignant neoplasm of female breast Includes: b reast (female) connective tissue soft parts Paget’s disease of: breast nipple Use additional code to identify estrogen receptor status (V86.0, V86.1) Excludes: skin of breast (172.5, 173.5) 174.0 Nipple and areola 174.1 Central portion 174.2 Upper-inner quadrant 174.3 Lower-inner quadrant 174.4 Upper-outer quadrant 174.5 Lower-outer quadrant 174.6 Axillary tail 174.8 Other specified sites of female breast Ectopic sites Inner breast Lower breast Malignant neoplasm of contiguous or overlapping sites of breast whose point of origin cannot be determined Midline of breast Outer breast Upper breast 174.9 Breast (female), unspecified 175 Malignant neoplasm of male breast Use additional code to identify estrogen receptor status (V86.0, V86.1) Excludes: skin of breast (172.5, 173.5) 175.0 Nipple and areola 175.9 Other and unspecified sites of male breast Ectopic breast tissue, male

October 2014

www.OncPracticeManagement.com

Drug Coding

FDA approved for breast cancer

Compendia off-label uses for breast cancer

CPT ® administration codes

Generic (brand) name

HCPCS code – code description

ado-trastuzumab emtansine (Kadcyla)

J9354 – Injection, ado-trastuzumab emtansine, 1 mg

√

96413, 96415

anastrozole (Arimidex)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

anastrozole (Arimidex)

S0170 – Anastrozole, oral, 1 mg

√

N/A

Bacillus CalmetteGuerin (Tice BCG, TheraCys)

90586 – Bacillus Calmette-Guerin vaccine (BCG) for bladder cancer, live, for intravesical use

√

51720

Bacillus CalmetteGuerin (Tice BCG, TheraCys)

J9031 – BCG (intravesical), per installation

√

51720

bendamustine (Treanda)

J9033 – Injection, bendamustine hydrochloride, 1 mg

√

96413

bevacizumab (Avastin)

C9257 – Injection, bevacizumab, 0.25 mg

√

67028

bevacizumab (Avastin)

J9035 – Injection, bevacizumab, 10 mg

√

96413, 96415

capecitabine (Xeloda)

J8520 – Capecitabine, oral, 150 mg

√

N/A

capecitabine (Xeloda)

J8521 – Capecitabine, oral, 500 mg

√

N/A

carboplatin (Paraplatin)

J9045 – Injection, carboplatin, 50 mg

√

96409, 96413, 96415

cisplatin (Platinol-AQ)

J9060 – Injection, cisplatin, powder or solution, per 10 mg

√

96409, 96413, 96415

cyclophosphamide (Cytoxan)

J8530 – Cyclophosphamide, oral, 25 mg

√

N/A

cyclophosphamide (Cytoxan)

J9070 – Cyclophosphamide, 100 mg

√

96409, 96413, 96415

dexamethasone (Decadron)

J1100 – Injection, dexamethasone sodium phosphate, 1 mg

√

11900, 11901, 20600, 20605, 20610, 96372, 96374

dexamethasone (Decadron)

J8540 – Dexamethasone, oral, 0.25 mg

√

N/A

docetaxel (Taxotere)

J9171 – Injection, docetaxel, 1 mg

√

96413

doxorubicin HCl (Adriamycin)

J9000 – Injection, doxorubicin hydrochloride, 10 mg

√

96409

doxorubicin HCl liposome (Doxil)

Q2050 – Injection, doxorubicin hydrochloride, liposomal, 10 mg, not otherwise specified

ONCOLOGY PRACTICE MANAGEMENT

I October 2014

√

96413

Drug Coding

FDA approved for breast cancer

Compendia off-label uses for breast cancer

CPT ® administration codes

Generic (brand) name

HCPCS code – code description

epirubicin (Ellence)

J9178 – Injection, epirubicin hydrochloride, 2 mg

√

96409, 96413

eribulin (Halaven)

J9179 – Injection, eribulin mesylate, 0.1 mg

√

96409

estradiol (Estrace)

J8499* – Prescription drug, oral, nonchemotherapeutic, not otherwise specified

√

N/A

etoposide (VePesid)

J8560 – Etoposide, oral, 50 mg

√

N/A

etoposide (Etopophos, Toposar)

J9181 – Injection, etoposide, 10 mg

√

96413, 96415

everolimus (Afinitor)

C9399* – Unclassified drugs or biologicals (hospital outpatient use ONLY)

√

N/A

everolimus (Afinitor)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

exemestane (Aromasin)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

exemestane (Aromasin)

S0156 – Exemestane, 25 mg

√

N/A

fluorouracil (Adrucil)

J9190 – Injection, fluorouracil, 500 mg

√

96409

fluoxymesterone (Androxy)

J8499* – Prescription drug, oral, nonchemotherapeutic, not otherwise specified

√

N/A

fulvestrant (Faslodex)

J9395 – Injection, fulvestrant, 25 mg

√

96402

gemcitabine (Gemzar)

J9201 – Injection, gemcitabine hydrochloride, 200 mg

√

96413

goserelin acetate (Zoladex 3.6 mg ONLY)

J9202 – Goserelin acetate implant, per 3.6 mg

√

96372, 96402

hydrocortisone sodium (Solu-Cortef)

J1720 – Injection, hydrocortisone sodium succinate, up to 100 mg

√

96365, 96366, 96372, 96374

hydroxyurea (Hydrea)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

hydroxyurea (Hydrea)

S0176 – Hydroxyurea, oral, 500 mg

√

N/A

ifosfamide (Ifex)

J9208 – Injection, ifosfamide, 1 gram

√

96413, 96415

October 2014

www.OncPracticeManagement.com

Drug Coding

FDA approved for breast cancer

Compendia off-label uses for breast cancer

CPT ® administration codes

Generic (brand) name

HCPCS code – code description

irinotecan (Camptosar)

J9206 – Injection, irinotecan, 20 mg

ixabepilone (Ixempra)

J9207 – Injection, ixabepilone, 1 mg

√

96413, 96415

lapatinib (Tykerb)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

letrozole (Femara)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

leucovorin calcium (Wellcovorin)

J0640 – Injection, leucovorin calcium, per 50 mg

√

96372, 96374, 96409

leuprolide (Eligard, Lupron Depot)

J9217 – Leuprolide acetate (for depot suspension), 7.5 mg

√

96402

leuprolide (Lupron)

J9218 – Leuprolide acetate, per 1 mg

√

96402

lomustine (CeeNu)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

lomustine (CeeNU)

S0178 – Lomustine, oral, 10 mg

√

N/A

medroxyprogesterone (Depo-Provera)

J1050 – Injection, medroxyprogesterone acetate, 1 mg

√

96402

megestrol (Megace)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

megestrol (Megace)

S0179 – Megestrol acetate, oral 20 mg

√

N/A

melphalan (Alkeran)

J8600 – Melphalan, oral, 2 mg

√

N/A

melphalan (Alkeran)

J9245 – Injection, melphalan hydrochloride, 50 mg

√

96409, 96413

methotrexate (Trexall)

J8610 – Methotrexate, oral, 2.5 mg

√

N/A

methotrexate sodium

J9250 – Methotrexate sodium, 5 mg

√

96372, 96374, 96401, 96409, 96450

methotrexate sodium

J9260 – Methotrexate sodium, 50 mg

√

96372, 96374, 96401, 96409, 96450

methylprednisolone (Depo-Medrol)

J1020 – Injection, methylprednisolone acetate, 20 mg

√

11900, 11901, 20600, 20605, 20610, 96372, 96374

methylprednisolone (Depo-Medrol)

J1030 – Injection, methylprednisolone acetate, 40 mg

√

11900, 11901, 20600, 20605, 20610, 96372, 96374

ONCOLOGY PRACTICE MANAGEMENT

I October 2014

√

96413, 96415

Drug Coding

FDA approved for breast cancer

Compendia off-label uses for breast cancer

CPT ® administration codes

Generic (brand) name

HCPCS code – code description

methylprednisolone (Depo-Medrol)

J1040 – Injection, methylprednisolone acetate, 80 mg

√

11900, 11901, 20600, 20605, 20610, 96372, 96374

methylprednisolone (Solu-Medrol)

J2920 – Injection, methylprednisolone sodium succinate, up to 40 mg

√

11900, 11901, 20600, 20605, 20610, 96372, 96374

methylprednisolone (Medrol)

J7509 – Methylprednisolone, oral, per 4 mg

√

N/A

mitomycin (Mutamycin)

J9280 – Mitomycin, 5 mg

√

96409

mitoxantrone (Novantrone)

J9293 – Injection, mitoxantrone hydrochloride, per 5 mg

√

96409, 96413

oxaliplatin (Eloxatin)

J9263 – Injection, oxaliplatin, 0.5 mg

√

96413, 96415

paclitaxel proteinbound particles (Abraxane)

J9264 – Injection, paclitaxel protein-bound particles, 1 mg

√

96413

paclitaxel (Taxol)

J9265 – Injection, paclitaxel, 30 mg

√

96413, 96415

pemetrexed (Alimta)

J9305 – Injection, pemetrexed, 10 mg

pertuzumab (Perjeta)

J9306 – Injection, pertuzumab, 1 mg

prednisolone (e.g., Orapred, Millipred)

J7510 – Prednisolone, oral, per 5 mg

√

N/A

prednisone (e.g., Deltasone, Orasone)

J7506 – Prednisone, oral, per 5 mg

√

N/A

tamoxifen (Nolvadex)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

tamoxifen (Nolvadex)

S0187 – Tamoxifen citrate, oral, 10 mg

√

N/A

thiotepa (Thiotepa)

J9340 – Injection, thiotepa, 15 mg

√

51720, 96409

topotecan (Hycamtin)

J8705 – Topotecan, oral, 0.25 mg

√

N/A

topotecan (Hycamtin)

J9351 – Injection, topotecan, 0.1 mg

√

96413

toremifene (Fareston)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

96413

√

N/A

√

October 2014

96409

www.OncPracticeManagement.com

Drug Coding

FDA approved for breast cancer

Compendia off-label uses for breast cancer

CPT ® administration codes

Generic (brand) name

HCPCS code – code description

trastuzumab (Herceptin)

J9355 – Injection, trastuzumab, 10 mg

triptorelin (Trelstar)

J3315 – Injection, triptorelin pamoate, 3.75 mg

vinBLAStine (Velban)

J9360 – Injection, vinblastine sulfate, 1 mg

vinCRIStine (Vincasar PFS)

J9370 – Vincristine sulfate, 1 mg

√

96409

vinorelbine (Navelbine)

J9390 – Injection, vinorelbine tartrate, per 10 mg

√

96409

zoledronic acid (Reclast, Zometa)

J3489 – Injection, zoledronic acid, 1 mg

√

96365, 96374, 96413

96413, 96415

√ √

96372, 96402 96409

√

*When billing a nonclassified medication using a CMS 1500 claim form, you must include both the HCPCS code (eg, J8999 Tykerb) in Item 24D and the drug name, strength, and NDC (National Drug Code) in Item 19 or Item 24A (shaded area) in order to ensure appropriate reimbursement. Please note: Check with payer regarding correct placement of medication information. References • HCPCS Level II Expert 2014 • Current Procedural Terminology (CPT®) 2014 • CPT copyright 2014 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association • ICD-9-CM for Professionals Volumes 1 & 2, 2014 • FDA-approved indication (product Prescribing Information) • Compendia references available upon request • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Rocky Hill, Connecticut • CMS (Centers for Medicare and Medicaid Services)

This information was supplied by:

30 Cold Spring Road, Rocky Hill, CT 06067 T: (860) 563-1223 • F: (860) 563-1650 • www.RJHealthSystems.com

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