AHDB August 2014 Vol 7, No 5

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ August 2014

Volume 7, Number 5

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

Beyond Paternalism David B. Nash, MD, MBA

Population Health and the Assessment of Value Joseph D. Jackson, PhD BUSINESS

™

Lessons from the Leucovorin Shortages Between 2009 and 2012 in a Medicare Advantage Population: Where Do We Go from Here?

Mary S. Hayes, PharmD; Melea A. Ward, PharmD, MS; S. Lane Slabaugh, PharmD, MBA; Yihua Xu, PhD Stakeholder Perspective: Drug Shortages Are Costly to Patients and to Payers

By Joseph P. Fuhr, Jr, PhD REGULATORY

Offering Lung Cancer Screening to High-Risk Medicare Beneficiaries Saves Lives and Is Cost-Effective: An Actuarial Analysis Bruce S. Pyenson, FSA, MAAA; Claudia I. Henschke, PhD, MD; David F. Yankelevitz, MD; Rowena Yip, MPH; Ellynne Dec, FSA, MAAA Stakeholder Perspective: Cost-Effectiveness and the Medicare Budget

By Joseph R. Antos, PhD CLINICAL

Impact of Linaclotide Treatment on Work Productivity and Activity Impairment in Adults with Irritable Bowel Syndrome with Constipation: Results from 2 Randomized, Double-Blind, Placebo-Controlled Phase 3 Trials Jessica L. Buono, MPH; Stavros Tourkodimitris, PhD; Phil Sarocco, RPh, MSc; Jeffrey M. Johnston, MD; Robyn T. Carson, MPH Stakeholder Perspective: Patient-Reported Outcomes Matter

By Walid F. Gellad, MD, MPH

© 2014 Engage Healthcare Communications, LLC

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NOW

APPROVED!

First oral treatment FDA-approved for adults with active psoriatic arthritis Please see Important Safety Information on the adjacent page.

INDICATION Otezla® (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis.

IMPORTANT SAFETY INFORMATION Otezla is contraindicated in patients with hypersensitivity to apremilast or to components in its formulation.

Depression was reported by patients taking Otezla, including serious depression. Some patients discontinued treatment due to depression.

Weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, and in patients who develop such symptoms while on Otezla.

Weight loss was reported in patients taking Otezla. Monitor body weight regularly.

Concomitant use of Otezla with CYP450 enzyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended.

The most common adverse reactions (≥5%) in clinical trials, and those most frequently leading to treatment discontinuation, were diarrhea, nausea, and headache.

Otezla is Pregnancy Category C; it has not been studied in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when Otezla is administered to a nursing woman.

Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information.

Please see Brief Summary of Full Prescribing Information on the following page.

Get the latest news at www.otezla.com

Otezla® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 04/14 USII-APR130013

Rx Only OTEZLA® (apremilast) tablets, for oral use The following is a Brief Summary of the Prescribing Information; see Full Prescribing Information for complete product information.

INDICATIONS AND USAGE OTEZLA® (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis.

CONTRAINDICATIONS OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Adverse Reactions (6.1)].

WARNINGS AND PRECAUTIONS Depression: Treatment with OTEZLA is associated with an increase in adverse reactions of depression. During the 0 to 16 weeks placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of patients treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of patients treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated patients (0/495). Depression was reported as serious in 0.2% (3/1441) of patients exposed to OTEZLA, compared to none in placebo treated patients (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of patients while receiving OTEZLA, compared to none in placebo treated patients (0/495). In the clinical trials, two patients who received placebo committed suicide compared to none in OTEZLA treated patients. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur.

Weight Decrease: During the controlled period of the studies, weight decrease between 5-10% of body weight was reported in 10% (49/497) of patients treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo [see Adverse Reactions (6.1)]. Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered.

Drug Interactions: Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended. [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

ADVERSE REACTIONS Clinical Trials Experience in Psoriatic Arthritis: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The majority of the most common adverse reactions presented in Table 2 occurred within the first two weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.

Table 2: Adverse Reactions Reported in ≥ 2% of Patients on OTEZLA 30 mg Twice Daily and ≥ 1% Than That Observed in Patients on Placebo For Up To Day 112 ( Week 16) Placebo

Preferred Term

OTEZLA 30 mg BID

Day 1 to 5 Day 6 to Day 112 Day 1 to 5 Day 6 to Day 112 (N=495) (N=490) (N=497) (N=493) n (%)c n (%) n (%) n (%)

Diarrhea a

6 (1.2)

8 (1.6)

46 (9.3)

38 (7.7)

Nauseaa

7 (1.4)

15 (3.1)

37 (7.4)

44 (8.9)

Headachea

9 (1.8)

11 (2.2)

24 (4.8)

29 (5.9)

Upper respiratory tract infectionb

3 (0.6)

9 (1.8)

3 (0.6)

19 (3.9)

Vomitinga

2 (0.4)

2 (0.4)

4 (0.8)

16 (3.2)

Nasopharyngitisb

1 (0.2)

8 (1.6)

1 (0.2)

13 (2.6)

Abdominal pain upperb

0 (0.0)

1 (0.2)

3 (0.6)

10 (2.0)

a

Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. b Of the reported adverse drug reactions none were serious. c n (%) indicates number of patients and percent.

Other adverse reactions reported in patients on OTEZLA were hypersensitivity, weight decrease, frequent bowel movement, gastroesophageal reflux disease, dyspepsia, decreased appetite*, migraine, cough, and rash. *1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.

DRUG INTERACTIONS Strong CYP 450 Inducers: Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C : OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy.

Information about the registry can be obtained by calling 1-877-311-8972.

Nursing Mothers: It is not known whether OTEZLA or its metabolites are present in human milk. Because many drugs are present in human milk, caution should be exercised when OTEZLA is administered to a nursing woman. Pediatric use: The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established. Geriatric use: Of the 1493 patients who enrolled in Studies PsA-1, PsA-2, and PsA-3 a total of 146 psoriatic arthritis patients were 65 years of age and older, including 19 patients 75 years and older. No overall differences were observed in the safety profile of elderly patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical studies. Renal Impairment: OTEZLA pharmacokinetics were not characterized in subjects with mild (creatinine clearance of 60-89 mL per minute estimated by the Cockroft– Gault equation) or moderate (creatinine clearance of 30-59 mL per minute estimated by the Cockroft–Gault equation) renal impairment. The dose of OTEZLA should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockroft– Gault equation) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Hepatic Impairment: Apremilast pharmacokinetics were characterized in subjects with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. No dose adjustment is necessary in these patients.

OVERDOSAGE In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should there be an overdose.

Manufactured for: Celgene Corporation, Summit, NJ 07901 OTEZLA® is a registered trademarks of Celgene Corporation.

Pat. www.celgene.com ©2014 Celgene Corporation, All Rights Reserved.

OTZPBS.001 03/14

editorial board Editor-in-Chief

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice Jefferson School of Pharmacy, Philadelphia Aging and Wellness

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY Research

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA

Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD

Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy Univ. of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA, FAMCP Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

health & value promotion

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC

Jeffrey A. Bourret, PharmD, MS, BCPS, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

HEALTH INFORMATION TECHNOLOGY

PATIENT ADVOCACY

Kelly Huang, PhD Operating Partner, Spindletop Capital Austin, TX Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine HEALTH OUTCOMES RESEARCH

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT

Vol 7, No 5

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August 2014

Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

Bruce Pyenson, FSA, MAAA Principal & Consulting Actuary Milliman, Inc New York, NY

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA

Personalized medicine

SPECIALTY PHARMACY

PAYER-PROVIDER FINANCES

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia

Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

PHARMACOECONOMICs

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc, Norwalk, CT

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American Health & Drug Benefits

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august 2014

Volume 7, number 5 The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

™

Table of Contents EDITORIAL

257 Beyond Paternalism

David B. Nash, MD, MBA PERSPECTIVE

260 Population Health and the Assessment of Value

Joseph D. Jackson, PhD BUSINESS

264 Lessons from the Leucovorin Shortages Between 2009 and 2012 in a Medicare Advantage Population: Where Do We Go from Here?

Mary S. Hayes, PharmD; Melea A. Ward, PharmD, MS; S. Lane Slabaugh, PharmD, MBA; Yihua Xu, PhD 270 Stakeholder Perspective: Drug Shortages Are Costly to Patients and to Payers

By Joseph P. Fuhr, Jr, PhD REGULATORY

272 O ffering Lung Cancer Screening to High-Risk Medicare Beneficiaries Saves Lives and Is Cost-Effective: An Actuarial Analysis Bruce S. Pyenson, FSA, MAAA; Claudia I. Henschke, PhD, MD; David F. Yankelevitz, MD; Rowena Yip, MPH; Ellynne Dec, FSA, MAAA 281 Stakeholder Perspective: Cost-Effectiveness and the Medicare Budget

By Joseph R. Antos, PhD Continued on page 256

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This publication further provides benefit design de­cision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

Contact Information: For subscription information and edi­torial queries, please contact: editorial@engagehc.com; tel: 732-992-1892; fax: 732-992-1881.

250

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

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Vol 7, No 5

APPROVED FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD) IN ADULTS The efficacy and safety of BRINTELLIX in the treatment of MDD was established in1:  6 short-term (6- to 8-week) randomized, double-blind, placebo-controlled, fixed-dose studies (including a dedicated study in the elderly) based on mean change from baseline to endpoint in MADRS or HAM-D24 total scores  1 long-term (24- to 64-week) maintenance study in adults based on time to recurrence of depressive episodes*  In clinical studies, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo in 6- to 8-week studies) were nausea, constipation, and vomiting  In pooled 6- to 8-week placebo-controlled studies, the incidence of patients who received BRINTELLIX and discontinued because of adverse reactions ranged from 5% to 8% over the 5- to 20-mg/day doses compared to 4% for placebo; nausea was the most common adverse reaction reported as a reason for discontinuation Recurrence of a depressive episode is defined as MADRS total score ≥22 or lack of efficacy as judged by the investigators.

*

Please visit BRINTELLIXHCP.com to learn more.

INDICATION

BRINTELLIX is indicated for the treatment of major depressive disorder (MDD) in adults.

IMPORTANT SAFETY INFORMATION WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older.

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors.

Advise families and caregivers of the need for close observation and communication with the prescriber.

BRINTELLIX has not been evaluated for use in pediatric patients.

CONTRAINDICATIONS Hypersensitivity: Hypersensitivity to vortioxetine or any components of the BRINTELLIX formulation. Angioedema has been reported in patients treated with BRINTELLIX. Monoamine Oxidase Inhibitors (MAOIs): Due to an increased risk of serotonin syndrome, do not use MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX. Do not use BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders. Do not start BRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue.

WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk: All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality (anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania), especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients daily.

Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants (SNRIs, SSRIs, and others), including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If such symptoms occur, discontinue BRINTELLIX and any concomitant serotonergic agents, and initiate supportive symptomatic treatment. If concomitant use of BRINTELLIX is clinically warranted, patients should be made aware of and monitored for potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Abnormal Bleeding: Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation.

Activation of Mania/Hypomania: Activation of mania/hypomania can occur with antidepressant treatment. Prior to initiating treatment with an antidepressant, screen patients for bipolar disorder. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.

Hyponatremia: Hyponatremia has occurred as a result of serotonergic drugs and in many cases, appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients and patients taking diuretics or who are otherwise volume-depleted can be at greater risk. More severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Discontinue BRINTELLIX in patients with symptomatic hyponatremia and initiate appropriate medical intervention.

Adverse Reactions: The most commonly observed adverse reactions for BRINTELLIX in 6- to 8-week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were by dose (5 mg, 10 mg, 15 mg, 20 mg) vs placebo: nausea (21%, 26%, 32%, 32% vs 9%), constipation (3%, 5%, 6%, 6% vs 3%), and vomiting (3%, 5%, 6%, 6% vs 1%).

Drug Interactions: Concomitant administration of BRINTELLIX and strong CYP2D6 inhibitors or strong CYP inducers may require a dose adjustment of BRINTELLIX.

BRINTELLIX is a trademark of H. Lundbeck A/S registered with U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. ©2014 Takeda Pharmaceuticals U.S.A., Inc. 92658 3/2014

Please see adjacent pages for Brief Summary of Prescribing Information and visit BRINTELLIXHCP.com for full Prescribing Information and Medication Guide.

Reference: 1. Brintellix (vortioxetine) prescribing information. Takeda Pharmaceuticals.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION BRINTELLIX (vortioxetine) tablets, for oral use WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions].

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions].

BRINTELLIX has not been evaluated for use in pediatric patients [see Use in Specific Populations].

INDICATIONS AND USAGE Major Depressive Disorder BRINTELLIX is indicated for the treatment of major depressive disorder (MDD). The efficacy of BRINTELLIX was established in six 6 to 8 week studies (including one study in the elderly) and one maintenance study in adults.

CONTRAINDICATIONS • Hypersensitivity to vortioxetine or any components of the formulation.

Angioedema has been reported in patients treated with BRINTELLIX. • The use of MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX is contraindicated because of an increased risk of serotonin syndrome.

The use of BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Warnings and Precautions].

Starting BRINTELLIX in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Warnings and Precautions].

WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a trend toward reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

The risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 of the BRINTELLIX Full Prescribing Information, which states: 14 additional cases in patients under the age of 18, 5 additional cases in patients between 18 and 24 years of age. There was 1 fewer case in patients between 25 and 64 years of age and 6 fewer cases in patients 65 years of age and over.

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebocontrolled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.

Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that BRINTELLIX is not approved for use in treating bipolar depression.

Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of BRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. BRINTELLIX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking BRINTELLIX. BRINTELLIX should be discontinued before initiating treatment with the MAOI [see Contraindications].

If concomitant use of BRINTELLIX with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Abnormal Bleeding The use of drugs that interfere with serotonin reuptake inhibition, including BRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Drug Interactions].

Activation of Mania/Hypomania Symptoms of mania/hypomania were reported in <0.1% of patients treated with BRINTELLIX in pre-marketing clinical studies. Activation of mania/ hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.

Hyponatremia Hyponatremia has occurred as a result of treatment with serotonergic drugs.

In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with BRINTELLIX in a pre-marketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant.

Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of BRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label.

• Hypersensitivity [see Contraindications] • Clinical Worsening and Suicide Risk [see Warnings and Precautions] • Serotonin Syndrome [see Warnings and Precautions] • Abnormal Bleeding [see Warnings and Precautions] • Activation of Mania/Hypomania [see Warnings and Precautions] • Hyponatremia [see Warnings and Precautions] Clinical Studies 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 studies of another drug and may not reflect the rates observed in clinical practice.

Patient Exposure BRINTELLIX was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre-marketing clinical studies; 2616 of those patients were exposed to BRINTELLIX in 6 to 8 week, placebocontrolled studies at doses ranging from 5 mg to 20 mg once daily and 204 patients were exposed to BRINTELLIX in a 24 week to 64 week placebocontrolled maintenance study at doses of 5 mg to 10 mg once daily. Patients from the 6 to 8 week studies continued into 12-month open-label studies. A total of 2586 patients were exposed to at least one dose of BRINTELLIX in open-label studies, 1727 were exposed to BRINTELLIX for six months and 885 were exposed for at least one year.

Adverse Reactions Reported as Reasons for Discontinuation of Treatment In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5%, 6%, 8% and 8%, respectively, compared to 4% of placebo-treated patients. Nausea was the most common adverse reaction reported as a reason for discontinuation.

Common Adverse Reactions in Placebo-Controlled MDD Studies The most commonly observed adverse reactions in MDD patients treated with BRINTELLIX in 6 to 8 week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were nausea, constipation and vomiting.

Table 2 shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebocontrolled studies.

Table 2 of the BRINTELLIX Full Prescribing Information shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebotreated patients in the 6- to 8-week placebo-controlled studies. The following values from Table 2 show the percentage of patients exhibiting the adverse reaction while receiving BRINTELLIX 5 mg (N=1013), 10 mg (N=699), 15 mg (N=449), 20 mg (N=455), and placebo (N=1621) respectively. Gastrointestinal Disorders: Nausea (21%, 26%, 32%, 32%, vs. 9%); Diarrhea (7%, 7%, 10%, 7%, vs. 6%); Dry Mouth (7%, 7%, 6%, 8%, vs. 6%); Constipation (3%, 5%, 6%, 6%, vs. 3%); Vomiting (3%, 5%, 6%, 6%, vs. 1%); Flatulence (1%, 3%, 2%, 1%, vs. 1%); Nervous System Disorders: Dizziness (6%, 6%, 8%, 9%, vs. 6%); Psychiatric Disorders: Abnormal Dreams (<1%, <1%, 2%, 3%, vs.

1%); Skin and Subcutaneous Tissue Disorders: Pruritus (including pruritus generalized) (1%, 2%, 3%, 3%, vs. 1%).

Nausea Nausea was the most common adverse reaction and its frequency was doserelated (Table 2). It was usually considered mild or moderate in intensity and the median duration was 2 weeks. Nausea was more common in females than

males. Nausea most commonly occurred in the first week of BRINTELLIX treatment with 15 to 20% of patients experiencing nausea after 1 to 2 days of treatment. Approximately 10% of patients taking BRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies.

Sexual Dysfunction Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment.

In the MDD 6 to 8 week controlled trials of BRINTELLIX, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the overall incidence was as follows. In male patients the overall incidence was 3%, 4%, 4%, 5% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2% in placebo. In female patients, the overall incidence was <1%, 1%, <1%, 2% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1% in placebo.

Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction.

The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects.

The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), the following values from Table 3 of the BRINTELLIX Full Prescribing Information show the ASEX incidence of patients who developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed-dose group. The incidence in female patients treated with BRINTELLIX 5 mg (N=65), 10 mg (N=94), 15 mg (N=57), 20 mg (N=67) or placebo (N=135), respectively was 22%, 23%, 33%, 34% vs. 20%. For male patients, the incidence of treatment-emergent sexual dysfunction when treated with BRINTELLIX 5 mg (N=67), 10 mg (N=86), 15 mg (N=67), 20 mg (N=59) or placebo (N=162), respectively was 16%, 20%, 19%, 29% vs. 14%. Incidence was based on the number of subjects with sexual dysfunction during the study / number of subjects without sexual dysfunction at baseline. Sexual dysfunction was defined as a subject scoring any of the following on the ASEX scale at two consecutive visits during the study: 1) total score ≥19; 2) any single item ≥5; 3) three or more items each with a score ≥4. The sample size for each dose group was the number of patients without sexual dysfunction at baseline. Physicians should routinely inquire about possible sexual side effects.

Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX Treatment Discontinuation symptoms have been prospectively evaluated in patients taking BRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials.

Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of BRINTELLIX 15 mg/day and 20 mg/day.

Laboratory Tests BRINTELLIX has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (except sodium), hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies.

Hyponatremia has been reported with the treatment of BRINTELLIX [see Warnings and Precautions]. In the 6-month, double-blind, placebocontrolled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there were no clinically important changes in lab test parameters between BRINTELLIX and placebo-treated patients.

Weight BRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies.

In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between BRINTELLIX and placebo-treated patients.

Vital Signs BRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.

Other Adverse Reactions Observed in Clinical Studies The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Ear and labyrinth disorders — vertigo Gastrointestinal disorders — dyspepsia Nervous system disorders — dysgeusia Vascular disorders — flushing DRUG INTERACTIONS CNS Active Agents Monoamine Oxidase Inhibitors Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI [see Contraindications and Warnings and Precautions].

Serotonergic Drugs Based on the mechanism of action of BRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when BRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if BRINTELLIX is co-administered with other serotonergic drugs.

Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs [see Warnings and Precautions].

Other CNS Active Agents No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of BRINTELLIX. Multiple doses of BRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between BRINTELLIX and bupropion can be found in Section 7.3, Potential for Other Drugs to Affect BRINTELLIX. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis.

Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin.

Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of BRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin [see Drug Interactions].

Coadministration of aspirin 150 mg/day with multiple daily doses of BRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid [see Drug Interactions].

Patients receiving other drugs that interfere with hemostasis should be carefully monitored when BRINTELLIX is initiated or discontinued [see Warnings and Precautions].

Potential for Other Drugs to Affect BRINTELLIX Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the BRINTELLIX dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose (Figure 1).

Figure 1. Impact of Other Drugs on Vortioxetine PK

Potential for BRINTELLIX to Affect Other Drugs No dose adjustment for the comedications is needed when BRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinid), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary.

Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected.

In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of BRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of BRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2).

Because vortioxetine is highly bound to plasma protein, coadministration of BRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of BRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed [see Drug Interactions].

Figure 2. Impact of Vortioxetine on PK of Other Drugs

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of BRINTELLIX in pregnant women. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits at doses 15 and 10 times the maximum recommended human dose (MRHD) of 20 mg, respectively. Developmental delays were also seen after birth in rats at doses 20 times the MRHD of vortioxetine given during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits at doses up to 77 and 58 times, the MRHD of vortioxetine, respectively, given during organogenesis. The incidence of malformations in human pregnancies has not been established for BRINTELLIX. All human pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. BRINTELLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying.

These features are consistent with either a direct toxic effect of these classes of drugs or possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. When treating a pregnant woman with

BRINTELLIX during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Neonates exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in one to two per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use in pregnancy and PPHN. Other studies do not show a significant statistical association.

A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with BRINTELLIX, the physician should carefully consider both the potential risks of taking a serotonergic antidepressant, along with the established benefits of treating depression with an antidepressant.

Animal Data In pregnant rats and rabbits, no teratogenic effects were seen when vortioxetine was given during the period of organogenesis at oral doses up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. Developmental delay, seen as decreased fetal body weight and delayed ossification, occurred in rats and rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD, respectively) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain). When vortioxetine was administered to pregnant rats at oral doses up to 120 mg/kg (58 times the MRHD) throughout pregnancy and lactation, the number of live-born pups was decreased and early postnatal pup mortality was increased at 40 and 120 mg/kg. Additionally, pup weights were decreased at birth to weaning at 120 mg/kg and development (specifically eye opening) was slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg (5 times the MRHD).

Nursing Mothers It is not known whether vortioxetine is present in human milk. Vortioxetine is present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from BRINTELLIX, 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 Clinical studies on the use of BRINTELLIX in pediatric patients have not been conducted; therefore, the safety and effectiveness of BRINTELLIX in the pediatric population have not been established.

Geriatric Use No dose adjustment is recommended on the basis of age (Figure 3). Results from a single-dose pharmacokinetic study in elderly (>65 years old) vs. young (24 to 45 years old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups.

Of the 2616 subjects in clinical studies of BRINTELLIX, 11% (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions].

Use in Other Patient Populations No dose adjustment of BRINTELLIX on the basis of race, gender, ethnicity, or renal function (from mild renal impairment to end-stage renal disease) is necessary. In addition, the same dose can be administered in patients with mild to moderate hepatic impairment (Figure 3). BRINTELLIX has not been studied in patients with severe hepatic impairment. Therefore, BRINTELLIX is not recommended in patients with severe hepatic impairment.

Figure 3. Impact of Intrinsic Factors on Vortioxetine PK

DRUG ABUSE AND DEPENDENCE BRINTELLIX is not a controlled substance.

OVERDOSAGE Human Experience There is limited clinical trial experience regarding human overdosage with BRINTELLIX. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of BRINTELLIX. The maximum single dose tested was 75 mg in men. Ingestion of BRINTELLIX in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing.

Management of Overdose No specific antidotes for BRINTELLIX are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.

Distributed and marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Marketed by: Lundbeck Deerfield, IL 60015 BRINTELLIX is a trademark of H. Lundbeck A/S and is used under license by Takeda Pharmaceuticals America, Inc. Š2013 Takeda Pharmaceuticals America, Inc. LUN205P R1_Brf. September 2013 90243 L-LUN-0913-2

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Table of Contents

(Continued)

CLINICAL

289 Impact of Linaclotide Treatment on Work Productivity and Activity Impairment in Adults with Irritable Bowel Syndrome with Constipation: Results from 2 Randomized, Double-Blind, Placebo-Controlled Phase 3 Trials Jessica L. Buono, MPH; Stavros Tourkodimitris, PhD; Phil Sarocco, RPh, MSc; Jeffrey M. Johnston, MD; Robyn T. Carson, MPH 296 Stakeholder Perspective: Patient-Reported Outcomes Matter

By Walid F. Gellad, MD, MPH

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Editorial

Beyond Paternalism David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Jefferson School of Population Health, Philadelphia, PA

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ost readers of American Health & Drug Benefits are leaders across the spectrum of the healthcare industry. We proudly represent nearly every stakeholder, including consumers, payers, providers, pharmaceutical executives, and others. As leaders in healthcare, there are important questions we must consider, such as “Are your employees healthy?” and “Why should you care about their health?” Let’s get past the idea of paternalism and examine the potentially controversial topics of employee wellness and productivity.

Recently, 2 major national groups collaborated to create a critically important report that helps to frame this issue. On March 24, 2014, the Health Enhancement Research Organization (HERO) and the Population Health Alliance (PHA) announced the release of their joint report entitled “Program Measurement and Evaluation Guide: Core Metrics for Employee Health Management.”1 HERO, a nonprofit corporation established in 1996 that is based in Edina, MN, is “dedicated to the creation and dissemination of employee health management research, education, policy, strategy and leadership” (www. the-HERO.org). The PHA is a global trade association of the population health industry with 80 members who represent stakeholders from across the delivery spectrum.

PHA’s mission is “to advance the principles of population health improvement, so they become pillars of our healthcare system” (www.populationhealthalliance.org).

The Program Measurement and Evaluation Guide was the result of a collaborative effort initiated by the 2 organizations in 2011. It included participation from 40 organizations representing many segments of our industry, including employers, health plans, academic research centers, and various certification agencies. The executive summary listed the following 7 essential measures for the success of employee wellness programs.2 1. Financial outcomes. The report notes that employee wellness programs deliver direct monetized claims savings and a monetized impact of wellness on hospital claims and health outcomes rather than a classic return on investment (ROI).

In my view, this is probably the most controversial aspect of the report. The value of an employee health management program should be measured in terms of savings realized (eg, monies not spent because of a prevented

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hospitalization or a prevented visit to the emergency department). ROI calculations are not transparent, and some employee health management “programs have also claimed implausible levels of ROI.”2 Kudos to HERO and PHA for making the distinction between reduction in expenses and ROI—these are not synonymous concepts.

Moving forward, specific financial metrics that may be appropriate include items such as long-term versus non– long-term spending comparisons, participant versus nonparticipant cross comparisons, and comparison with matched controls in a nonexposed population.

2. Health impact. This area attempts to measure the impact of employee wellness programs on the overall health and well-being of specific, targeted populations.

After an extensive review of the literature in this arena, the authors of the report note that all aspects of health (eg, physical health, mental and emotional health, healthy behaviors, and current health status) should be included in any initial set of measures.

Again, I am very supportive of the authors in this respect, because they specifically observe that measures that are available in the public domain are preferred over measures that are proprietary and therefore have additional costs for use.

3. Participation. This, too, is controversial. The report notes that there is no industry standard that directly links the number of contacts for every time period with an employee and the outcome of the employees’ efforts to improve their personal health and wellness. Simply put, we do not know how many nurse calls, in-person visits, e-mail reminders, and text messages it takes to change behavior.

This is the first time, I believe, that these 2 major national organizations have frankly noted the lack of clear connectivity between the number and type of contact with individual employees and the specific health outcomes. This is a courageous step. As a result, “even if being non-prescriptive, there are too many variables to recommend a specific threshold, or even a range, for the number of contacts constituting participation.”2 We still have a lot of work to do regarding how we should connect with employees.

4. Employee satisfaction. This is relatively straightforward and noncontroversial. There are many specific

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domains that one could consider, including overall satisfaction; satisfaction with the scope, convenience, individual patient experience; and reporting of the program.

5. Organizational support. This is probably the core challenge. Without senior leadership support that is visible and consistent throughout the organization, any attempt, in my view, to improve employee wellness is doomed to fail. The authors of the report essentially concur and call for top-down organizational support for these kinds of efforts.

6. Productivity and performance of employee health management systems. The authors noted the key challenge that the purchasers of these programs need to get beyond the “singular focus on health care costs” and demand “focus on the effects of…work outcomes, such as attendance, performance and turnover. These measures are more readily linked to operations measures that typically matter to business leaders.”2 The report notes the spectrum that includes concepts such as time away from work because of health (eg, unscheduled absences, shortand long-term disability) all the way to productivity loss while at work.

Time away from work and productivity loss while at work are important concepts in the human resources arena.

7. Value on investment (VOI). As opposed to ROI, “VOI better reflects the broader savings potential of wellness programs and provides a framework for constructing a VOI analysis.”1 You may ask, what is the difference between ROI and VOI? “First, the VOI framework uses the conventions of cost-effectiveness analysis (CEA). A CEA expresses its results in terms of the costs per unit of out-

come. The numerator therefore represents the cost component and the denominator the outcome (this is the opposite of an ROI ratio). CEA analytic techniques can be abstruse, but the central idea is quite simple and straightforward: how to get the most for the money.”2 I applaud the use of the VOI framework rather than the classic ROI analysis. It is consistent with excellent work being done in the area of health economics and outcomes research.

In summary, this critically important report (and the publicly available guide for easy-to-use metrics that may be implemented at your organization) represents an important step in the right direction to getting us beyond corporate paternalism and giving us clearer measures for implementing effective employee health management programs. Leaders in every sector represented by our readership have an obligation to promote the health and wellness of their employees. Now we have a framework and a platform for rigorous discussion of the implementation and measurement of the outcomes of these programs. As always, I am interested in your views, and you can reach me via e-mail at david.nash@jefferson.edu. n

References

1. Health Enhancement Research Organization, Population Health Alliance. HERO and Population Health Alliance collaborate on employer guidance for measuring employee health management outcomes. Press release. March 24, 2014. www.the-­ hero.org/Press/releases/NR_core%20metrics_guide_annc_FINAL_032414-3.pdf.

Accessed July 15, 2014.

2. Health Enhancement Research Organization, Population Health Alliance. Program measurement and evaluation guide: core metrics for employee health management. Executive summary. July 1, 2014. www.the-hero.org/Research/PHA-HERO-­ Executive-Summary_7-1-14v1.pdf. July 15, 2014.

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If only it were this easy to spot SLE* organ damage

33% to 50% of SLE patients experience permanent organ damage within the first 5 years of diagnosis.1,2

To learn more about SLE, visit

www.TalkSLE.com

SLE can affect nearly every major organ, including the skin, kidneys, joints, lungs, and heart.3 Even when minimal symptoms are present, organ damage can still occur.2 *systemic lupus erythematosus

REFERENCES: 1. Chambers SA, Allen E, Rahman A, Isenberg D. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years. Rheumatology (Oxford). 2009;48(6):673-675. 2. Urowitz MB, Gladman DD, Ibañez D, et al. Evolution of disease burden over five years in a multicenter inception systemic lupus erythematosus cohort. Arthritis Care Res (Hoboken). 2012;64(1):132-137. 3. Lopez R, Davidson JE, Beeby MD, Egger PJ, Isenberg DA. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort.

Rheumatology (Oxford). 2012;51(3):491-498. ©2014 GSK group of companies.

All rights reserved. Printed in USA. BN2671R0 April 2014

Perspective

Population Health and the Assessment of Value

By Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Associate Professor, Jefferson School of Population Health, Thomas Jefferson University, Philadelphia, PA, and Deputy Editor, American Health & Drug Benefits

T

rue managed care is based on the notion of an integrated delivery system, an industrialized system of care designed to enhance population, as well as individual health status. The Affordable Care Act (ACA) and the philosophy embodied in the Triple Aim (ie, the triangle of care, population health, and costs)1 are leading the evolution toward the integrated delivery system and away from the component-based episode of care strategy or the fee-for-service method, where goods and services are applied and reimbursed individually, usually during an episode of sick care.

The pace of change is, at times, frustratingly slow for the providers and industries that are entrenched in the fee-for-service method of healthcare delivery. However, the evolution toward what Fineberg calls a “health system” as opposed to a “healthcare system” is under construction.2 Fineberg makes the distinction between a system that is focused on health (ie, population and individual health system) and systems focused “only on the formal system of care designed primarily to treat illness.”2 He concludes that the current system, which focuses largely on sick care, is neither financially sustainable nor yielding the levels of population health that investments in the US healthcare system would suggest.2 Increasingly, systems are bundled into care packages in which care is continuous across providers and settings to achieve and maintain optimal health status for the populations. George C. Halvorson, Chief Executive Officer of Kaiser Permanente, stated, “We sell care by the package, not by the piece.”3 A widespread interest in outcomes research has flourished anew, stimulated by the push of integrated health systems. The passage of the ACA in 2010 is certainly part of the emerging change. New funds were appropriated and were authorized to support research on outcomes, effectiveness, and patient-centered outcomes research.

Much of this work has been coordinated through the US Agency for Healthcare Research and Quality. Thus, outcomes research will play a prominent role in the restructuring of the US healthcare system.

Applied health economics and outcomes research (AHEOR) is a discipline that considers the evaluative clinical sciences and the roles they play in the quest for

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better value in the integrated health system, as outlined in the Table. The tools of AHEOR and integrated delivery systems are care pathways and heuristics grounded in the convergence of evaluative clinical sciences, such as epidemiology, risk assessment, wellness, e-Health and informatics, evidence-based medicine, healthcare quality and safety, comparative effectiveness research, patient-centered research, health services research, and cost-effectiveness analyses.

Practitioners of AHEOR apply the evaluative sciences to actual practice settings by converting structure, process, and outcome systems’ variables into strategies for more effective, patient-centered, and efficient care.

Once an institution commits to restructuring for population health, many of the historical foundations of healthcare are challenged and are changed. For example, Kaiser maintains patient registries for dozens of conditions, such as spine surgery, cancers, and heart attacks, where patients are monitored over time for the total health impact, not limited to the condition that occasioned entry into the registry.4 The evaluative clinical sciences are the means of applying these measurement principles and “making medicine more scientific.”5 The focus on population health is an essential aspect of the effort to reform the current healthcare system. Kindig and Stoddart defined population health as “the health outcomes of a group of individuals, including the distribution of such outcomes within the group.”6 The Triple Aim also deals with population health, by advocating for simultaneously “improving the experience of care, improving the health of populations, and reducing per capita costs of health care.”1 In their guide to measuring the Triple Aim, Stiefel and Nolan present the following key measurement principles7: • The need for a defined population • The need for data over time • The need to distinguish between outcome and process measures, and between population and project measures • The value of benchmark or comparison data.

Therefore, the need to inventory, log, monitor, and compare health status over time in a systematic manner represents the kind of reengineering that the US healthcare system needs to be sustainable.

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Table The Contribution of Evaluative Clinical Sciences to Population Health Evaluative clinical sciences Investigation supporting value in population health Anthropology/sociology/ psychology

• Studies the cultural, social, and humanistic determinants of population health in

Cost-effectiveness analysis

• Consistent with the Triple Aim, evaluates the value proposition for the intervention

the context of social engagement

• Recognizes and examines the social factors relevant to health and illness

from multiple perspectives, including the population health perspective

• Performs the classic metrics to yield relative value assessments among competing

interventions, with special attention to the quality of the evidence supporting the estimates of benefit and risk

Epidemiology

• Studies the occurrence of disease in human populations • Examines the etiology and prevalence of disease and relates effort and resources

to modify disease trajectories

• Explores the foundations of research design and the methodologic challenges to

generate credible findings

Evidence-based medicine and health technology assessment

• Evaluates the foundation for best clinical practices and the quality of the

evidence to support optimal clinical strategies

• Enables population health assessments of the relative value of alternative

interventions employed to establish and to maintain health status

Health economics

• Applies principles of economics to the healthcare sector • Recognizes the importance of scarcity and incentives • Covers supply and demand and market characteristics

Modeling

• Synthesizes evidence of health consequences and costs to generate mathematical

frameworks linking numerical values to outcomes in a decision-relevant manner

• Enables frameworks at the cohort, patient, and object level by utilizing decision

analytic, discrete event simulation, and differential equation modeling techniques and practices

Observational and econometric methods

• Provides an overview of observational research, with a targeted focus on

Operations research

• Relates industrial processes to healthcare organization and delivery to optimize

econometric methods

• Considers techniques to limit confounding and improve statistical inference

health outcomes for populations at risk

• Employs practices of quality management and continuous improvement • Focuses on vertically integrated delivery systems to align goods and services for

optimal effectiveness and efficiency in healthcare

Statistics and analytics

• Provides the foundation for describing and summarizing population health data, for

examining probabilities, for uncovering relationships, and for making predictions

• Enables the systematic examination of structure, process, and outcomes variables

relevant to population health

Subjective outcomes research in health evaluation

• Focuses on concepts, theories, and applications for evaluating subjective outcomes

of patients, practitioners, and caregivers

• Covers the regulatory and academic landscape concerning patient-reported

outcomes/health-related quality of life/patient satisfaction/patient preferences

A more recent advocate of changing the medical population health framework is Jeffrey Brenner, MD. Dr Brenner is a 2013 MacArthur Fellow, an unrestricted $625,000 award that he received for his work on behalf of the Camden Coalition of Healthcare Providers to design and deliver population health in the underserved community of Camden, NJ.8 He defines population health as the delivery of “better care, at a lower cost, for everyone, every day.”9 Dr Brenner contends that medi-

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cine must industrialize to “build on what works.” In his opinion, population health is an organizing function, where cost is an essential component and can be characterized by the following 3 “big ideas”9: • Data: analytics and surveillance need to be contemporary with patient care, to facilitate guidance in real time with adaptive systems • Redesign: industrialization is the theme where data incorporation leads to experimentation, innovation,

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and refined processes to deliver better care, resulting in better outcomes and enhanced value • Engagement: the focus is on patient-centered care, in which navigators (and the team) are engaged with patients to explain what is happening, and often why it is happening, in their setting.

Central to these accomplishments is collaboration between disciplines (eg, medicine, business, sociology, anthropology) or “consilience,” to accomplish better care at lower cost for everyone, every day.10 Dr Brenner’s experience represents a “systems framework” to reengineering healthcare.

The scope of outcomes research tends to be broader than traditional forms of clinical research and is applied more to real-world practice issues.

Kaiser Permanente Northern California supported a clinical experiment of integrated population health management over 10 years on a population subset of patients who had an acute myocardial infarction (MI).11 This Kaiser Permanente experience could be considered a disease-specific approach to reengineering managed care.

The study design included the following elements11: 1. Care guided by published evidence that was thoroughly reviewed, and best practices that were established for the management of acute MI 2. Systems that were developed, including an electronic medical record and a vertically integrated care team, to implement evidence-based practices 3. Engagement that was managed and monitored to ensure adherence to the care plan.

The results demonstrated a 24% decrease in mortality, and a more than 50% decrease in cardiovascular events for the post–acute MI cohort.11 The authors cautioned that organizational characteristics in the Kaiser Permanente setting could limit generalizability of this approach to other healthcare settings.11 Medication nonadherence is a major deficit in our current healthcare system, with nearly 33% of initial prescriptions not being filled as prescribed, especially medications prescribed for the long-term prevention of specific conditions.12 Choudhry and colleagues collaborated with a health insurance company on a study that included 1 cohort of patients who received post-MI medications at no cost and a control group that was subject to copays.13 In the group receiving medications at no cost, adherence was 4% to 6% better than in the control group, and although the primary end point events and spending were not statistically less, both were reduced.12 Other subset costs were statistically

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lower, so much so that the program generated a positive cost balance for the free medicine group, and this strategy was eventually implemented across the entire health plan for post-MI medications.12 Of note, only approximately 50% of the cohort receiving free medications adhered to the post-MI regimen, indicating a substantial need for further refinements in care, such as active monitoring by health professionals, depot formulations of medicines, and incentives to encourage adherence.12 These experiments by 2 different health plans represent bona fide outcomes research examples that highlight the translation of science into practice, and further the prospects for adjusting systems of care to enhance population health and the Triple Aim. The basic premise of outcomes research is that choices between alternatives must be made to promote efficiency, without compromising quality of care.14 The determination of safety and efficacy remains essential to evidence-based clinical care, but patient-centered care strategies have broadened the scope to include programs such as wellness and navigator-encouraged health maintenance options, often involving incentives and disincentives to healthful practices. Patient-centered outcomes research makes use of the evaluative clinical sciences to extend the investigation of value in population health. The AHEOR discipline includes the measurement of effectiveness; real-world performance; considerations of quality of life and patient preferences; and the evaluation of benefits, risks, and costs.

The scope of outcomes research tends to be broader than traditional forms of clinical research and is applied more to real-world practice issues. Whereas traditional randomized clinical trials emphasize the biomedical perspective—the safety and efficacy of an intervention in a well-controlled experiment—outcomes research evaluates a wider spectrum of health interventions and con­ sequences in actual practice care settings. Outcomes research–related disciplines—such as economics, epidemiology, and cost-effectiveness research—identify, measure, and compare the costs (ie, resources consumed) and consequences (ie, efficacy, safety, effectiveness, and quality of life [utility]) of health interventions. Outcomes research may also consider patient-centered outcomes, such as satisfaction and real-world care outcomes.

A variety of tools and methods are employed in the conduct of outcomes research. Assessments using patient-administered validated questionnaires, patient-­ reported outcomes assessments, multivariate analyses of nonexperimental data from large observational databases, meta-analyses, decision analysis, discrete event simulation, and economic modeling characterize efforts in outcomes research. Outcomes research continues to

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draw on traditional areas of scientific research, including randomization when feasible, while incorporating techniques and methods of researchers in disciplines such as economics, epidemiology, health services research, operations research, pharmacy, psychology, psychometrics, and public health. Outcomes research is a discipline that studies the studies.

Findings from outcomes research add to the traditional foundation of evidence-based medicine and supplement randomized controlled trials evidence to provide information that is useful to care strategies among a variety of audiences and settings, especially integrated care delivery settings. The scientific evidence underlying 53 American College of Cardiology/American Heart Association clinical practice guidelines was evaluated for clinical usefulness, ranging from effective (class I) to ineffective/harmful (class III), and for the level of evidence supporting the recommendations, ranging from level A (multiple studies of randomized controlled trials) to level C (expert opinion, case studies, or standards of care).15 Only approximately 20% of the guidelines were supported by class I, level A evidence, such as those supporting the Kaiser Permanente’s investigation of acute MI.15 The need to carefully evaluate evidence supporting care strategies and to implement them accordingly is, therefore, a major feature of evidence-based practice and outcomes research.

The distinguishing feature of outcomes research is that, although it is grounded in evidence from randomized trials, it focuses primarily on the effectiveness (ie, real-world performance) of an intervention, by raising questions such as “How sensitive and specific are the indicators of benefits and risks in various populations?”

For example, will patients adhere to the medication regimen, given its side-effect profile? Or, how are the benefits and risks associated with costs and, ultimately, with cost-effectiveness? Choices regarding the value of care, interventions, and strategies therefore adopt a broader context and are consistent with aspects of population health, including integrated delivery systems and the Triple Aim. The US healthcare system must change to be sustainable in the 21st century. That is, healthcare expenditures at the state and national levels are challenging the fiscal limits of governmental funding and budgeting. Given the demographics of healthcare consumers, especially the baby boomers, “business as usual” will not work to make our healthcare system sustainable. The fiscal health of our healthcare system demands a focus on population health and a culture of wellness.16 The focus must be on health outcomes rather than on units of care.

Outcomes research can provide decision makers with the knowledge necessary to improve the efficiency of health

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interventions, while providing clinicians with data to improve patient care outcomes. Outcomes research represents a discipline that can further the Triple Aim, can

Outcomes research can provide decision makers with the knowledge necessary to improve the efficiency of health interventions, while providing clinicians with data to improve patient care outcomes. highlight the interests of patients in cost-conscience care in the real-world settings, and can bring a rational focus to the value of health for populations. n Acknowledgments I wish to thank Juan Leon, PhD, Director of Online Learning, and Caroline Golab, PhD, Associate Dean, Academic and Student Affairs at the Jefferson School of Population Health, Thomas Jefferson University, for their thoughtful contributions.

Author Disclosure Statement Dr Jackson receives a pension from Bristol-Myers Squibb and Hoechst-Roussel Pharmaceuticals, Inc.

References

1. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost.

Health Aff (Millwood). 2008;27:759-769.

2. Fineberg HV. Shattuck Lecture. A successful and sustainable health system—how to get there from here. N Engl J Med. 2012;366:1020-1027.

3. O’Donnell J. Kaiser Permanente CEO on saving lives, money. USATODAY. October 23, 2012. www.usatoday.com/story/money/personalfinance/2012/10/23/kaiser-­ health-care-costs/1639913/. Accessed July 14, 2014.

4. Levine S. Integrating comparative effectiveness research into clinical practice— the Kaiser Permanente experience. Presented at the Third National Comparative Effectiveness Summit; October 12-14, 2011; Washington, DC. 5. Hiatt H, Goldman L. Making medicine more scientific. Nature. 1994;371:100.

6. Kindig D, Stoddart G. What is population health? Am J Public Health. 2003;93: 380-383.

7. Stiefel M, Nolan K. A guide to measuring the triple aim: population health, experience of care, and per capita cost. White paper. 2012. www.ihi.org/resources/Pages/ IHIWhitePapers/AGuidetoMeasuringTripleAim.aspx. Accessed April 24, 2014.

8. MacArthur Foundation. 24 extraordinarily creative people who inspire us all: meet the 2013 MacArthur fellows. Jeffrey Brenner. Press release. September 25, 2013. www.macfound.org/fellows/886/. Accessed July 14, 2014.

9. Brenner J. Super-utilizers, introductions. Presented at the Population Health Colloquium; March 17-19, 2014; Philadelphia, PA. 10. Brenner J. A world of darkness: what if Thomas Edison had to write grant proposals to invent the light bulb? Grant Makers Health. February 17, 2014. www.gih.org/ files/FileDownloads/Health_Care_Philanthropy_Brenner_Feb_2014.pdf. Accessed April 24, 2014.

11. Yeh RW, Sidney S, Chandra M, et al. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med. 2010;362:2155-2165.

12. Tamblyn R, Eguale T, Huang A, et al. The incidence and determinants of primary nonadherence with prescribed medication in primary care: a cohort study. Ann Intern Med. 2014;160:441-450.

13. Choudhry NK, Avorn J, Glynn RJ, et al; for the Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) Trial. Full coverage for preventive medications after myocardial infarction. N Engl J Med. 2011;365:2088-2097.

14. Jackson JD. Outcomes research: issues of evidence, timing and application. J Pharm Pract. 1995;8:178-184.

15. Tricoci P, Allen JM, Kramer JM, et al. Scientific evidence underlying the ACC/ AHA clinical practice guidelines. JAMA. 2009;301:831-841. Erratum in: JAMA. 2009;301:1544.

16. Nash DB. Population health: moving forward. Popul Health Manag. 2014;17:1-2.

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BUSINESS

Original Research

Lessons from the Leucovorin Shortages Between 2009 and 2012 in a Medicare Advantage Population: Where Do We Go from Here?

Mary S. Hayes, PharmD; Melea A. Ward, PharmD, MS; S. Lane Slabaugh, PharmD, MBA; Yihua Xu, PhD Stakeholder Perspective, page 270

Am Health Drug Benefits.

2014;7(5):264-270 www.AHDBonline.com Received April 4, 2014.

Accepted in final form July 1, 2014.

Disclosures are at end of text

Background: Three distinct shortages of the generic drug leucovorin, a reduced form of folic acid used in several chemotherapy regimens, were reported by the US Food and Drug Administration (FDA) between 2008 and 2014. Levoleucovorin, an alternative therapy to leucovorin, failed to demonstrate superiority over leucovorin in clinical trials and is substantially more expensive.

Objective: To calculate the impact of the leucovorin shortages on primary treatment costs to patients and a health plan, and to present strategies for health plans to deal with future drug shortages.

Methods: This retrospective descriptive study was conducted using Humana’s Medicare Advantage prescription drug plan administrative claims database between January 1, 2009, and December 31, 2012. A total of 1542 patients with at least 1 medical or pharmacy claim for either leucovorin or levoleucovorin during the first 3 months of the respective plan year (between 2009 and 2012) who had continuous enrollment for the entirety of the same plan year, were included in this study. Trends in primary treatment costs––defined as the drug cost of leucovorin or levoleucovorin––over the 4-year evaluation period were assessed. The mean annual patient out-of-pocket (OOP) costs and the mean plan-paid per member per month (PMPM) costs were also calculated.

Results: The percentage of patients receiving leucovorin decreased annually, with a 15.8% drop from 2010 to 2011. This reduction was accompanied by a 6.6% increase in patients receiving levoleucovorin.

The mean annual patient OOP costs were $167 to $714 higher for levoleucovorin than for leucovorin.

Similarly, the mean plan-paid PMPM costs were higher (up to $1667 PMPM) for levoleucovorin than for leucovorin. The aggregate costs for the 2 drugs increased steadily, including the patient OOP costs and the plan-paid PMPM costs. The most prominent cost increase occurred between 2010 and 2011, with a 3.8-fold increase in patient OOP costs and a 5-fold increase in the plan-paid PMPM costs. This corresponded to the timing of the second leucovorin shortage announcement by the FDA in June 2010.

Conclusions: Health plans can play an important role in minimizing the impact of drug shortages by identifying the affected patient population, identifying therapeutic alternatives, assisting providers with alternative sourcing strategies when possible, adjusting approval processes, and implementing quality management or pathway programs.

D

rug shortages continue to be a growing challenge in the United States, adversely affecting the quality of care and contributing to the rising healthcare costs. According to the US Food and Drug Administration (FDA), the number of annual drug shortages tripled from 61 in 2005 to 178 in 2010.1 More than 80% of these shortages were for lower-cost generic medications or injectable therapies used in critical therapeutic areas, such as oncology, infectious diseases, and central Dr Hayes is Clinical Pharmacist, Humana Inc, Louisville, KY; Dr Ward was Clinical Pharmacist, Humana, Inc, Louisville, KY, at the time this work was completed; Dr Slabaugh and Dr Xu are Researchers, Comprehensive Health Insights, Humana Inc, Louisville, KY.

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nervous system disorders.2,3 The negative clinical impact of drug shortages is manifested in the form of delays in therapy, increased risk for medication errors, and drug-­ related adverse events.4,5 The economic implications of shortages include increased medication and labor costs.4,5 It is estimated that drug shortages contribute $216 million annually to the rising healthcare costs because of the increased time and effort required to manage the shortages.6 A Drug Shortages Summit that was convened in 2010 by the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists, the American Society of Clinical Oncology, and the Institute for Safe Medication Practices concluded that the causes of drug shortages are multifactorial.3 Although regulatory and

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Lessons from the 2009-2012 Leucovorin Shortages

Key Points

Figure 1 Leucovorin Shortage Time Line

Drug shortages continue to be a challenge in the United States, adversely affecting the quality of care and contributing to the rising healthcare costs. ➤ This is the first study to calculate the economic impact of the shortages of generic leucovorin (a reduced form of folic acid used in several chemotherapy regimens) from 2009 to 2012 to patients and to a health plan. ➤ Levoleucovorin, which was approved by the FDA during the initial leucovorin shortage, failed to demonstrate clinical superiority to leucovorin and is marketed at a much higher price. ➤ During the 4-year study period, the rate of patients receiving leucovorin decreased annually, while the rate of patients receiving levoleucovorin increased. ➤ The mean annual patient OOP costs were $167 to $714 higher for levoleucovorin than for leucovorin. ➤ Similarly, the annual plan-paid costs per member for folic acid analogs increased significantly during the study period. ➤ Health plans can play an important role in minimizing the impact of drug shortages by identifying therapeutic alternatives, adjusting approval processes, and implementing quality management or pathway programs. ➤

legislative factors play a role, the most frequently cited causes are related to the drug supply chain.3 Upon the initial approval of the abbreviated or new drug applications, the FDA timeliness of drug approval can be unpredictable, which contributes to uncertainty in market demand and associated drug production capability. In addition, during drug production, manufacturers must comply with Good Manufacturing Practices, as well as with their own quality metrics; inability to comply with these standards is a major contributor to drug shortages.

Finally, the business climate for marketing a medication can also affect drug shortages, such as a lower priority by a manufacturer being assigned to low profit margin generic drugs, agents being produced by a small number of manufacturers, and manufacturers choosing to discontinue a medication.3 The causes of drug shortages are often interconnected.3 For example, if a generic drug is produced by only a few manufacturers, and one of them encounters production issues, the other manufacturers may experience increased demand for the drug, followed by insufficient production capacity, thus perpetuating the initial shortage.3 This interconnectedness is demonstrated by a

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FDA approves levoleucovorin March 2008 First leucovorin shortage December 2008

Second leucovorin shortage

June 2010

Ongoing leucovorin shortage 2014

2008 2009 2010 2011 2012 2013 2014

Analysis period (2009-2012) Classified HCPCS code released for levoleucovorin January 2009

FDA indicates US Food and Drug Administration; HCPCS, Healthcare Common Procedure Coding System.

shortage of the generic drug leucovorin, a reduced form of folic acid used in several chemotherapy regimens.7 A shortage of leucovorin was first reported by the FDA in late 2008, citing manufacturing delays by Bedford Laboratories8 (Figure 1). Approximately 1 month later, Teva Pharmaceuticals, the only other manufacturer of leucovorin at that time, reported a shortage because of an increase in demand.9 This shortage was reported to be resolved by the spring of 2009, only to resurface 1 year later.10,11 Manufacturing delays were again cited as the cause of the 2010 shortage.11 The 2010 shortage was never clearly resolved, because Teva Pharmaceuticals and Bedford Laboratories could not meet the demand. In 2014, the FDA has reported that the leucovorin shortage remains ongoing.12 During the year of the initial leucovorin shortage in 2008, the FDA approved levoleucovorin (Fusilev), an active levo isomer that is marketed as an alternative to leucovorin.13 Although the availability of levoleucovorin reduces disruptions to patients, the levo isomer does not provide incremental clinical benefit. In a randomized controlled trial, a chemotherapy regimen containing levoleucovorin failed to demonstrate superiority to a regimen containing leucovorin in overall survival in patients with advanced metastatic colorectal cancer.14,15 In addition, a 2009 systematic literature review of 125 studies concluded that levoleucovorin had similar efficacy and tolerability compared with racemic leucovorin.16 Despite the lack of clinical benefits over leucovorin, levoleucovorin is priced substantially higher than leucovorin. In 2013, the Medicare allowable monthly price of levoleucovorin treatment was nearly $2500 compared with less than $200 for leucovorin.17 Therefore, patients who were unable to get leucovorin during the shortage did have access to an alternative therapy, albeit a therapy with a substantially higher price, and with no demonstrated incremental efficacy or tolerability benefits.

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Table Study Population Characteristics Year 1: 2009 Characteristic (N = 359)

Year 2: 2010 (N = 395)

Year 3: 2011 (N = 365)

Year 4: 2012 (N = 423)

71 (7.7)

71 (6.6)

70 (6.9)

71 (6.9)

Female, %

43.7

42.5

37.3

45.4

Caucasian, %

77.2

83.8

81.9

83.7

Dual-eligible for Medicare + Medicaid, %

0.6

1.3

1.9

1.7

Low-income subsidy, % Geographic region

17.0

18.7

17.5

18.0

Northeast, %

1.9

1.0

1.1

1.7

Midwest, %

24.2

22.3

20.5

23.4

South, %

62.7

68.9

69.9

65.7

West, % Primary treatment

11.1

7.8

8.5

9.2

326 (90.8)

364 (92.2)

279 (76.4)

294 (69.5)

Levoleucovorin only, N (%)

6 (1.7)

3 (0.8)

27 (7.4)

76 (18.0)

Mixed treatment, N (%)

27 (7.5)

28 (7.1)

59 (16.2)

53 (12.5)

Age at first claim, mean (SD)

Leucovorin only, N (%)

SD indicates standard deviation.

Previous surveys of health system pharmacy directors have concluded that drug shortages result in increased medication and labor costs4,5; however, no study to our knowledge has directly quantified the impact of a single drug shortage on treatment costs to the payer and the patient. Therefore, the objective of this study was to evaluate the impact of the leucovorin shortage on primary treatment costs during a 4-year period. In addition, we discuss strategies for health plans to manage drug shortages.

Methods Design and Data Source This retrospective descriptive study was conducted using the Medicare Advantage prescription drug plan population from Humanaâ&#x20AC;&#x2122;s administrative claims database between January 1, 2009, and December 31, 2012.

The start date was selected to correspond with the first leucovorin shortage announcement in December 2008.

In addition, the levoleucovorin Healthcare Common Procedure Coding System (HCPCS) billing code was released on January 1, 2009; before this date, claims for levoleucovorin could not have been accurately identified in the data set.

The Humana research database includes pharmacy claims, medical claims, and enrollment data for approximately 6 million members from all 50 states. Pharmacy claims data include adjudication information from the pharmacy related to the memberâ&#x20AC;&#x2122;s prescription, including the drug name, national drug codes, date of prescrip-

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tion fill, quantity and day supply of medication plan-paid amount, and member out-of-pocket (OOP) costs for the prescription.

For this study, drug claims were also identified through outpatient physician office medical claims using the HCPCS codes (J0640 for leucovorin; J0641 for levoleucovorin). The plan-paid amount and member OOP costs were available for all claims included in the analysis. Enrollment data include information on the member demographics and coverage start and end dates. This retrospective descriptive study was approved by the Schulman Associates Institutional Review Board.

Study Population Selection Patients included in the analysis were aged 19 to 89 years and had to have at least 1 medical or pharmacy claim (individuals aged <65 years with disabilities may be covered by Medicare; depending on the plan benefit design, leucovorin and levoleucovorin may be processed through medical or pharmacy claims) for leucovorin or for levoleucovorin during the first 3 months of each respective plan year and continuous enrollment for the entirety of the same plan year. The medical or pharmacy claim was required to be in the first 3 months of a respective plan year so that a continuous treatment cost trend could be established throughout each plan year. Patients were excluded if they had at least 1 inpatient or outpatient hospital claim for leucovorin or levoleucovorin in which the cost of the medication was not itemized.

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Folic Acid Utilization There were 380 patients who received leucovorin in the reference year (ie, 2008). During the evaluation period, there was a decreasing trend in the percentage of patients receiving leucovorin from 2010 to 2011 (absolute value of 15.8%; Table). This was accompanied by an increase in the percentage of patients receiving levoleucovorin (6.6%) and mixed treatment (9.1%). These trends for leucovorin and levoleucovorin persisted in 2012.

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$725

700

$658

600 500

$416

400

$315

$274

300

$301

$184 $185

200 100

$17

$14

0

$11

$13

2009 2010 2011 2012

Year

OOP indicates out-of-pocket.

Figure 3 Mean Plan-Paid PMPM Primary Treatment Costs Leucovorin Levoleucovorin Mixed treatment

1800 1600 1400 1200 1000 800 600 400 200

n09 Ap r-0 Au 9 g0 De 9 c0 Ja 9 n10 Ap r-1 Au 0 g1 De 0 c10 Ja n11 Ap r-1 Au 1 g1 De 1 c11 Ja n12 Ap r-1 Au 2 g1 De 2 c12

0 Ja

Results Patient Characteristics A total of 1542 unique patients received a folic acid analog between January 2009 and December 2012 (Table). The average age of the study population was 71 years and the majority (57.8%) of them were male. More than 60% of the patients resided in the southern region of the United States, a trend that is consistent with the geographic distribution of the health plan. During the study period, the percentage of patients receiving low-­ income subsidy ranged from 17.0% to 18.7%, and the percentage of patients who were dual-eligible for Medicare and Medicaid ranged from 0.6% to 1.9%.

Leucovorin Levoleucovorin Mixed treatment

800

Patient OOP costs, $

Outcomes and Analyses Trends in the primary treatment costs during the 4-year evaluation period are reported. The primary treatment costs were defined as the drug cost of leucovorin or levoleucovorin identified through medical or pharmacy claims, depending on which benefit covered the drug in the various plan designs.

The primary treatment costs to the patient and to the plan are reported separately. The patient OOP costs were defined as the costs incurred by the member either as a copay or coinsurance for each treatment, and are reported as mean annual costs. The plan-paid costs were defined as the amount paid by the plan (ie, drug cost minus patient OOP cost) and are reported as the mean per member per month (PMPM) costs. The mean annual patient OOP costs and the mean plan-paid PMPM costs are reported for each study year and for each of the 3 cohorts. The results are also reported in aggregate for the folic acid analogs combined. All analyses were performed using SAS Enterprise Guide, version 4.3 (SAS Institute; Cary, NC).

Figure 2 Mean Annual Patient OOP Primary Treatment Costs

Plan-paid PMPM costs, $

Overall, 3 cohorts were defined based on receipt of the drug index in the respective plan year––(1) leucovorin only, (2) levoleucovorin only, and (3) mixed treatment (ie, patients who received leucovorin and levoleucovorin during the plan year). The number of patients receiving leucovorin in 2008 was reported as the reference point.

Date

PMPM indicates per member per month.

Patient OOP Costs The mean annual patient OOP costs were between $167 and $714 higher for levoleucovorin than for leucovorin (Figure 2). Between 2009 and 2011, the mean annual patient OOP costs for levoleucovorin increased from $275 to $725, a 2.65-fold increase. Costs in the mixed-treatment group fluctuated during the 4-year period, and in 2009 the mean annual patient OOP costs were higher for the mixed-treatment group ($416) than

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Figure 4 Primary Treatment Costs for Folic Acid Analogs Mean annual patient OOP costs Mean plan-paid PMPM costs

Primary treatment costs, $

400

$365

350 300

Leucovorin shortage June 2010

250 200

$164

150

$113

100

$48

50

$18

0

$129

$30 $26

2009 2010 2011 2012

Year

OOP indicates out-of-pocket; PMPM, per member per month.

for either the leucovorin-alone ($14) or the levoleucovorin-alone ($274) cohort.

Plan-Paid Costs Similar to the trends in the mean annual patient OOP costs, the mean plan-paid PMPM costs for levoleucovorin were higher (up to $1667 PMPM higher) than for leucovorin (Figure 3). The plan-paid costs for levoleucovorin and the mixed-treatment group increased steadily over time, with noticeable peaks in the first quarter of each year.

Aggregate Folic Acid Analog Costs When the combined costs of leucovorin and levoleucovorin were considered in aggregate, the mean annual patient OOP costs and the mean plan-paid PMPM costs increased annually between 2009 and 2012 (Figure 4).

The most prominent increase occurred between 2010 and 2011, with a 3.8-fold increase in patient OOP costs and a 5-fold increase in plan-paid PMPM costs, corresponding to the timing of the second leucovorin shortage announcement by the FDA.11 Discussion This retrospective descriptive analysis of a Medicare Advantage prescription drug plan population reveals trends in the patient OOP costs and plan costs for leucovorin and levoleucovorin during a 4-year period of sequential leucovorin shortages. We found that patients and the health plan experienced an annual increase in costs for therapy. The most notable increase occurred between 2010 and 2011, which corresponded to the second leucovorin shortage (in June 2010) and to a shift from leucovorin to levoleucovorin use in the study population.

Several factors may have contributed to the trends

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reported in this study. First, plan benefit designs directly affect patient OOP costs. Traditionally, patients covered

by Medicare have a 20% coinsurance for medications that are covered by Medicare Part B; therefore, patient OOP costs directly correlate with medication unit costs.

However, this study population was highly concentrated in the southern United States; the most common benefit design of Humana in that region includes a 0% coinsurance for preferred Part B medications. During the study period, leucovorin was eligible for 0% coinsurance, but levoleucovorin was not. Therefore, patients receiving leucovorin had little fluctuation in their OOP costs, but those receiving levoleucovorin were greatly affected by price changes. These variations in benefit design may also explain the fluctuations observed in OOP costs for the mixed-treatment cohort.

Price fluctuations during the study period might have also contributed to the observed trends. For example, the Medicare allowable price for levoleucovorin was reduced during the second and third quarters of 2010 to provide relief at the onset of the second leucovorin shortage.18 In late 2010, the levoleucovorin price began to increase steadily, from an average selling price of $0.69 in July 2010 to $1.73 in July 2011.18 This increase coincided with the FDA approval of a new indication for levoleucovorin for use in combination chemotherapy with 5-fluorouracil for the palliative management of patients with advanced metastatic colorectal cancer in April 2011.19 The newly approved indication might have been another factor related to the increased use of levoleucovorin beginning in 2011.

Health Plan Strategies to Address Drug Shortages Opportunities exist for health plans to consider alternative strategies to mitigate the effects of drug shortages.

ASHP offers guidelines for the management of drug shortages in hospitals and in other health systems.20 Although there are no parallel guidelines for health plans, Humana and its insured population have benefited from implementing these concepts in the health plan setting.

For example, Humana proactively worked to identify alternative sources for providers who did not have access to leucovorin through their usual suppliers, when possible. Then, Humana pharmacists conducted a therapeutic assessment to identify the affected patient population and the therapeutic alternative. The clinical review process was also adjusted to facilitate approval when prescribers indicated that they were using levoleucovorin because of the shortage.

In addition, it is important for health plans to monitor drug shortages even after these shortages are resolved.

Under some reimbursement models, physicians may lack financial incentive to return patients to generic medica-

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tions, even though returning to the original medication could result in reduced costs for the patient and the plan.

Therefore, health plans may need to implement strategies that help facilitate the reutilization of the original medication once a shortage is resolved, unless it is not clinically warranted. Traditional pharmacy utilization management techniques, such as step therapy, may not be possible for some drugs and are prohibited for drugs billed through Medicare Part B benefits. One possible strategy is to adjust the approval duration (eg, from 6 months to 3 months) to allow for reassessment of a drug supply during a drug shortage.

Alternative methods include quality management or pathway programs, which often incentivize providers to use the most cost-effective therapy supported by an evidence-based approach. Humana has an Oncology Quality Management Program that is based on evidence-based care standards and uses a counseling model within traditional preauthorization management.21 The program is administered by New Century Health and Oncology Analytics in different markets.21,22 Future research should evaluate the impact of such programs in relation to drug shortages.

Limitations This is a descriptive study of trends in patient and health plan costs during a 4-year period and has impor­ tant limitations. First, given the descriptive nature of this study, we do not attempt to assign association or causation of cost trends to the leucovorin shortage alone.

The study design might have influenced some observations. Specifically, monthly analysis of mean plan-paid PMPM costs revealed peaks during the first quarter of each year, particularly for the levoleucovorin and mixed treatment cohorts. This pattern was likely associated with the requirement that all patients have a claim during the first 3 months of the year, and may have also been influenced by variability in the individualsâ&#x20AC;&#x2122; chemotherapy cycles and discontinuation of therapy during the year.

In addition, this study is subject to limitations of claims-based analyses, including missing data, miscoded claims, and inability to identify information not included in the database, such as reasons for discontinuation.

Finally, patients were excluded if they had nonitemized hospital claims for the study drugs; this exclusion criterion might have affected the cohorts disproportionally, creating a selection bias.

Conclusions Drug shortages continue to threaten patient access to critical medications. Through the example of the persisting leucovorin shortage, this study highlights that the effects of drug shortages extend beyond the clinical con-

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sequences to include increased costs to the patient and to the health plan. Health plans play an important role in assisting providers with identifying alternative sourcing strategies and choosing the best course of treatment once the shortage is resolved. Future studies should evaluate the impact of drug shortages on health outcomes. n Acknowledgments The authors wish to recognize Tyler Whisman, a clinical pharmacist at Humana, Inc, for his contributions to the concept and design of this study.

Funding Source This study was funded by Humana, Inc. Author Disclosure Statement Dr Hayes, Dr Ward, and Dr Xu reported no conflicts of interest. Dr Slabaugh owns stocks in Humana, Inc.

References

1. US Food and Drug Administration. FDA and manufacturers work to prevent drug shortages. Updated June 9, 2011. www.fda.gov/drugs/drugsafety/drugshortages/ucm 257746.htm. Accessed March 10, 2014.

2. IMS Institute for Healthcare Informatics. Drug shortages: a closer look at products, suppliers and volume volatility. Executive summary. November 2011. www.imshealth. com/deployedfiles/ims/Global/Content/Insights/IMS%20Institute%20for%20 Healthcare%20Informatics/Static%20Files/IIHI_Drug_Shortage_Media_Exec Summ.pdf. Accessed March 10, 2014.

3. American Society of Health-System Pharmacists. Drug shortages summit: summary report; November 5, 2010. January 10, 2011. www.ashp.org/drugshortages/summitreport.

Accessed May 12, 2013.

4. McLaughlin M, Kotis D, Thomson K, et al. Effects on patient care caused by drug shortages: a survey. J Manag Care Pharm. 2013;19:783-788.

5. McBride A, Holle LM, Westendorf C, et al. National survey on the effect of oncology drug shortages on cancer care. Am J Health Syst Pharm. 2013;70:609-617.

6. Kaakeh R, Sweet BV, Reilly C, et al. Impact of drug shortages on U.S. health systems. Am J Health Syst Pharm. 2011;68:1811-1819.

7. Fight Colorectal Cancer. Tag archives: leucovorin shortage. http://fightcolorectal cancer.org/tag/leucovorin_shortage/. Accessed March 11, 2014.

8. Fight Colorectal Cancer. Leucovorin shortage threatens colorectal cancer treatment.

December 15, 2008. http://fightcolorectalcancer.org/leucovorin_shortage_threatens_ colorectal_cancer_treatment/. Accessed July 15, 2014.

9. Fight Colorectal Cancer. Leucovorin shortage update. January 22, 2009. http:// fightcolorectalcancer.org/leucovorin_shortage_update/. Accessed July 15, 2014.

10. Fight Colorectal Cancer. Colorectal cancer news in brief: May 8. May 8, 2009. http://fightcolorectalcancer.org/colorectal_cancer_news_in_brief_may_8/. Accessed July 15, 2014.

11. Fight Colorecal Cancer. New leucovorin shortage should be fixed soon. June 24, 2010. http://fightcolorectalcancer.org/new_leucovorin_shortage_should_be_fixed_soon/.

Accessed July 15, 2014.

12. US Food and Drug Administration. Current and resolved drug shortages and discontinuations reported to FDA: leucovorin calcium lyophilized powder for injection.

Search results. www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredient Details.cfm?AI=Leucovorin%20Calcium%20Lyophilized%20Powder%20for%20 Injection&st=c#. Accessed July 21, 2014.

13. US Center for Drug Evaluation and Research. Levoleucovorin approval letter.

March 7, 2008. www.accessdata.fda.gov/drugsatfda_docs/nda/2008/020140s000 Approv.pdf. Accessed March 11, 2014.

14. Goldberg RM, Hatfield AK, Kahn M, et al. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997;15:3320-3329.

15. Fusilev (levoleucovorin) injection [prescribing information]. Irvine, CA: Spectrum Pharmaceuticals, Inc; April 2011.

16. Kovoor PA, Karim SM, Marshall JL. Is levoleucovorin an alternative to racemic leucovorin? A literature review. Clin Colorectal Cancer. 2009;8:200-206.

17. Centers for Medicare & Medicaid Services. Payment allowance limits for Medicare Part B drugs. Updated November 25, 2013. www.cms.gov/apps/ama/license.asp?file=/ McrPartBDrugAvgSalesPrice/downloads/Apr-13-ASP-Pricing-file.zip. Accessed May 20, 2013.

18. RJ Health Systems Reimbursement Codes. Leucovorin and levoleucovorin pric-

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ing tables. http://reimbursementcodes.com. Accessed March 11, 2014.

19. Spectrum Pharmaceuticals. FDA approves FUSILEV® for use in patients with colorectal cancer. Press release. April 29, 2011. http://investor.spectrumpharm.com/ releasedetail.cfm?ReleaseID=573364. Accessed July 16, 2014.

20. Fox ER, Birt A, James KB, et al. ASHP Guidelines on managing drug product shortages in hospitals and health systems. Am J Health Syst Pharm. 2009;66:1399-1406.

21. Humana. Chemotherapy—New Century Health. www.humana.com/provider/ medical-providers/education/referral/chemotherapy-new-century-cincy. Accessed March 11, 2014.

22. Humana. Chemotherapy—Oncology Analytics. www.humana.com/provider/ medical-providers/education/referral/chemotherapy-oncology-tampa. Accessed March 11, 2014.

Stakeholder Perspective Drug Shortages Are Costly to Patients and to Payers

By Joseph P. Fuhr, Jr, PhD Professor of Economics, Widener University, Chester, PA

Drug shortages are an increasing problem in the United States and have many implications for different stakeholders. In this issue of the journal, Hayes and colleagues present a study of shortages of generic leucovorin, which is used in various chemotherapy regimens.1 The study, which uses data from a Medicare Advantage population from a national health plan, adds valuable insight into the problems that a drug shortage can cause, and how payers can help alleviate some of these problems.

PATIENTS: When drug shortages occur, patients can be faced with the inability to take their normally prescribed drug. This can result in unfavorable outcomes and increased out-of-pocket (OOP) costs. In some cases, patients have to postpone procedures. In their study, Hayes and colleagues estimate that the mean annual added OOP cost for levoleucovorin, a nongeneric substitute for leucovorin, was between $167 and $714 higher than for leucovorin, which can be a significant increased cost burden for the patient.

PROVIDERS: Medical professionals have increased their use of labor resources in an attempt to find drugs affected by shortages and to find alternatives for these drugs. Providers who are using less familiar treatment alternatives for drugs in shortage can be more prone to medical errors.

PAYERS: Third-party payers have experienced higher drug prices related to drug shortages. A grey market has evolved for these drugs, leading to considerably higher prices. In addition, the grey market has increased the potential for counterfeit drugs to enter the supply chain.

The reasons for the drug shortages are multifaceted and have become a major public health issue.

The initial reason for the shortage of leucovorin was manufacturing delays by 1 of the 2 manufacturers of the generic drug. There was also no incentive to increase production of leucovorin, because of the relatively low

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price of the generic drug. An alternative for leucovorin, levoleucovorin, was found; however, according to results of clinical trials, levoleucovorin was not superior to the generic drug, yet it was substantially more expensive.

The study by Hayes and colleagues examines the various ways that health plans can minimize the impact of drug shortages, by taking an active role in helping patients. The authors note several strategies that payers can use to help alleviate problems created by drug shortages, such as identifying affected patients, finding alternative drugs, assisting providers in finding the drug, and adjusting the payers’ drug coverage process.

One tactic that payers could have taken in the case of leucovorin was to give the generic companies an incentive to supply more of the drug, by increasing the generic price. This would have increased the supply of the drug, and also might have lowered overall spending, as long as the negotiated price was below the price of the alternative drug. Payers and Medicare need to have more flexibility in drug pricing when a shortage occurs.

Such flexibility will help eliminate the grey market, help alleviate the shortage, and will decrease the negative impact on consumers, providers, payers, and the overall healthcare cost.

Hayes and colleagues estimate the additional cost of using a higher-priced, but not superior, drug substitute.

Drug shortages can result in postponed procedures to patients and can contribute to less favorable outcomes; the authors did not measure the costs for this, which should be done by future research. The present study is indeed very informative, but it represents only a first step in addressing drug shortages and estimates only a portion of the cost of shortages to patients and to payers. n 1. Hayes MS, Ward MA, Slabaugh SL, Xu Y. Lessons from the leucovorin shortages between 2009 and 2012 in a Medicare Advantage population: where do we go from here? Am Health Drug Benefits. 2014;7:264-270.

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VISIT THE NEW ONLINE RESOURCE FOR THE ENTIRE MULTIPLE MYELOMA CARE TEAM

“Better informed teams provide better care.”

Matthew P. Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth Murray, UT

Value-Based Care IN Myeloma

™

RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues.

Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

www.ValueBasedMyeloma.com Value-Based Care in Myeloma is a publication of Engage Healthcare Communications, a member of The Lynx Group. © 2014 All rights reserved.

VBMAsize_Mitchell_81214

REGULATORY

Original Research

Offering Lung Cancer Screening to HighRisk Medicare Beneficiaries Saves Lives and Is Cost-Effective: An Actuarial Analysis Bruce S. Pyenson, FSA, MAAA; Claudia I. Henschke, PhD, MD; David F. Yankelevitz, MD; Rowena Yip, MPH; Ellynne Dec, FSA, MAAA Stakeholder Perspective, page 281

Am Health Drug Benefits.

2014;7(5):272-282 www.AHDBonline.com Received July 7, 2014.

Accepted in final form July 16, 2014.

Disclosures are at end of text

Background: By a wide margin, lung cancer is the most significant cause of cancer death in the United States and worldwide. The incidence of lung cancer increases with age, and Medicare beneficiaries are often at increased risk. Because of its demonstrated effectiveness in reducing mortality, lung cancer screening with low-dose computed tomography (LDCT) imaging will be covered without cost-sharing starting January 1, 2015, by nongrandfathered commercial plans. Medicare is considering coverage for lung cancer screening.

Objective: To estimate the cost and cost-effectiveness (ie, cost per life-year saved) of LDCT lung cancer screening of the Medicare population at high risk for lung cancer.

Methods: Medicare costs, enrollment, and demographics were used for this study; they were derived from the 2012 Centers for Medicare & Medicaid Services (CMS) beneficiary files and were forecast to 2014 based on CMS and US Census Bureau projections. Standard life and health actuarial techniques were used to calculate the cost and cost-effectiveness of lung cancer screening. The cost, incidence rates, mortality rates, and other parameters chosen by the authors were taken from actual Medicare data, and the modeled screenings are consistent with Medicare processes and procedures.

Results: Approximately 4.9 million high-risk Medicare beneficiaries would meet criteria for lung cancer screening in 2014. Without screening, Medicare patients newly diagnosed with lung cancer have an average life expectancy of approximately 3 years. Based on our analysis, the average annual cost of LDCT lung cancer screening in Medicare is estimated to be $241 per person screened. LDCT screening for lung cancer in Medicare beneficiaries aged 55 to 80 years with a history of ≥30 pack-years of smoking and who had smoked within 15 years is low cost, at approximately $1 per member per month. This assumes that 50% of these patients were screened. Such screening is also highly cost-effective, at <$19,000 per life-year saved.

Conclusion: If all eligible Medicare beneficiaries had been screened and treated consistently from age 55 years, approximately 358,134 additional individuals with current or past lung cancer would be alive in 2014. LDCT screening is a low-cost and cost-effective strategy that fits well within the standard Medicare benefit, including its claims payment and quality monitoring.

L

ung cancer is a lethal disease that claims the lives of more people in the United States annually than the next 4 most lethal cancers combined, which are, in order, colon, breast, pancreas, and prostate cancers.1,2 In the United States, an estimated 224,210 people will be diagnosed with lung cancer, and an estimated 159,260 people will die of the disease in 2014.3 The inMr Pyenson is Principal & Consulting Actuary, Milliman, Inc, New York; Dr Henschke is Clinical Professor, Radiology, Icahn School of Medicine at Mount Sinai; Dr Yankelevitz is Professor, Radiology, Icahn School of Medicine at Mount Sinai; Ms Yip is Senior Biostatistician, Icahn School of Medicine at Mount Sinai, New York; Ms Dec is Actuary, Milliman, Inc, New York.

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cidence of lung cancer increases with age,4 and the risk increases with the cumulative effects of past smoking.

Millions of Medicare beneficiaries are at significant risk.5 On December 31, 2013, lung cancer screening using low-dose computed tomography (LDCT) was rated as a level “B” recommendation by the US Preventive Services Task Force (USPSTF),6 a panel of independent experts convened by the Agency for Healthcare Research and Quality to evaluate the strength of evidence and the balance of benefits and harms of preventive services.7 The USPSTF recommendation applies to people aged 55 to 80 years with a history of heavy smoking.6 LDCT is an imaging technology that enables 3-dimensional visualization of internal body structures, including the lungs, using low doses of radiation.

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Under the Affordable Care Act, the “B” recommendation means that LDCT lung cancer screening must be covered without cost-sharing by qualified health plans starting January 1, 2015.6,8 Qualified health plans include commercial insurance and self-insured benefit plans, with the exclusion of grandfathered plans. Several private insurers have initiated LDCT screening coverage in advance of the 2015 requirement.9 Furthermore, versions of the USPSTF recommendations have been adopted essentially by every major academic body with an interest in lung cancer, including the National Comprehensive Cancer Network, American Association for Thoracic Surgery, American College of Radiology, Society of Thoracic Surgeons, International Association for the Study of Lung Cancer, American College of Chest Physicians, and the American Cancer Society.

Medicare has begun a national coverage analysis to determine whether LDCT lung cancer screening meets its criteria for coverage, which includes whether screening is reasonable and necessary for early detection, whether the service has an “A” or a “B” recommendation by the USPSTF, and whether screening is appropriate for Medicare beneficiaries.

High doses of radiation can be harmful. LDCT can be performed at very low doses of <0.7 mSv per procedure10 by comparison, the annual natural background radiation in New York City (sea level) is 3 mSv. LDCT technology refinements and protocol optimization have translated into patient benefits, supporting the detection of ever-smaller lung cancers, reducing the rate of surgical procedures, and providing higher cure rates.11-14 Advances in LDCT technology, promising results from nonrandomized trials,14 and unchanged survival statistics over the previous 30 years, led to the implementation of the National Lung Screening Trial (NLST), the most expensive and one of the largest randomized screening trials ever sponsored by the National Cancer Institute.13 The trial of 53,454 people aged 55 to 74 years at high risk for lung cancer was conducted to determine whether LDCT screening could reduce mortality from lung cancer.

Participants in this 2-arm US study received 3 annual screenings with either an LDCT or a chest x-ray. Based on the study protocol, the trial was stopped when findings demonstrated a relative reduction of 20% in lung cancer mortality in the LDCT arm versus the chest x-ray arm.13 Observational data and epidemiologic arguments for breast cancer also suggest that additional rounds of screening would reduce lung cancer mortality by much more than 20%.15-22 Other large studies have shown that computed tomography (CT) screening is associated with a high proportion (much higher than 70%) of the lung cancer diagnoses being early stage15-17,21 compared with 15% in the national data.23 Long-term survival rates of

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Key Points Lung cancer is the leading cause of cancer death in the United States and worldwide. ➤ Because the risk increases with age and with a history of smoking, some Medicare beneficiaries are at high risk for this type of cancer. ➤ Low-dose computed tomography (LDCT) has been shown to reduce mortality from lung cancer by more than 20%. ➤ Under healthcare reform, LDCT must be covered without cost-sharing by nongrandfathered commercial health plans beginning in 2015. ➤ Based on this new analysis, LDCT screening of high-risk Medicare beneficiaries is cost-effective and will cost approximately $1 per member per month. ➤ The average annual cost of such a screening policy is estimated to be $241 for a Medicare beneficiary screened. ➤ Given all causes of mortality, without screening, Medicare patients newly diagnosed with lung cancer have an average of 3 years life expectancy. ➤ With screening, these patients would have an additional 4 years of additional life expectancy incremental to the life expectancy without screening. ➤ If all eligible beneficiaries had been screened and treated consistently from age 55 years, approximately 358,134 additional individuals with current or past lung cancer would be alive in 2014. ➤

approximately 80% have been reported for patients with lung cancer who are diagnosed by CT screening12,15,16 compared with a 16.8% 5-year survival rate from the national data.23 One of the coauthors of this article was the lead author of an actuarial analysis of LDCT lung cancer screening for the commercially insured population.24 This report used similar methodology, types of structures, and data to examine lung cancer screening for the Medicare program. The Medicare program faces significant budget limitations, and any new coverage benefit will face scrutiny regarding its costs and benefits.

The purpose of the present study was to estimate the hypothetical 2014 costs and benefits associated with the responsible implementation of widespread lung cancer screening in the high-risk US population covered by Medicare.

Study Data and Methods Our study had 2 phases. First, we determined Medicare’s cost of screening, assuming a 50% uptake rate for the por-

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Figure 1 Decision Tree for Initial Baseline Screening Smoking-cessation session and baseline LDCT scan 89% No candidate nodules present Repeat LDCT in 1 yr

85% No growth Repeat LDCT in 1 yr

63% Positive result Surgery

2% Any nodule ≥15 mm Evaluate

9% Solid or part-solid nodule ≥6 mm and <15 mm Follow-up LDCT scan in 3 mon

15% Growth at a rate indicating malignancy Biopsy

15% Biopsy

37% Negative result Repeat LDCT in 1 yr

89% Positive result Surgery

46% Follow-up PET and/or CT

31% No growth Repeat LDCT in 1 yr

11% Negative result Repeat LDCT in 1 yr

39% Repeat LDCT in 1 yr

69% Growth at a rate indicating malignancy Biopsy

90% Positive result Surgery

10% Negative result Repeat LDCT in 1 yr

CT indicates computed tomography; LDCT, low-dose CT; PET, positron emission tomography.

tion of eligible individuals who would use the screening.

Then, we determined Medicare’s cost per life-year saved.

Screening-Eligible Populations The Medicare enrollment and demographics were derived from the 2012 Centers for Medicare & Medicaid Services (CMS) beneficiary files and were forecast to 2014 based on US Census Bureau projections.25 Screening-­ eligible patients with Medicare coverage were defined as smokers and former smokers aged 55 to 80 years who had a ≥30 pack-year smoking history and had smoked within the previous 15 years. These criteria reflect key elements of the USPSTF recommendation.6 Pack-years represent the product of the number of years an individual has smoked and the average number of packs of cigarettes daily. The group eligible for lung cancer screening was estimated to comprise approximately 4.9 million people, or approximately 10% of Medicare beneficiaries, based on actuarially adjusted (to 2014) populations reported by Ma and colleagues for 2010.5 Data Sources and Methods for Cost of Screening We estimated the cost of LDCT lung cancer screening and follow-up components of the screening process using 2014 Medicare fees. We analyzed medical claims in the Medicare 5% sample to determine the cost and dis-

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tribution of biopsy types (fine-needle aspiration, bronchoscopy, and video-assisted thoracic surgery). We applied these costs to the established screening protocols and the observed distribution of outcomes in lung cancer screening trials, such as those used in the NLST13 and the International Early Lung Cancer Action Program (I-ELCAP).18,26 Each screening included a 30-minute smoking-cessation session.

Observational studies have determined that the initial baseline and annual repeat LDCT screenings are likely to find nodules with different characteristics,27 and we followed the various standard protocols for each. The initial baseline protocol is shown in Figure 1, and the annual repeat protocol is described in the Appendix (see www.AHDBonline.com). All data were from HIPAA-­ compliant studies with Institutional Review Board–­ approved protocol.

The services performed after LDCT lung screening, if any, depend on the round of screening (ie, baseline or repeated annually), nodule size and morphology, and other clinical considerations.28,29 These services could potentially include an additional LDCT scan, a course of antibiotics, or in <3% of baseline or <1% of annual screenings, a biopsy of a lung nodule. Evidence shows that 13% of patients who undergo baseline LDCT screening require diagnostic evaluation before their next annual

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screening, whereas only 5% of patients who undergo repeated annual screening require such an evaluation.12,28 The I-ELCAP investigators reported that lung cancers are diagnosed in 1.3% and 0.3% of Medicare-age individuals based on the I-ELCAP protocol for initial and repeat screenings, respectively.12 Clearly, most screenings do not detect lung cancer, and 97% of initial screenings and 99% of follow-up screenings do not lead to an invasive procedure. Published probabilities reflect the investigators’ populations. To better match the Medicare population, similar (yet distinct) follow-up probabilities were developed based on the population aged ≥65 years in a large observational trial, which are specified in the Appendix (online).

To determine costs, we applied the 2014 national Medicare fee schedule30 for the prices of CT scanning and a 30-minute smoking-cessation program. The screening and smoking-cessation program had no patient cost-sharing, as required of Medicare-covered preventive benefits. A patient cost-sharing of 30%, which reflects the actual patient experience in the authors’ database analysis, was applied to follow-up outpatient diagnostic services. Details of the codes and the costs that were used are provided in the Appendix (online).

Because systematic screening for lung cancer had not been used in the past, we assumed that the 2014 Medicare enrollment demographics reflected the accrued lung cancer incidence and mortality exposure of an unscreened population. We constructed an alternative 2014 population assuming the mortality experience in a screened population. The alternative 2014 population included the patient cohort that was newly diagnosed in 2014 and patients diagnosed in previous years who have survived to 2014, assuming that screening had started 25 years earlier.

Half of the high-risk Medicare population aged 55 to 80 years, or approximately 2.4 million people, were assumed to participate in lung cancer screening, based on comparisons with other types of screening. This is lower than the 75.2% adherence rate in 2010 to colorectal cancer screening for the Medicare population aged ≥65 years, which took many years of promotion to achieve.31 We spread the annual cost of screening across all 50 million Medicare beneficiaries, and divided it by 12 to produce the per-member per-month (PMPM) cost; PMPM units are often used by Medicare and other health insurance programs.

Methods and Data Sources for the Cost-Benefit Analysis In our model, stage shifting, in which screening identifies cancers at earlier stages, is fundamental to the ability of lung cancer screening to reduce mortality. LDCT screening results in a greater number of lung cancers being

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pproximate Mapping of TNM Lung Cancer Table 1 A Stages to Modeled Stages IIA, IIB, TNM stages IA, IB IIIA IIIB, IV Modeled stages

A

B

C

detected at an earlier stage,13 which leads to earlier treatment and lower treatment costs and to more people living after having been diagnosed with lung cancer.

We analyzed the Medicare 5% sample data by disease stage at diagnosis to determine treatment cost for the years after diagnosis. The treatment cost for lung cancer reflects clinical treatment decisions that depend in part on the disease stage at diagnosis. The International Classification of Diseases, Ninth Revision diagnosis codes on claims data do not explicitly identify the cancer stage; therefore, we established 3 stage designations—A, B, and C—based on treatment patterns for patients in the 9-month period after diagnosis.

We grouped TNM cancer stages into 3 categories that we believe corresponds approximately to early or localized lung cancer, regionally advanced lung cancer, or metastatic disease, which were denoted as stages A, B, and C, respectively (Table 1). Our 3 stages represent tumors similar to those classified as local, regional, and distant cancer, respectively, in the Surveillance, Epidemiology, and End Results (SEER) registry.32 This methodology allowed the use of claims histories to assign patients to these 3 categories. The Appendix (see online) contains details of our stage designation methodology and results.

We created several screening scenarios—status quo (ie, no screening), base-case screening, and other scenarios—to analyze how varying key model assumptions would change the cost-benefit results. The status quo scenario assumes that LDCT screening was not performed. The differences in costs and life-years lived between the status quo and the base-case scenarios provide the net cost of screening and the number of life-years saved as a result of screening.

In the status quo scenario, lung cancers were categorized by stage at diagnosis (from the SEER cancer registry using SEER*Stat software), with corresponding treatment costs and mortality. In the screening scenarios for the cost-benefit analyses, we assumed that the entire target population was screened annually and that the screening-eligible population would generate 80% of the population’s cases of cancer, slightly lower than the 90% of lung cancers attributed to smoking by the Centers for Disease Control and Prevention.33 Because LDCT can detect nodules before a cancer becomes symptomatic, the incidence of screening-detected cancers at a given age was taken from the SEER

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Table 2 Expected Number of US Lung Cancer Survivors in Medicare in 2014: Base-Case Scenario Lung cancer survivors at end of year (diagnosed at age ≥55 yrs) Patients with lung cancer Without With screening Additional patients within 3 yrs of diagnosis People screened screening, (excludes with lung cancer (not included in additional Age, yrs in 2014, N N lead-time yrs), N in 2014, N patient count), N 55-59

201,786

1595

2794

1199

2374

60-64

284,117

4917

9777

4859

4433

65-69

1,879,943

40,169

70,421

30,252

18,988

70-74

1,489,434

69,882

145,128

75,246

28,745

75-80

1,039,049

88,278

209,037

120,759

27,237

N/A

49,356

175,176

125,819

2058

4,894,329

254,197

612,333

358,138

83,835

81-100

Total, 55-110

Source: Authors’ analysis.

incidence for an age 3 years older, but with earlier stages.

For example, a cancer diagnosed through screening in a patient aged 67 years represents an earlier stage of the same cancer that would have been diagnosed 3 years later, when that person would have been age 70 years.

This is consistent with the time for a 6-mm cancer detected in screening to grow from stage I to stage III, with a diameter of >7 cm, assuming a volume doubling time (ie, measure of the tumor growth rate) of 98 days.34 For all scenarios in the cost-benefit analyses, we assumed 100% uptake to allow direct comparisons to alternative protocols and to other studies of lung cancer screening and screening for other cancers. In 2014, the surviving 65-year-old patients would have received annual screenings since 2004, when they were age 55 years, but the 55-year-old patients would have been screened only once. In contrast, we assumed a 50% uptake rate for the PMPM cost of screening, because our goal for the price of screening analysis was to develop a realistic PMPM Medicare cost.

We compiled historical cohorts of high-risk Medicare beneficiaries starting at age 55 years to actuarially match the 2014 population of high-risk patients aged 55 to 80 years. In each model year and scenario, we applied SEER cancer incidence rates by age, sex, and stage to identify the incidence at status quo. We reduced the number of lives in each cohort annually with an all-cause mortality rate that is appropriate for smokers.35 For screened patients with lung cancer, we applied stage-specific lung cancer mortality rates, and we tracked patients with lung cancer who would have been survivors.

Because the USPSTF recommendation means that lung cancer screening must be covered without cost-sharing in qualified health plans (commercial coverage), we assumed that any Medicare beneficiaries initiating coverage after the age of 55 years would have had the benefit

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of screening under their previous form of coverage. For example, all high-risk individuals aged 65 years in 2014 were assumed to have been screened for 10 years. For Medicare, most of the screenings of patients aged <65 years were assumed to have occurred through commercial insurance, because Medicare beneficiaries represent only a small proportion of people aged 55 to 64 years.

Earlier cancer detection produces longer apparent cancer survival in diagnosed patients (ie, both younger age when diagnosed and at an earlier stage). This is known as “lead time bias.” To avoid attributing additional survival time because of lead-time bias, we calculated life-years saved based on the impact of the disease stage shift only. As a result, although we included costs that are associated with longer treatment of patients with lung cancer resulting from lead-time (ie, earlier) detection, we assumed no lead time in calculating the life-years survival benefit.

We used 2014 cost levels throughout our analysis to eliminate the need for discounting or trending (other than trending historical data to 2014), a strategy that is more straightforward than forecasting future healthcare costs over 20 years and discounting them to the present time.

Study Results Cost of Screening We estimated the average annual cost of lung cancer screening to be $241 per person screened, assuming that 75% of the screenings were annual repeat screenings (see Appendix online). Our assumption is consistent with the ratio reported in a large collaborative study of LDCT screening.12 The cost to Medicare for an annual LDCT screening plus follow-up is approximately 11% lower than that for baseline screening, because of the lower rate of new nodules requiring near-term diagnostic evaluation relative to

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a Table 3 E stimated Impact of Lung Cancer Screening on Life-Years Saved and Cost per Life-Year Saved, Using Base-Case (I-ELCAP Data for Screening Results) Impact of screening Total Male Female

Cumulative life-years saved, yrs

2,825,652

Lead-time correction, yrs

1,313,423

1,512,229

568,599

276,563

292,036

2,257,053

1,036,860

1,220,193

41,647,811,614

23,241,454,701

18,406,356,913

18,452

22,415

15,085

Average life expectancy without screening, yrs

3.07

2.81

3.36

Average life expectancy with screening (with no lead time), yrs

7.01

6.30

7.83

Average increased life span because of screening, yrs

3.94

3.49

4.47

True life-years saved (0-yr lead time life-year saved), yrs Cumulative extra cost, $ Cost per additional life-year, $ Patients diagnosed with lung cancer in 2014

Life-years saved and cost are for patients with cancer aged 55-110 years.

I-ELCAP indicates International Early Lung Cancer Action Program.

Source: Authors’ analysis.

a

Figure 2 Sensitivity Analysis: Cost per Additional Life-Year Saved $5000

$15,000

$10,000

Cost to treat, by disease stage at diagnosis

Base : Medicare 5% analysis High : All stages equal cost

Expected annual screen cost/person

Low : $230 Base : $241

Trial data to use for phase shift

Base : I-ELCAP12

Percent of lung cancers among smokers

Low: 90% Base : 80%

Pseudo-disease multiple

Base : No pseudo-disease

$20,000

$25,000

$30,000

High : $500 High : NLST13 High : 50% High : 20% more stage Aa cancers

a For this cost analysis, cancer stage was designated as A, B, or C based on treatment patterns for patients in the 9-month period after diagnosis.

I-ELCAP indicates International Early Lung Cancer Action Program; NLST, National Lung Screening Trial.

the initial baseline screening. Assuming that 50% of the patients aged 55 to 80 years with ≥30 pack-years of smoking were screened, the Medicare cost spread across the Medicare population would be $1.02 PMPM, assuming no cost-sharing for the initial or annual screening LDCT or smoking-cessation session. This cost is lower than the Medicare cost for screening mammography (see Appendix online). By comparison, in 2012, the average monthly cost of Medicare benefits was approximately $672 per beneficiary for Medicare Part A and Part B; the total monthly spending for Part D (including enrollee spending) was approximately $235.36

Cost-Benefit Analysis Approximately 4.9 million high-risk Medicare beneficiaries would meet the USPSTF criteria for lung cancer

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screening in 2014. If all had been screened and treated consistently from age 55 years, approximately 358,134 additional individuals with current or past lung cancer would be alive in 2014 (Table 2).

The additional number of 358,134 individuals does not include patients who were cured of lung cancer but who died of other causes, or the estimated 83,835 “lead-time” cases—that is, additional patients living with lung cancer (generally at a less-advanced stage) because their cancer was detected earlier through LDCT screening. The “leadtime” patients were not counted as “lung cancer survivors” until they have reached the age when they would have been diagnosed with lung cancer in the absence of screening.

Table 3 shows the total life-years saved by early treatment as the sum of all years of additional life for all screening-eligible Medicare patients with lung cancer who are

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Table 4 Key Assumptions and Sensitivity Results Key cost-benefits model component Base-case assumption

Sensitivity assumption and impact on cost per life-year saved

Annual treatment cost, The 5-year cost to treat a patient diagnosed at stage Aa is approximately by stagea at diagnosis 73% of the 5-year cost to treat if the patient was diagnosed at stage Ca

If 5-year treatment costs were the same, regardless of stage at diagnosis, the cost per life-year saved would be higher, at approximately $28,000

Cost of screening

The expected cost of annual screening and follow-up is $241 for each screened patient

If annual screening cost per person was $500, the cost per life-year saved would be approximately $25,000

Stagea at diagnosis

Distribution of stage at diagnosis is consistent with the I-ELCAP experience,12 with 78% at stage Aa

If diagnosed patients exhibit the stage distribution reported in NLST (63% at local early-stage disease),13 the cost per life-year saved would be approximately $24,000

Lung cancers inside/ outside screened population

Of lung cancer in patients aged 55-80 years, 80% occur in the population eligible for screening, and 20% of lung cancers occur among those lower-risk patients outside of the target population

If lower-risk females (not eligible for screening) account for patients with lung cancer at twice the rate as males (40% and 20%, respectively), females would cost approximately $16,000 per life-year saved, and the overall cost per life-year saved would be approximately $20,000. If only 50% of all lung cancers occur among the screening-eligible population, the cost per life-year saved would be approximately $22,000

Overdiagnosis/pseudodisease

No pseudo-disease

If 20% more patients are identified with stage Aa cancer, without any reduction in the number of patients with stage Ba or Ca cancers, the cost per life-year saved would be $20,000

For this cost analysis, cancer stage was designated as A, B, or C based on treatment patterns for patients in the 9-month p­ eriod after diagnosis.

I-ELCAP indicates International Early Lung Cancer Action Program; NLST, National Lung Screening Trial.

a

alive in 2014, until their death or until age 110 years, if earlier. Consistent with Table 1, “true life-years saved” does not include the life-years associated with lead time.

The cumulative extra cost reflects the expected cost of annual screening and follow-up ($241) for all eligible Medicare patients for every year. It includes offsets for the reduced cost associated with earlier stage treatment and is increased by extra costs of treatment for additional years (see Appendix online). This cost is useful only in the context of the model’s calculation of cost per life-year saved, because it is not necessarily calculated to be consistent with Medicare’s own multiyear financial projections.

Overall, we estimated that 1 life-year is saved at a cost of approximately $18,452. The earlier treatment of lung cancer enabled by early diagnosis through screening increases the average life expectancy of people who are screened, as well as that of the entire Medicare population.

Without screening, patients newly diagnosed with lung cancer who are covered by Medicare have an average life expectancy of approximately 3 years. Screening results in an additional life expectancy of approximately 4 years for patients incremental to the life expectancy without screening, and with a greater improvement for younger patients.

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Women with late-stage lung cancer lose more life expectancy than do men. As a result, systematic screening and earlier treatment can save relatively more lifeyears for screening-eligible women than for screening-­ eligible men. The cost of 1 life-year saved for a woman is approximately $15,085.

The costs and benefits of screening differed according to our sensitivity scenarios (Figure 2). Figure 2 illustrates various sensitivity analyses of cost per 1 life-year saved, based on changes in key assumptions. The base-case scenario shows that 1 life-year is saved at a cost of approximately $18,452. The main base-case and sensitivity assumptions for the key model components are outlined in Table 4.

Lung and Other Cancer Screenings The published estimates for the cost per life-year saved for the screening of breast, cervical, and colorectal cancers, trended to 2012 dollars, are reported elsewhere.24 The cost per life-year saved figures reported here for LDCT lung cancer screening in the Medicare population are comparable with or lower than the estimates for the other cancer screenings.37 From the standpoint of

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cost per life-year saved, lung cancer with LDCT meets or exceeds the value of these other screenings. It is worth noting that the cost per life-year saved figures for other cancers cited above were performed when screening and treatment costs were much lower than today’s costs, and when practices and therapies might have been different.

Discussion The Medicare program is one of the world’s largest health insurers, and using life and health actuarial techniques and actual Medicare data to model financial and mortality outcomes helps to make our forecasts more realistic and relevant to Medicare practices and procedures. Important assumptions in this present study, such as the types of biopsies, the cost of treatment, and the mortality rates, reflect real-world “community practice” rather than assumptions from clinical trials.

Lung cancer screening is cost-effective for several reasons. First, suspicious nodules can be assessed for changes in nodule volume without biopsy between LDCT screenings. Second, the high-risk, 4.9 million Medicare population that is the target for lung cancer screening is smaller than the target population for other cancer screenings. Third, lung cancer detected in symptomatic patients is much more often rapidly fatal than is the case in other cancers; thus, the number of life-years saved by screening for lung cancer is greater than the number in other cancer screenings.

Our estimates related to the cost of lung cancer screening are more favorable than the NLST findings because (1) the NLST design required trial termination if the difference in mortality between the 2 study arms was >20%,13 and (2) the assumptions based on improved screening strategies, notably what have become established protocols for follow-up, were not part of the NLST. In particular, “volume change analysis,” which measures the volume growth rate of a suspicious clinical nodule in serial LDCT scans across a defined time interval, reduces the need for biopsies.38,39 Given the benefits of lung cancer screening, adherence to screening in the target Medicare population should be encouraged. Full adherence is ideal, but we believe that our assumption of 50% uptake to estimate the PMPM cost to Medicare in an average year will still require substantial efforts to inform primary care physicians and high-risk individuals.

Medicare uses numerous tools to police the quality of services provided to beneficiaries. These include retrospective audits to detect billing errors, fraud (ie, making false statements or misrepresenting the facts to obtain payment or benefit), and abuse (eg, misusing codes on a claim, overcharging for services or supplies, and billing for services that were not medically necessary).40 We

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believe that these tools can be used to ensure the efficient and safe rollout of LDCT screening across the entire Medicare population. Medicare may choose to implement quality programs in different ways by region to determine which work best. In addition, the assignment of a separate Current Procedural Terminology®(CPT®) code for LDCT lung cancer screening would help to distinguish screening from nonscreening diagnostics, help to avoid the use of high-dose CTs, and make it easier to track other quality metrics (eg, appropriate follow-up and the portion of cancers detected by screening).

We note that in its June 30, 2014, update of procedure codes (effective October 2014), CMS has assigned a new CPT code, S8032, for LDCT for lung cancer screening.41 National professional organizations have or are developing certification standards that will allow widespread lung cancer screening with appropriate quality controls, such as those of the American College of Radiology Lung Imaging Reporting and Data System.42 Follow-up on nodules depends on the size of the nodule and whether it appears on the initial baseline screening or a subsequent annual screening. Most nodules requiring follow-up are resolved without biopsy through subsequent LDCT scans. Even so, biopsy complications have declined over time with minimally invasive surgical techniques. Our cost of screening assumes that nodules ≥6 mm are followed up after the initial LDCT scan.29 Although we did not explicitly examine the benefits of smoking cessation in our model, adding smoking-­ cessation programs to a commercial population LDCT screening program improved the program’s cost-effectiveness by between 20% and 45%.43,44 A recent retrospective analysis of the NLST data showed that patients with suspicious findings on LDCT scans quit smoking at high rates, regardless of whether the finding was cancerous, thus supporting the view that lung cancer screening offers a “teachable moment.”45

Limitations We acknowledge several limitations in our study design. First, we appreciate that no one source can provide all of the necessary data46; however, using multiple sources can produce confounding results. The trial populations on which we based our stage-shift assumptions could have had different characteristics than those in the larger population.

We understand that screening costs could be higher and that benefits could be lower than those shown in our findings under different conditions (eg, if the screening population includes individuals other than the high-risk population, or if follow-up care differs from that in the clinical trial settings). Alternatively, the costs could be lower and the benefits of screening might be higher. The

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costs to treat early stage lung cancer could decrease with the identification of very early stage lung cancers, more emphasis on minimally invasive surgery, and other treatment innovations.

In addition, our cost per life-year saved results are the differences in costs and life-years between the status quo and the screening scenarios, and some potential biases in assumptions (eg, excessively high smoker mortality or systemically too-low costs of treatment for cancer) would apply to both scenarios. Nonetheless, we believe that our calculations of the cost per life-year saved of screening offer reliable comparisons with respect to the cost of other services, because such calculations are often based on assumptions from clinical trials.

Finally, we did not take into account the likely positive effects of the smoking-cessation counseling built into each screening session or effects on productivity, taxes, disability, life insurance costs, or the likely additional costs incurred by Social Security programs because of survivorship from lung cancer.

Conclusions If all eligible Medicare beneficiaries had been screened and treated consistently from age 55 years, approximately 358,134 additional individuals with current or past lung cancer would be alive in 2014. Our study demonstrates that for the high-risk Medicare population of smokers and former smokers, LDCT screening for lung cancer is low cost, as well as cost-effective. The cost, incidence rates, mortality rates, and other parameters presented in this study represent real-world, community practice data and are consistent with Medicare processes and procedures. LDCT screening for lung cancer fits well within the current standard Medicare benefit. The widespread LDCT screening of Medicare beneficiaries would allow the use of Medicare claims data to identify key outcomes within months, and this information could be used to further refine actual practice. Designing and establishing systems to immediately track these data and to quickly identify best practices would be an exemplar of a rapid, patient-centered system change.

Furthermore, LDCT screening has the ability to identify other disease states that are prevalent in the screened age-group and among smokers and former smokers, such as coronary artery disease, aortic aneurysms, other thoracic tumors, and upper abdominal tumors. n Acknowledgment The authors would like to thank Kathleen Wildasin for her editorial support.

Funding Source The study was funded by the Early Diagnosis and Treat-

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ment Research Foundation, whose main source of funding for this project came from a grant from the Medical Imaging & Technology Alliance, a division of the National Electrical Manufacturers Association.

Author Disclosure Statement Mr Pyenson provides actuarial consulting services to General Electric and Covidien, and is an employee of Milliman, Inc, which provides actuarial consulting services to numerous health insurance organizations, pharmaceutical and device manufacturers, and advocacy groups. Dr Henschke has received grants from Flight Attendant Medical Research Institute and the American Legacy Foundation during and outside of this study and is the President of the Early Diagnosis and Treatment Research Foundation. Dr Yankelevitz is a named inventor on several patents and patent applications relating to the evaluation of diseases of the chest, including measurement of nodules, some of which are owned by Cornell Research Foundation and are nonexclusively licensed to General Electric, and for which Dr Yankelevitz is entitled to a share of any compensation which Cornell Research Foundation may receive from its commercialization of these patents. Ms Yip reported no conflicts of interest. Ms Dec provides actuarial consulting services to General Electric and Covidien, and is an employee of Milliman, Inc. Milliman Inc. was paid for their work on this project.

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7. US Preventive Services Task Force. AHRQâ&#x20AC;&#x2122;s support of the USPSTF. Fact sheet. www.uspreventiveservicestaskforce.org/bulletins/ahrqsupportfact.pdf. Accessed June 18, 2014.

8. US Preventive Services Task Force. Grade definitions. May 2008. www.uspreventive servicestaskforce.org/uspstf/grades.htm. Accessed July 29, 2014.

9. Kauffman L. New analysis bolsters validity of low-dose CT screening for lung cancer. Radiol Bus J. May 30, 2013. www.imagingbiz.com/topics/business/new-analysisbolsters-validity-low-dose-ct-screening-lung-cancer. Accessed July 29, 2014.

10. Humphrey L, Deffebach M, Pappas M, et al. Screening for lung cancer: systematic review to update the U.S. Preventive Services Task Force recommendation.

Evidence Synthesis No. 105. AHRQ Publication No. 13-05188-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; July 2013. www.uspreventive servicestaskforce.org/uspstf13/lungcan/lungcanes103.pdf. Accessed August 3, 2014.

11. Mulshine JL, Sullivan DC. Clinical practice. Lung cancer screening. N Engl J Med. 2005;352:2714-2720.

12. Henschke CI, Yankelevitz DF, McCauley DI, et al; for the International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;355:1763-1771. Errata in: N Engl J Med. 2008;359:871-873; N Engl J Med. 2008;358:1862; and N Engl J Med. 2008;358:1875.

13. Aberle DR, Adams AM, et al; for the National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screen-

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ing. N Engl J Med. 2011;365:395-409.

14. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet. 1999;354:99-105.

15. Sobue T, Moriyama N, Kaneko M, et al. Screening for lung cancer with low-dose helical computed tomography: Anti-Lung Cancer Association project. J Clin Oncol.

2002;20:911-920.

16. Sone S, Nakayama T, Honda T, et al. Long-term follow-up study of a population-based 1996-1998 mass screening programme for lung cancer using mobile lowdose spiral computed tomography. Lung Cancer. 2007;58:329-341.

17. Veronesi G, Maisonneuve P, Rampinelli C, et al. Computed tomography screening for lung cancer: results of ten years of annual screening and validation of cosmos prediction model. Lung Cancer. 2013;82:426-430.

18. Henschke CI. International Early Lung Cancer Action Program: enrollment and screening protocol. April 1, 2014. www.ielcap.org/sites/default/files/I-ELCAP%20 protocol-v21-3-1-14.pdf. Accessed June 16, 2014.

19. Hanley JA, McGregor M, Liu Z, et al. Measuring the mortality impact of breast cancer screening. Can J Public Health. 2013;104:e437-e442.

20. Miettinen OS, Henschke CI, Pasmantier MW, et al. Mammographic screening: no reliable supporting evidence? Lancet. 2002;359:404-405.

21. Wang T, Nelson RA, Bogardus A, Grannis FW Jr. Five-year lung cancer survival: which advanced stage nonsmall cell lung cancer patients attain long-term survival? Cancer. 2010;116:1518-1525.

22. Yankelevitz DF, Smith JP. Understanding the core result of the National Lung Screening Trial. N Engl J Med. 2013;368:1460-1461. Erratum in: N Engl J Med. 2013;368:1757.

23. National Cancer Institute. Table 15.10: cancer of the lung and bronchus (invasive): SEER incidence and U.S. death rates, age-adjusted and age-specific rates, by race and sex. In: Altekruse SF, Kosary CL, Krapcho M, et al, eds; National Cancer Institute. SEER cancer statistics review 1975-2007. 2010. Revised January 7, 2011. http://seer.cancer.gov/csr/1975_2007/results_merged/sect_15_lung_bronchus.pdf.

Accessed August 3, 2014.

24. Pyenson BS, Sander MS, Jiang Y, et al. An actuarial analysis shows that offering lung cancer screening as an insurance benefit would save lives at relatively low cost.

Health Aff (Millwood). 2012;31:770-779.

25. US Census Bureau. 2012 National population projections. Table 1: Projected population by single year of age, sex, race, and Hispanic origin for the United States: 2012 to 2060. Middle series. www.census.gov/population/projections/files/download ables/NP2012_D1.csv. Accessed July 31, 2014.

26. International Early Lung and Cardiac Action Program: Pathology protocol.

March 1, 2007. www.ielcap.org/sites/default/files/pathology_protocol.pdf. Accessed July 22, 2014.

27. Carter D, Vazquez M, Flieder DB, et al; for the ELCAP, NY-ELCAP Investigators. Comparison of pathologic findings of baseline and annual repeat cancers diagnosed on CT screening. Lung Cancer. 2007;56:193-199.

28. New York Early Lung Cancer Action Project Investigators, Henschke CI, Yankelevitz DF, McCauley DI, et al. CT screening for lung cancer: diagnoses resulting from the New York Early Lung Cancer Action Project. Radiology. 2007;243:239-249.

29. Henschke CI, Yip R, Yankelevitz DF, Smith JP; for the International Early Lung Cancer Action Program Investigators. Definition of a positive test result in computed

tomography screening for lung cancer: a cohort study. Ann Intern Med. 2013;158: 246-252.

30. Centers for Medicare & Medicaid Services. Physician fee schedule look-up tool. www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/PFSlookup/index.html.

Accessed August 3, 2014.

31. US Department of Health & Human Services. Percentage of adults who receive colorectal cancer screening as appropriate. https://healthmeasures.aspe.hhs.gov/ measure/25. Accessed August 3, 2014.

32. National Cancer Institute. Review: summary staging. http://training.seer.cancer. gov/ss2k/staging/review.html. Accessed June 16, 2014.

33. Centers for Disease Control and Prevention. Lung cancer: what are the risk factors? Updated November 21, 2013. www.cdc.gov/cancer/lung/basic_info/risk_factors. htm. Accessed August 3, 2014.

34. Henschke CI, Yankelevitz DF, Yip R, et al; for the Writing Committee for the I-ELCAP Investigators. Lung cancers diagnosed at annual CT screening: volume doubling times. Radiology. 2012;263:578-583. Erratum in: Radiology. 2012;264:306.

35. Goldberg SW, Mulshine JL, Hagstrom D, Pyenson BS. An actuarial approach to comparing early stage and late stage lung cancer mortality and survival. Popul Health Manag. 2010;13:33-46.

36. Medicare Payment Advisory Commission. Data book: health care spending and the Medicare program. June 2014. www.medpac.gov/documents/Jun14DataBook EntireReport.pdf. Accessed July 30, 2014.

37. Gross CP, Long JB, Ross JS, et al. The cost of breast cancer screening in the Medicare population. JAMA Intern Med. 2013;173:220-226.

38. Field JK, Smith RA, Aberle DR, et al; for the IASLC CT Screening Workshop 2011 Participants. International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 report. J Thorac Oncol. 2012;7:10-19.

39. Yankelevitz DF, Reeves AP, Kostis WJ, et al. Small pulmonary nodules: volumetrically determined growth rates based on CT evaluation. Radiology. 2000;217:251-256.

40. US Department of Health & Human Services. Medicare fraud & abuse: prevention, detection, and reporting. Fact sheet. November 2012. www.cms.gov/Outreach-­ and-Education/Medicare-Learning-Network-MLN/MLNProducts/Downloads/ Fraud_and_Abuse.pdf. Accessed June 6, 2014.

41. Centers for Medicare & Medicaid Services. HCPCS quarterly update: other codes effective October 1, 2014. www.cms.gov/Medicare/Coding/HCPCSRelease CodeSets/Downloads/Other-Codes-Effective-100114.zip. Accessed June 6, 2014.

42. American College of Radiology. Lung CT Screening Reporting and Data System (Lung-RADS). www.acr.org/Quality-Safety/Resources/LungRADS. Accessed June 6, 2014.

43. Villanti AC, Jiang Y, Abrams DB, Pyenson BS. A cost-utility analysis of lung cancer screening and the additional benefits of incorporating smoking cessation interventions. PLoS One. 2013;8:e71379.

44. Deppen SA, Grogan EL, Aldrich MC, Massion PP. Lung cancer screening and smoking cessation: a teachable moment? J Natl Cancer Inst. 2014;106:dju122.

45. Tammemägi MC, Berg CD, Riley TL, et al. Impact of lung cancer screening results on smoking cessation. J Natl Cancer Inst. 2014;106:dju084.

46. Actuarial Standards Board. Actuarial Standards of Practice No. 23. Data quality.

December 2004. Updated May 1, 2011. www.actuarialstandardsboard.org/pdf/asops/ asop023_141.pdf. Accessed July 23, 2014.

Stakeholder Perspective Cost-Effectiveness and the Medicare Budget

By Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care and Retirement Policy, American Enterprise Institute, Washington, DC

PAYERS/RESEARCHERS: How should Medicare decide whether to expand coverage to its beneficiaries to include a new medical technology, or a new application of an existing technology? According to the Centers for Medicare & Medicaid Services (CMS), Medicare coverage is “limited to items and services that are reasonable and necessary for the diagnosis or treatment of an illness or injury.”1 Millions of lives and billions of dollars can be at stake, depending on how CMS determines whether a technology is reasonable and necessary.

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Although the effectiveness of a technology in diagnosing or treating a disease is an important factor in a coverage decision, cost-effectiveness analysis is not formally considered by CMS, despite the long-standing concern that Medicare spending is growing at an unsustainable rate. The concerns range from skepticism about the methods used in cost-effectiveness analyses to fears that such analyses could be used to ration care.

Perhaps the best-known critique of cost-effectiveness methodology was delivered by Kassirer and Angell in a Continued

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REGULATORY

Stakeholder Perspective Continued 1994 editorial in the New England Journal of Medicine.2 They pointed out that cost-effectiveness analysis is a modeling exercise that depends critically on the data and the assumption used. Consequently, there can be ambiguity in the results, and various studies could yield different conclusions about the cost-effectiveness of a particular technology.2 That is certainly true, but hardly a disqualification.

The study by Pyenson and colleagues in this issue of American Health & Drug Benefits is a case in point.3 Their meticulous analysis depends critically on assumptions regarding the incidence of disease, the rate at which high-risk individuals would use low-dose computed tomography (LDCT) screening for lung cancer, the rate of subsequent treatment, the cost of such screening and subsequent treatment, and other factors. Different assumptions—such as those regarding the rate of overdiagnosis4 and subsequent testing and treatment that could have been avoided—could result in higher estimated costs than these investigators find.

The present study by Pyenson and colleagues, which is focused on patients with lengthy histories of heavy smoking who are most likely to develop lung cancer, demonstrates the need for Medicare coverage to pair the LDCT technology with the population most likely to benefit from it.

Clinical trials are not immune to such uncertainty, despite their methodologic purity. Actual patient populations and providers who care for them cannot be counted on to do everything according to the research protocol. Any analysis of the costs and benefits of a technology before its general adoption is a prediction, not a certainty.

POLICYMAKERS: The real issue is how the results of a cost-effectiveness analysis are used. Policymakers have distanced themselves from any hint of government rationing of healthcare. In establishing the Patient-Centered Outcomes Research Institute, Congress prohibited the US Secretary of Health & Human Services from

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using a cost-effectiveness standard to determine coverage or payment by Medicare.5 Nonetheless, there remains a concern that budgetary pressures could increasingly favor technologies with low estimated costs per quality-adjusted life-year, without sufficient flexibility to account for variations in the health needs of patients.

Ironically, cost-effectiveness analyses may not lead to reductions in Medicare spending.6 The coverage process is like an iceberg: it focuses on new technologies, which are likely to account for a small fraction of Medicare spending, while largely ignoring services that are already covered and account for the bulk of its spending. It is simply not feasible to do a full review of all past coverage decisions. As a result, there is a built-in bias toward more—not less—spending, regardless of the analytic tools used to drive coverage decisions.

The best strategy is the obvious one. Medicare should use all of the information that is available in its coverage decisions, including cost-effectiveness analysis. For technologies that offer great potential benefits but also great potential cost, coverage with evidence development— temporary coverage targeted at specific patient populations, which allows detailed data collection on all aspects of the treatment—could be a useful approach.

The present study by Pyenson and colleagues, which is focused on patients with lengthy histories of heavy smoking who are most likely to develop lung cancer, demonstrates the need for Medicare coverage to pair the LDCT technology with the population most likely to benefit from it. The coverage decision takes us only part of the way to that goal. Both patients and the Medicare program rely on the physician to make that judgment at the point of service. n 1. Centers for Medicare & Medicaid Services. Medicare coverage determination process. Updated November 27, 2013. www.cms.gov/Medicare/Coverage/Determination Process/index.html. Accessed August 9, 2014.

2. Kassirer JP, Angell M. The journal’s policy on cost-effectiveness analyses. N Engl J Med. 1994;331:669-670.

3. Pyenson BS, Henschke CI, Yankelevitz DF, et al. Offering lung cancer screening to high-risk Medicare beneficiaries saves lives and is cost-effective: an actuarial analysis. Am Health Drug Benefits. 2014;7:272-282.

4. Patz EF Jr, Pinsky P, Gatsonis C, et al; for the NLST Overdiagnosis Manuscript Writing Team. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med. 2014;174:269-274. Erratum in: JAMA Intern Med. 2014;174:828.

5. The Patient Protection and Affordable Care Act, HR 3590, 111th Congress, 2nd Session (2010), §6301.

6. Neumann PJ, Rosen AB, Weinstein MC. Medicare and cost-effectiveness analysis.

N Engl J Med. 2005;353:1516-1522.

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Call for Papers Cardiometabolic Health Theme Issue American Health & Drug Benefits will be publishing a theme issue on Cardiometabolic Health in 2014 Readers are invited to submit articles for publication in this theme issue on topics relevant to the clinical, business, and policy aspects of cardiometabolic health and wellness. Original research, comparative effectiveness analyses, cost-effective analyses, evidence-based systematic reviews, and case studies are of particular interest. All articles will undergo the journal’s rigorous peer-review process and acceptance is contingent on that review.

Topics of high interest include:

• Insulin resistance and type 2 diabetes

• Benefit designs to improve cardiometabolic outcomes

• Lifestyle strategies and cardiometabolic health and wellness

• Best practices in insulin control, lipid management, blood pressure control

• Lipid management in patients with diabetes

• Cardiovascular disease: diagnosis and treatment

• Medication adherence • New biomarkers for assessing cardiometabolic risk

• Comparative effectiveness analyses • Cost-effective analyses of current therapies • Current recommendations for optimizing A1c target outcomes • Diabetes management and prevention

• Optimal therapies for cardiovascular disease, diabetes, and/or obesity • Pharmacoeconomic analyses

• Employers’ strategies to enhance employees’ cardiometabolic wellness • Health plan initiatives for cardiometabolic health and prevention • Hot topics in diabetes management

• New therapies for diabetes, cardiovascular disease, or obesity

• Prevention strategies for cardiovascular disease • Wellness programs for patients with heart disease, diabetes, obesity

New submission deadline: September 12, 2014 Submit articles at www.AHDBonline.com Articles must follow the Manuscript Instructions for Authors, available online

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For your members with chronic obstructive pulmonary disease (COPD) who require maintenance bronchodilator treatment

Consider once-daily ANORO ELLIPTA for formulary inclusion

Indication • ANORO ELLIPTA is a combination anticholinergic/long-acting beta2-adrenergic agonist indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

• ANORO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

Important Safety Information for ANORO ELLIPTA WARNING: ASTHMA-RELATED DEATH • Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in ANORO ELLIPTA, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol.

This finding with salmeterol is considered a class effect of all LABA, including vilanterol.

• The safety and efficacy of ANORO ELLIPTA in patients with asthma have not been established.

ANORO ELLIPTA is not indicated for the treatment of asthma.

CONTRAINDICATIONS • The use of ANORO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to umeclidinium, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS • ANORO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. • ANORO ELLIPTA should not be used for the relief of acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

• ANORO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Patients using ANORO ELLIPTA should not use another medicine containing a LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

• Caution should be exercised when considering the coadministration of ANORO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (eg, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased cardiovascular adverse effects may occur.

• If paradoxical bronchospasm occurs, discontinue ANORO ELLIPTA and institute alternative therapy.

• Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ANORO ELLIPTA may need to be discontinued. ANORO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

The first and only FDA-approved product for patients with COPD combining 2 long-acting bronchodilators in 1 inhaler Contact your GSK Account Manager to schedule a presentation

Important Safety Information for ANORO ELLIPTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a physician immediately if signs or symptoms of acute narrow-angle glaucoma develop.

• Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a physician immediately if signs or symptoms of urinary retention develop.

• Be alert to hypokalemia and hyperglycemia.

ADVERSE REACTIONS • The most common adverse reactions (≥1% and more common than placebo) reported in four 6-month clinical trials with ANORO ELLIPTA (and placebo) were: pharyngitis, 2% (<1%); sinusitis, 1% (<1%); lower respiratory tract infection, 1% (<1%); constipation, 1% (<1%); diarrhea, 2% (1%); pain in extremity, 2% (1%); muscle spasms, 1% (<1%); neck pain, 1% (<1%); and chest pain, 1% (<1%).

• In addition to the 6-month efficacy trials with ANORO ELLIPTA, a 12-month trial evaluated the safety of umeclidinium/vilanterol 125 mcg/25 mcg in subjects with COPD. Adverse reactions (incidence ≥1% and more common than placebo) in subjects receiving umeclidinium/vilanterol 125 mcg/25 mcg were: headache, back pain, sinusitis, cough, urinary tract infection, arthralgia, nausea, vertigo, abdominal pain, pleuritic pain, viral respiratory tract infection, toothache, and diabetes mellitus.

DRUG INTERACTIONS • Caution should be exercised when considering the coadministration of ANORO ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors (eg, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic exposure to vilanterol and cardiovascular adverse effects may occur.

• ANORO ELLIPTA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists, such as vilanterol, on the cardiovascular system may be potentiated by these agents.

• Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with COPD. • Use with caution in patients taking non–potassium-sparing diuretics, as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists.

• Avoid coadministration of ANORO ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for ANORO ELLIPTA on the following pages.

ANORO ELLIPTA was developed in collaboration with

BRIEF SUMMARY ANOROTM ELLIPTATM (umeclidinium and vilanterol inhalation powder) FOR ORAL INHALATION USE The following is a brief summary only; see full prescribing information for complete product information.

WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABA, including vilanterol, one of the active ingredients in ANORO ELLIPTA [see Warnings and Precautions (5.1)].

The safety and efficacy of ANORO ELLIPTA in patients with asthma have not been established. ANORO ELLIPTA is not indicated for the treatment of asthma.

1 INDICATIONS AND USAGE ANORO ELLIPTA is a combination anticholinergic/long-acting beta2-adrenergic agonist (anticholinergic/LABA) indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Important Limitations of Use: ANORO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

4 CONTRAINDICATIONS The use of ANORO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to umeclidinium, vilanterol, or any of the excipients [see Warnings and Precautions (5.6), Description (11) of full Prescribing Information].

5 WARNINGS AND PRECAUTIONS 5.1 Asthma-Related Death • Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by LABA. • A 28-week, placebo-controlled, US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in ANORO ELLIPTA. • No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with ANORO ELLIPTA has been conducted. The safety and efficacy of ANORO ELLIPTA in patients with asthma have not been established. ANORO ELLIPTA is not indicated for the treatment of asthma.

5.2 Deterioration of Disease and Acute Episodes ANORO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. ANORO ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of ANORO ELLIPTA in this setting is not appropriate.

ANORO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. ANORO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

When beginning treatment with ANORO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing ANORO ELLIPTA, the healthcare provider should also prescribe an inhaled, shortacting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled, short-acting beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If ANORO ELLIPTA no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once.

Increasing the daily dose of ANORO ELLIPTA beyond the recommended dose is not appropriate in this situation.

5.3 Excessive Use of ANORO ELLIPTA and Use With Other Long-Acting Beta2-Agonists ANORO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ANORO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.4 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of ANORO ELLIPTA with long-term ketoconazole and other known strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3) of full Prescribing Information].

5.5 Paradoxical Bronchospasm As with other inhaled medicines, ANORO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with ANORO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; ANORO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

5.6 Hypersensitivity Reactions Hypersensitivity reactions may occur after administration of ANORO ELLIPTA. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not use ANORO ELLIPTA [see Contraindications (4)].

5.7 Cardiovascular Effects Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms [see Clinical Pharmacology (12.2) of full Prescribing Information]. If such effects occur, ANORO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown.

Therefore, ANORO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.8 Coexisting Conditions ANORO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.9 Worsening of Narrow-Angle Glaucoma ANORO ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

5.10 Worsening of Urinary Retention ANORO ELLIPTA should be used with caution in patients with urinary retention.

Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

5.11 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medicines may produce transient hyperglycemia in some patients. In 4 clinical trials of 6-month duration evaluating ANORO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

6 ADVERSE REACTIONS LABA, such as vilanterol, one of the active ingredients in ANORO ELLIPTA, increase the risk of asthma-related death. ANORO ELLIPTA is not indicated for the treatment of asthma. [See Boxed Warning and Warnings and Precautions (5.1).]

The following adverse reactions are described in greater detail in other sections: • Paradoxical bronchospasm [see Warnings and Precautions (5.5)] • Cardiovascular effects [see Warnings and Precautions (5.7)]

• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.9)] • Worsening of urinary retention [see Warnings and Precautions (5.10)] 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The clinical program for ANORO ELLIPTA included 8,138 subjects with COPD in four 6-month lung function trials, one 12-month long-term safety study, and 9 other trials of shorter duration. A total of 1,124 subjects have received at least 1 dose of ANORO ELLIPTA (umeclidinium/vilanterol 62.5 mcg/25 mcg), and 1,330 subjects have received a higher dose of umeclidinium/vilanterol (125 mcg/25 mcg).

The safety data described below are based on the four 6-month and the one 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.

6-Month Trials: The incidence of adverse reactions associated with ANORO ELLIPTA in Table 1 is based on four 6-month trials: 2 placebo-controlled trials (Trials 1 and 2; n = 1,532 and n = 1,489, respectively) and 2 active-controlled trials (Trials 3 and 4; n = 843 and n = 869, respectively). Of the 4,733 subjects, 68% were male and 84% were Caucasian. They had a mean age of 63 years and an average smoking history of 45 pack-years, with 50% identified as current smokers. At screening, the mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV1) was 48% (range: 13% to 76%), the mean post-bronchodilator FEV1/forced vital capacity (FVC) ratio was 0.47 (range: 0.13 to 0.78), and the mean percent reversibility was 14% (range: -45% to 109%).

Subjects received 1 dose once daily of the following: ANORO ELLIPTA, umeclidinium/ vilanterol 125 mcg/25 mcg, umeclidinium 62.5 mcg, umeclidinium 125 mcg, vilanterol 25 mcg, active control, or placebo.

Table 1. Adverse Reactions With ANORO ELLIPTA With ≥1% Incidence and More Common Than With Placebo in Subjects With Chronic Obstructive Pulmonary Disease Placebo (n = 555) %

ANORO ELLIPTA (n = 842) %

<1 <1

2 1

1 <1

2 1

<1

1

<1

<1

Gastrointestinal disorders Constipation Diarrhea

<1 1

1 2

<1 <1

<1 2

Musculoskeletal and connective tissue disorders Pain in extremity Muscle spasms Neck pain

1 <1 <1

2 1 1

<1 <1 <1

2 <1 <1

General disorders and administration site conditions Chest pain

<1

1

<1

<1

T:10.5”

S:9.5”

B:11.25”

Adverse Reaction Infections and infestations Pharyngitis Sinusitis Lower respiratory tract infection

Umeclidinium Vilanterol 62.5 mcg 25 mcg (n = 418) (n = 1,034) % %

Other adverse reactions with ANORO ELLIPTA observed with an incidence less than 1% but more common than with placebo included the following: productive cough, dry mouth, dyspepsia, abdominal pain, gastroesophageal reflux disease, vomiting, musculoskeletal chest pain, chest discomfort, asthenia, atrial fibrillation, ventricular extrasystoles, supraventricular extrasystoles, myocardial infarction, pruritus, rash, and conjunctivitis.

12-Month Trial: In a long-term safety trial, 335 subjects were treated for up to 12 months with umeclidinium/vilanterol 125 mcg/25 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo-controlled efficacy trials described above. Adverse reactions that occurred with a frequency of greater than or equal to 1% in the group receiving umeclidinium/vilanterol 125 mcg/25 mcg that exceeded that in placebo in this trial were: headache, back pain, sinusitis, cough, urinary tract infection, arthralgia, nausea, vertigo, abdominal pain, pleuritic pain, viral respiratory tract infection, toothache, and diabetes mellitus.

7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 Vilanterol, a component of ANORO ELLIPTA, is a substrate of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to vilanterol. Caution should be exercised when considering the coadministration of ANORO ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3) of full Prescribing Information].

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Vilanterol, like other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

7.3 Beta-Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, a component of ANORO ELLIPTA, but may produce severe bronchospasm in patients with COPD. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as vilanterol, a component of ANORO ELLIPTA, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of ANORO ELLIPTA with non– potassium-sparing diuretics.

7.5 Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of ANORO ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.9, 5.10), Adverse Reactions (6)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials of ANORO ELLIPTA or its individual components, umeclidinium and vilanterol, in pregnant women. Because animal reproduction studies are not always predictive of human response, ANORO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking ANORO ELLIPTA. Umeclidinium: There was no evidence of teratogenic effects in rats and rabbits at approximately 50 and 200 times, respectively, the MRHDID (maximum recommended human daily inhaled dose) in adults (on an AUC basis at maternal inhaled doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits).

Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 70 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 450 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals.

Nonteratogenic Effects: Umeclidinium: There were no effects on perinatal and postnatal developments in rats at approximately 80 times the MRHDID in adults (on an AUC basis at maternal subcutaneous doses up to 180 mcg/kg/day).

Vilanterol: There were no effects on perinatal and postnatal developments in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day).

8.2 Labor and Delivery There are no adequate and well-controlled human trials that have investigated the effects of ANORO ELLIPTA during labor and delivery.

Because beta-agonists may potentially interfere with uterine contractility, ANORO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk.

8.3 Nursing Mothers ANORO ELLIPTA: It is not known whether ANORO ELLIPTA is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be

exercised when ANORO ELLIPTA is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of ANORO ELLIPTA by nursing mothers, based on the data for the individual components, a decision should be made whether to discontinue nursing or to discontinue ANORO ELLIPTA, taking into account the importance of ANORO ELLIPTA to the mother.

Umeclidinium: It is not known whether umeclidinium is excreted in human breast milk. However, administration to lactating rats at approximately 25 times the MRHDID in adults resulted in a quantifiable level of umeclidinium in 2 pups, which may indicate transfer of umeclidinium in milk.

Vilanterol: It is not known whether vilanterol is excreted in human breast milk.

However, other beta2-agonists have been detected in human milk.

8.4 Pediatric Use ANORO ELLIPTA is not indicated for use in children. The safety and efficacy in pediatric patients have not been established.

8.5 Geriatric Use Based on available data, no adjustment of the dosage of ANORO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

Clinical trials of ANORO ELLIPTA for COPD included 2,143 subjects aged 65 and older and, of those, 478 subjects were aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

8.6 Hepatic Impairment Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls. Studies in subjects with severe hepatic impairment have not been performed [see Clinical Pharmacology (12.3) of full Prescribing Information].

8.7 Renal Impairment There were no significant increases in either umeclidinium or vilanterol exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3) of full Prescribing Information].

10 OVERDOSAGE No case of overdose has been reported with ANORO ELLIPTA. ANORO ELLIPTA contains both umeclidinium and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to ANORO ELLIPTA. Treatment of overdosage consists of discontinuation of ANORO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm.

Cardiac monitoring is recommended in cases of overdosage.

10.1 Umeclidinium High doses of umeclidinium may lead to anticholinergic signs and symptoms.

However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD. 10.2 Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility ANORO ELLIPTA: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with ANORO ELLIPTA; however, studies are available for individual components, umeclidinium and vilanterol, as described below.

Umeclidinium: Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 mcg/kg/day and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively).

Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.

No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and inhaled doses up to 294 mcg/kg/ day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis).

Vilanterol: In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 7,800 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/ kg/day (approximately 210 times the MRHDID in adults on an AUC basis).

In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/ day (greater than or equal to approximately 20 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 1 time the MRHDID in adults on an AUC basis).

These tumor findings in rodents are similar to those reported previously for other betaadrenergic agonist drugs. The relevance of these findings to human use is unknown.

Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay.

Vilanterol tested equivocal in the in vitro mouse lymphoma assay.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (approximately 12,000 and 14,500 times, respectively, the MRHDID in adults on a mcg/m2 basis).

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Asthma-Related Death: Inform patients that LABA, such as vilanterol, one of the active ingredients in ANORO ELLIPTA, increase the risk of asthma-related death.

ANORO ELLIPTA is not indicated for the treatment of asthma.

Not for Acute Symptoms: Inform patients that ANORO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise them to treat acute symptoms with a rescue inhaler such as albuterol. Provide patients with such medicine and instruct them in how it should be used.

Instruct patients to seek medical attention immediately if they experience any of the following: • Symptoms get worse • Need for more inhalations than usual of their rescue inhaler Patients should not stop therapy with ANORO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta2-Agonists: Instruct patients to not use other medicines containing a LABA. Patients should not use more than the recommended once-daily dose of ANORO ELLIPTA. Instruct patients who have been taking inhaled, short-acting beta2-agonists on a regular basis to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.

Paradoxical Bronchospasm: As with other inhaled medicines, ANORO ELLIPTA can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue ANORO ELLIPTA. Risks Associated With Beta-Agonist Therapy: Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Worsening of Narrow-Angle Glaucoma: Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Worsening of Urinary Retention: Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination).

Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

ANORO and ELLIPTA are trademarks of GSK group of companies.

ANORO ELLIPTA was developed in collaboration with

.

GSK Research Triangle Park, NC 27709 ©2013, GSK group of companies. All rights reserved.

Revised 12/2013 ©2014 GSK group of companies.

All rights reserved. Printed in USA. MH3871R0 April 2014

ANR:1BRS

CLINICAL

Original Research

Impact of Linaclotide Treatment on Work Productivity and Activity Impairment in Adults with Irritable Bowel Syndrome with Constipation: Results from 2 Randomized, Double-Blind, Placebo-Controlled Phase 3 Trials

Jessica L. Buono, MPH; Stavros Tourkodimitris, PhD; Phil Sarocco, RPh, MSc; Jeffrey M. Johnston, MD; Robyn T. Carson, MPH Background: Irritable bowel syndrome with constipation (IBS-C), a chronic functional gastrointestinal disorder, has been shown to negatively affect work productivity and impair daily activity, resulting in a substantial burden for patients and employers. Linaclotide is a first-in-class guanylate cyclase-C agonist approved for the treatment of adults with IBS-C and chronic idiopathic constipation in the United States.

Objective: To analyze the impact of treatment with linaclotide on work productivity and daily activity impairment in adults with IBS-C and estimate the indirect costs associated with this condition.

Methods: This was a post-hoc analysis of data on IBS-C–related work time missed and work and activity impairment from 2 phase 3 clinical trials that assessed the efficacy and safety of linaclotide therapy in adults with IBS-C. The Work Productivity and Activity Impairment Questionnaire for IBS-C (WPAI:IBS-C) was self-administered at baseline and at weeks 4, 8, and 12 during the 12-week treatment periods in Trials 1 and 2 and at weeks 16, 20, and 26 during the extended treatment period in Trial 2. An analysis of covariance was conducted to assess changes from baseline to all study weeks for each WPAI:IBS-C measure. Indirect costs were calculated by converting overall work productivity losses into monetary values using the human capital cost approach.

Results: Of the 1602 patients with IBS-C who were randomized in the 2 clinical trials, 1555 (97.1%) completed a baseline and at least 1 postbaseline WPAI:IBS-C assessment and were included in the analysis cohort; 1148 (71.7%) of these patients were employed. Once-daily treatment with linaclotide significantly reduced overall work productivity loss and daily activity impairment among patients with IBS-C at all study weeks. From baseline to week 12, compared with placebo, linaclotide significantly reduced presenteeism by 5.2%, overall work productivity loss by 6.1%, and daily activity impairment by 4.7% (all P <.01) and led to a numerically greater decrease in absenteeism. From baseline to week 26, compared with placebo, reductions with linaclotide were 5.9% for presenteeism, 7.5% for overall work productivity loss, and 6.7% for daily activity impairment (all P <.05). Reductions in overall work productivity loss from baseline to week 26 translate to 103 hours to 156 hours annually and correspond to an avoided overall work loss of $3209 to $4861 annually for an employee with IBS-C. Conclusion: The results of this analysis indicate that appropriate treatment of IBS-C with medications such as linaclotide can reduce work-related impairment associated with IBS-C. In addition, IBS-C therapies that effectively manage this chronic condition and improve employees’ quality of life and work productivity may represent significant cost-savings for employers in the form of avoided work productivity losses.

I

rritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort accompanied by chang-

Stakeholder Perspective, page 296

Am Health Drug Benefits.

2014;7(5):289-297 www.AHDBonline.com Received March 28, 2014.

Accepted in final form June 15, 2014.

Disclosures are at end of text

es in bowel habits.1 IBS with constipation (IBS-C) is a subtype of IBS characterized by hard or lumpy stools for ≥25% of bowel movements and loose or watery stools for

Ms Buono is Manager, Health Economics and Outcomes Research, Forest Research Institute, LLC, a subsidiary of Actavis plc, Jersey City, NJ; Dr Tourkodimitris is Director, Biostatistics, Forest Research Institute, LLC, a subsidiary of Actavis plc, Jersey City, NJ; Mr Sarocco was Senior Director, Health Economics and Outcomes Research, Ironwood Pharmaceuticals, Cambridge, MA, during this study; Dr Johnston is Senior Principal Clinical Scientist, Clinical Affairs, Ironwood Pharmaceuticals, Cambridge, MA; and Ms Carson is Director, Health Economics and Outcomes Research, Forest Research Institute, LLC, a subsidiary of Actavis plc, Jersey City, NJ.

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Key Points Irritable bowel syndrome with constipation (IBS-C) negatively affects work productivity and impairs daily activity, resulting in a substantial burden for patients and employers. ➤ This is the first study to assess the impact of linaclotide therapy on work productivity and daily activity among patients with IBS-C and to analyze indirect costs associated with this condition. ➤ Among this study population, an average work productivity loss of 35.1% at baseline translated into a loss of 730 hours, or $22,747 in lost costs, annually, for each employed patient with IBS-C. ➤ Linaclotide therapy significantly reduced overall work productivity loss and daily activity impairment among patients with IBS-C at all study weeks. ➤ Therapies for IBS-C that effectively manage this chronic condition and improve work productivity may present opportunities for cost-savings for employers in the form of avoided work losses. ➤

<25% of bowel movements in the absence of an antidiarrheal or laxative use.1 IBS-C is estimated to affect 1.3% to 5.2% of the adult population in the United States2-5 and occurs more frequently in women than in men.6,7 Women have been found to have 1.33 times the odds of IBS compared with men overall,8 and nearly 2.5 times the odds of having the IBS-C subtype compared with men among patients with IBS.7,9 The prevalence of IBS has also been found to be highest among younger agegroups; patients aged >60 years have half the odds of having IBS compared with patients aged <40 years.8 The peak age range for patients who currently have symptoms of IBS was reported to be between 25 and 54 years.3 The symptom burden experienced by patients with IBS has been shown to negatively affect their health-­ related quality of life (HRQOL) and work productivity, and result in significant direct (ie, healthcare resource utilization) and indirect (ie, lost work productivity) costs.10-16 Although the majority of cost estimates focus on IBS overall rather than specific subtypes of IBS, with the direct cost estimates for inpatient, outpatient, physician, and prescription drug services ranging from $1674 (in 2010 USD) to $1896 (in 2010 USD) per patient annually, IBS-C has been shown to impose a substantial burden in direct healthcare costs for third-party payers, estimated at $3856 (in 2010 USD) in incremental costs per patient with IBS-C annually compared with matched controls in a commercially insured population.13-17 However, the total costs incurred by employers include the direct costs related to insurance payments for medical

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care, as well as the indirect costs associated with absenteeism (ie, missed days of work) and presenteeism (ie, impairment in productivity while at work).

Few studies report the indirect costs associated with IBS, and no studies to date have reported the indirect costs specifically for IBS-C. Considering that the majority (approximately 79%) of patients with IBS are of working age, the indirect costs and the associated economic impact on employers could be substantial.18 The indirect medical costs related to absenteeism have been estimated at approximately $3400 annually (in 2013 USD) for 1 employee with IBS, an excess of approximately $670 compared with the indirect costs of age- and sex-matched controls.14 Overall, lost work productivity resulting from absenteeism in patients with IBS has been estimated to result in $27 billion (in 2013 USD) in indirect costs annually for US employers.18 However, because these estimates only account for costs related to absenteeism, and IBS symptom-related losses in work productivity are predominantly driven by presenteeism rather than absenteeism, it is likely that these costs significantly under­ estimate the true economic burden of IBS to US employers.11,14,19-21 A previous analysis specific to IBS-C based on data from the US National Health and Wellness Survey showed that adults with IBS-C had significantly higher mean levels of presenteeism (31.7% vs 21.4%, respectively), overall work productivity loss (35.5% vs 25.3%, respectively), and daily activity impairment (45.8% vs 33%, respectively) compared with matched controls.19 This study, however, did not estimate the costs associated with lost work productivity.

Linaclotide, a minimally absorbed guanylate cyclase-C agonist, is a first-in-class therapy approved for the treatment of adults with IBS-C and chronic idiopathic constipation in the United States,22 and for moderate-to-severe IBS-C in Europe.23 In 2 randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 3 clinical trials in adults with IBS-C, treatment with linaclotide was shown to significantly improve abdominal and bowel symptoms.24,25 The effects of treatment with linaclotide on work productivity and daily activity, however, have not yet been described. The objective of this study was to evaluate the impact of treatment with linaclotide on work productivity and on daily activity impairment in adults with IBS-C using data from these 2 phase 3 clinical trials.

Methods Patient Population and Study Design Data on IBS-C–related work time missed and work and activity impairment were evaluated using informa-

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Linaclotide Therapy and Work Productivity in Adults with IBS-C

tion from 2 randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 3 IBS-C trials (henceforth, Trial 1 and Trial 2) for which clinical results have been reported previously.24,25 Briefly, adults meeting modified Rome II criteria1 for IBS-C were eligible to participate if they had the following symptoms for ≥12 weeks (which need not be consecutive) in the 12 months before the screening visit24,25: • Abdominal pain or abdominal discomfort associated with at least 2 of the following symptoms: – Relieved with defecation – Onset associated with a change in frequency of stool – And/or onset associated with a change in form (appearance) of stool • Less than 3 spontaneous bowel movements (defined as bowel movements occurring in the absence of laxative, enema, or suppository use during the 24 hours before the bowel movement) weekly • At least 1 additional bowel symptom (straining, lumpy or hard stools, and sensation of incomplete evacuation during >25% of bowel movements) weekly.

In addition, patients were required to have an average weekly score of ≥3 for daily abdominal pain at its worst (on an 11-point numerical rating scale), as well as <3 complete spontaneous bowel movements (defined as spontaneous bowel movements with a feeling of complete evacuation) and ≤5 spontaneous bowel movements weekly during the 14-day pretreatment period (ie, baseline period).

Eligible patients were randomized to receive an oral capsule of linaclotide 290 μg once daily or placebo for at least 12 weeks. Trial 1 included a 12-week treatment period, with an additional 4-week randomized withdrawal period,24 whereas Trial 2 featured a treatment period of 26 weeks.25 In both trials, the primary efficacy end points were assessed over the initial 12 weeks of treatment.24,25

Work Productivity and Activity Impairment Questionnaire The Work Productivity and Activity Impairment (WPAI) questionnaire is a self-administered questionnaire consisting of 6 items intended to assess work time missed and work and activity impairment during the past 7 days.26 Evidence of the validity and accuracy of the WPAI in patients with IBS (WPAI:IBS) has been previously published.27 The WPAI:IBS was modified for use in patients with IBS-C in phase 3 clinical trials of linaclotide by removing “diarrhea” from the description of symptoms related to IBS to ensure that the questionnaire was specific to the study population.

The WPAI:IBS-C measures 4 domains, including absenteeism (ie, work hours missed because of IBS-C),

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presenteeism (ie, the degree to which the symptoms of IBS-C affect productivity while at work), overall work productivity loss (ie, absenteeism plus presenteeism resulting from IBS-C), and daily activity impairment (the degree to which the symptoms of IBS-C affect regular daily activities, such as housework, shopping, child care, exercising, studying, etc). Patients with IBS-C who were randomized in the 2 trials completed a self-administered paper version of the WPAI:IBS-C at baseline and at weeks 4, 8, and 12 during the 12-week treatment period for each trial (Trial 1 and Trial 2). In Trial 2, patients also completed the WPAI:IBS-C at weeks 16, 20, and 26. The WPAI:IBS-C scores are represented as percentages, with higher percentages indicating greater work productivity loss and activity impairment.

Patient responses to the following questions on absenteeism, presenteeism, and daily activity impairment were used to calculate the scores for each measure: • Absenteeism (Q: During the past 7 days, how many hours did you miss from work because of problems associated with your IBS?) Calculation = [hours missed/(hours missed + hours worked)] × 100 • Presenteeism (Q: During the past 7 days, how much did IBS symptoms affect your productivity while you were working?)

Calculation = (item score/10) × 100 • Overall work productivity loss Calculation = [absenteeism + (hours worked × presenteeism)] × 100 • Daily activity impairment (Q: During the past 7 days, how much did IBS symptoms affect your ability to do your regular daily activities, other than work at a job?)

Calculation = (item score/10) × 100.

The WPAI:IBS-C was translated into US Spanish by bilingual translators through a harmonization process of forward and back translations.28,29

Statistical Analyses The analyses of all WPAI:IBS-C measures were based on the intent-to-treat (ITT) population and used the last postbaseline observation carried forward for missing assessments. The analysis cohort included patients with a baseline and at least 1 postbaseline WPAI:IBS-C assessment. The mean WPAI:IBS-C scores for daily activity impairment were computed for all patients. The mean scores for absenteeism, presenteeism, and overall work productivity loss were calculated for employed patients only.

Changes from baseline to weeks 4, 8, and 12 for all 4 WPAI:IBS-C scores for pooled phase 3 clinical trial data were assessed using an analysis of covariance

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emographic Characteristics and Mean Baseline Table 1 D WPAI:IBS-C Scores of the Pooled Analysis Cohort Placebo Linaclotide Total Demographics (N = 772) (N = 783) (N = 1555) Age Mean, yrs

43.9

44.1

44

43 (5.6)

41 (5.2)

84 (5.4)

687 (90)

717 (91.6)

1404 (90.3)

White, N (%)

593 (76.8)

616 (78.7)

1209 (77.8)

Other, N (%)

179 (23.2)

167 (21.3)

346 (22.3)

â&#x2030;Ľ65 yrs, N (%) Sex Female, N (%) Race

Baseline WPAI:IBS-C scores, mean Absenteeism, % (N)

2.8 (486)

3.1 (512)

3 (998)

Presenteeism, % (N)

33.1 (495)

33.7 (529)

33.4 (1024)

Overall work productivity loss (absenteeism + presenteeism), % (N)

34.5 (486)

35.7 (512)

35.1 (998)

Daily activity impairment, % (N)

39.9 (772)

40.1 (783)

40 (1555)

WPAI:IBS-C indicates Work Productivity and Activity Impairment Questionnaire for Irritable Bowel Syndrome with Constipation.

(ANCOVA) model with the baseline score as a covariate and the treatment group and protocol as factors. In analyses of data from Trial 2, changes from baseline to weeks 4, 8, 12, 16, 20, and 26 for all 4 WPAI:IBS-C scores were assessed using an ANCOVA model with the baseline score as a covariate and the treatment group as a factor. The treatment effects were measured as the least-squared mean difference between linaclotide and placebo based on the ANCOVA results. All treatment comparisons were performed at a nominal P <.05 significance level.

Indirect Costs The calculation of average work hours lost as a result of overall work productivity loss reported among the analysis cohort assumed full-time employment of 40 hours weekly and 2080 hours of potential work time annually per employed patient. The overall work productivity losses were converted into monetary values using the human capitalâ&#x20AC;&#x201C;cost approach,30 by multiplying the total number of hours lost by the average hourly employment cost of a US employee ($31.16 in September 2013, comprising an average hourly wage of $21.54 and average benefits worth $9.61).31 All costs are reported in 2013 US dollars, unless otherwise noted.

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Results Demographic and Clinical Characteristics The pooled ITT population included a total of 1602 patients from the 2 phase 3 clinical trials of linaclotide.

The patientsâ&#x20AC;&#x2122; mean age was 44 years, and the majority (90.1%) of patients were female. The pooled analysis cohort included 1555 (97.1%) patients from the 2 trials who completed a baseline and at least 1 postbaseline WPAI:IBS-C assessment (783 patients receiving linaclotide and 772 receiving placebo), of which 1148 (71.7%) patients were currently employed (585 patients receiving linaclotide and 563 receiving placebo). The demographic characteristics of the pooled analysis cohort are shown in Table 1.

For analyses conducted over 26 weeks based on data from Trial 2,25 a total of 804 patients were included in the ITT population. The mean age was 44 years, and the treatment groups were well balanced with respect to demographics, except that the placebo group had a greater proportion of males compared with the linaclotide group (12.7% vs 8.2%, respectively; P = .038).25 The analysis cohort comprised a total of 780 (97%) patients from Trial 2 who completed a baseline WPAI:IBS-C assessment and at least 1 postbaseline WPAI:IBS-C assessment (N = 390 each in the cohorts receiving linaclotide and placebo). Of these, 586 (75.1%) patients were currently employed (294 patients receiving linaclotide and 292 receiving placebo).

Work Productivity and Daily Activity Impairment At baseline, 20.7% of patients reported missing time from work, 82.4% reported reduced productivity while at work, and 88.7% reported impairment in daily activities as a result of their IBS-C. Based on baseline results of the WPAI:IBS-C, these patients had approximately 3% absenteeism, 33.4% presenteeism, 35.1% overall work productivity loss, and 40% daily activity impairment during the previous 7 days as a result of IBS-C, regardless of treatment assignment (Table 1).

Table 2 shows the changes from baseline in work productivity and daily activity impairment outcomes at weeks 4, 8, and 12 among the pooled analysis cohort by treatment group. Significant reductions in presenteeism, overall work productivity loss, and daily activity impairment were seen for patients receiving linaclotide compared with patients receiving placebo as early as week 4 (all P <.01) and remained significant at week 8 (all P <.01) and week 12 (all P <.001). A numerically greater decrease in absenteeism was also observed in patients receiving linaclotide compared with those receiving placebo from baseline to weeks 4, 8, and 12, but this reduction was not statistically significant.

The treatment effect for linaclotide compared with

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Table 2 Mean WPAI Scores for Linaclotide versus Placebo, by Treatment Group (Analysis Cohort) Data pooled across Trials 1 and 2 Trial 2 data only Week 8, Week 12, Week 16, Week 20, Week 26, Week 4, mean % mean % mean % mean % mean % WPAI:IBS-C mean % (Na) CFB (Na) CFB (Na) CFB (Na) CFB (Na) CFB (Na) CFB outcomes Absenteeism Linaclotide

1.8 (431)

–1.4

2 (455)

–1.1

1.5 (457)

–1.6

1.5 (280)

–2.1

1.2 (283)

–2.4

2.1 (284)

–1.6

Placebo

1.9 (414)

–0.9

1.8 (443)

–1

1.9 (445)

–0.9

2.7 (273)

0.1

2.5 (277)

–0.3

2.4 (279)

–0.7

P valueb

.761

.864

.311

.056

.023

.718

Presenteeism Linaclotide Placebo P value

b

17 (459)

–16.7

15.4 (471)

–18.2

15.3 (472)

–18.4

15.7 (283)

–16.8

15.2 (285)

–17.8

15.7 (286)

–17.5

20.9 (447)

–12.5

19.3 (458)

–14.2

20.4 (458)

–13.1

20.8 (280)

–12

20.3 (282)

–12.3

21.5 (284)

–11.3

<.001

.002

<.001

.011

.002

<.001

Overall work productivity loss Linaclotide

18.4 (431)

–17.2

16.8 (455)

–18.6

16 (457)

–19.4

16.3 (280)

–18.5

15.7 (283)

–19.7

16.4 (284)

–19.2

Placebo

22.3 (414)

–12.4

20.3 (443)

–14.7

21.9 (445)

–13

23.4 (273)

–10.8

22.3 (277)

–11.9

22.6 (279)

–11.2

P valueb

.002

.007

<.001

<.001

<.001

<.001

Daily activity impairment Linaclotide

21.9 (783)

–18.2

20.4 (783)

–19.7

20.2 (783)

–19.9

20.6 (390)

–18.8

19.8 (390)

–19.7

20.2 (390)

–19.3

Placebo

25.2 (771)

–14.7

24.1 (772)

–15.8

24.8 (772)

–15.2

25.7 (390)

–14.2

24.4 (390)

–15.6

27.1 (390)

–12.9

P value

b

.001

<.001

<.001

.001

.004

<.001

Sample sizes vary as a result of missing information for patients who did not complete all WPAI:IBS-C assessments at all study weeks.

P value for weeks 4, 8, and 12 from ANCOVA for least squares mean change from baseline to each week indicated for linaclotide compared with placebo, with baseline score as a covariate and treatment and protocol as factors. P value for weeks 16, 20, and 26 from ANCOVA for least squares mean change from baseline to each week indicated for linaclotide compared with placebo, with baseline score as a covariate and treatment as a factor.

NOTES: Absenteeism, presenteeism, and overall work productivity loss (absenteeism + presenteeism) include employed patients only (N = 1148 for pooled cohort; N = 586 for Trial 2). Daily activity impairment includes all patients (N = 1555 for pooled cohort; N = 780 for Trial 2). All scores are presented as percent of impairment.

ANCOVA indicates analysis of covariance; CFB, change from baseline; WPAI:IBS-C, Work Productivity and Activity Impairment Questionnaire for Irritable Bowel Syndrome with Constipation. a

b

placebo is shown in Table 3. From baseline to week 12, compared with placebo, treatment with linaclotide was associated with significant reductions of 5.2% for presenteeism, 6.1% for overall work productivity loss, and 4.7% for daily activity impairment (all P <.01).

The impact of linaclotide treatment over 26 weeks is provided in Table 2. Treatment with linaclotide was associated with significant reductions from baseline in presenteeism, overall work productivity loss, and daily activity impairment compared with placebo at weeks 4, 8, 12, 16, 20, and 26. Significant reductions observed at weeks 4, 8, and 12 were consistent with analyses of the pooled analysis cohort (data not shown). Absenteeism was reduced at all weeks measured, with increasing reductions seen from weeks 4 through 20, but statistical significance was not achieved (Table 2).

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From baseline to week 26, treatment with linaclotide led to significant reductions of 5.9% for presenteeism (P <.05), 7.5% for overall work productivity loss (P <.001), and 6.7% for daily activity impairment (P <.001; Table 3).

These results translate into a reduction in overall work productivity loss (absenteeism plus presenteeism) in the pooled analysis cohort of 2.4 hours weekly at week 12 as a result of treatment with linaclotide, which translates into 127 hours annually. In the 26-week trial, treatment with linaclotide reduced overall work productivity loss by 3 hours weekly at week 26, which translates into 156 hours annually. Based on a potential inflation rate of 33.7% for work productivity loss in patients with IBS caused by errors in 1-week recall, as observed in previous research,27 a conservative estimate of the difference in work productivity loss between the group receiving pla-

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Table 3 Treatment Effecta for Linaclotide versus Placebo (Analysis Cohort) Data pooled across Trials 1 and 2 Trial 2 data only WPAI:IBS-C Week 8, % Week 12, % Week 16, % Week 20, % Week 26, % outcomes Week 4, % Absenteeism

–0.18

0.10

–0.46

–1.56

–1.42

–0.27

Presenteeism

–4.07b

–3.94b

–5.21b

–4.56c

–5.26c

–5.92c

Overall work productivity loss

–4.27b

–3.66b

–6.09b

–7.28c

–7.39c

–7.54c

Daily activity impairment

–3.40b

–3.84b

–4.68b

–4.87c

–4.42c

–6.69c

Treatment effect = least squares means difference between linaclotide and placebo based on ANCOVA analysis.

P <.01 based on ANCOVA, with baseline score as covariate and treatment group and protocol as fixed effects. c P <.05 based on ANCOVA, with baseline score as covariate and treatment group as a fixed effect.

NOTE: Overall work productivity loss = absenteeism plus presenteeism.

ANCOVA indicates analysis of covariance; WPAI:IBS-C, Work Productivity and Activity Impairment Questionnaire for Irritable Bowel Syndrome with Constipation. a

b

cebo and the group receiving linaclotide is 1.6 hours to 2.4 hours weekly, or 84 hours to 127 hours annually at week 12. Conservative estimates for the 26-week analyses range from 2 hours to 3 hours weekly, or 103 hours to 156 hours annually at week 26.

Indirect Costs The overall work productivity loss of 35.1% observed among the pooled analysis cohort at baseline translates into an average loss of 14 hours weekly or 730 hours annually before the initiation of treatment. These losses equate to lost costs of $436 weekly or $22,747 annually for each employed patient with IBS-C. Based on the reduction in overall work productivity loss of 103 hours to 156 hours annually that was estimated as a result of treatment with linaclotide in the 26-week analysis, overall work losses of $62 to $93 per patient weekly (or $3209 to $4861 per patient annually) could potentially be avoided.

Discussion Data from previous studies indicate that the majority of patients seeking healthcare for IBS experience significant impairment in work productivity and daily activities of living. To our knowledge, this study is the first to evaluate the impact of treatment with linaclotide on work productivity and activity impairment and report indirect costs associated with work productivity loss among patients with IBS-C. Previous analyses of work productivity among patients with IBS-C have reported on shorter time frames of 2 weeks and 4 weeks.32 However, for a chronic condition, such as IBS-C, it is important to be able to assess the long-term impact of this condition and its treatment on patient HRQOL and work productivity. This present study is the first to assess work

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productivity and daily activity impairment over a longer time period of 12 weeks and 26 weeks.

The baseline WPAI:IBS-C scores reported in our study are comparable with baseline WPAI:IBS-C scores reported in previous research,32 suggesting that work pro­ ductivity and daily activity continue to be substantially affected by IBS-C, and there remains a significant unmet need for effective treatments for this condition.

The impact of IBS-C on work and daily activity can be put into perspective by comparing it with the impact of other chronic gastrointestinal and nongastrointestinal conditions.

Specifically, baseline presenteeism, overall work productivity loss, and daily activity impairment seen among patients with IBS-C are comparable with impairment observed among patients with severe asthma, moderate-to-severe ulcerative colitis, and Crohn’s disease, and higher than the impairment seen among patients with mild-to-moderate gastroesophageal reflux disease (GERD) and mild ulcerative colitis based on the WPAI scores reported for these conditions.33-36 Furthermore, the indirect costs found among patients with IBS-C in our study are comparable with the indirect costs estimated for patients with GERD37,38; however, these comparisons should be made with caution, because methodologies used to estimate the indirect costs differ across studies, and other studies do not always include both absenteeism and presenteeism when calculating indirect costs.

Treatment with linaclotide led to significant reductions in presenteeism, overall work productivity loss, and daily activity impairment compared with placebo. These reductions were observed as early as week 4 and were maintained at all time points, including through week 26 of treatment in a subset of patients. Although no signifi-

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cant differences were observed for absenteeism between linaclotide and placebo, a numerically greater decrease in absenteeism was seen for linaclotide compared with placebo. However, baseline absenteeism levels were low for both linaclotide and placebo, which was consistent with previous findings,19 and the overall work productivity loss was primarily driven by presenteeism, also consistent with previous research.11,19,20 Before treatment with linaclotide, the overall work productivity loss resulting from IBS-C corresponded to an average of 730 work hours lost annually, equating to annual indirect costs of $22,747 per patient for employed patients in this study. The reduction in overall work productivity loss estimated as a result of treatment with linaclotide at week 26 of 103 hours to 156 hours annually could result in an avoided overall work loss of $62 to $93 per patient weekly, or $3209 to $4861 per patient annually.

ployerâ&#x20AC;&#x2122;s perspective, therapies for IBS-C that effectively manage this chronic, symptomatic condition and improve employee HRQOL and work productivity may represent significant cost-savings in the form of avoided work productivity losses that are associated with IBS-C. n

Limitations Although the 7-day patient recall period used in the WPAI is considered acceptable for health economic evaluations and has been tested in all previous WPAI validation studies, including the IBS-specific version,27 a shorter recall period may improve the accuracy of patient responses. In addition, although the long-term impacts of treatment with linaclotide on work productivity and daily activity impairment were assessed based on 26 weeks of treatment, this could only be evaluated based on the data from 1 trial.

Estimates of the indirect costs associated with IBS-C and treatment with linaclotide were extrapolated based on average 2013 US wage data and may not be representative of all employed patients with IBS-C. Furthermore, this analysis was conducted among patients meeting modified Rome II criteria for IBS-C and may not be sufficiently representative of all patients with IBS-C in the general population.

References

Conclusion IBS-C continues to represent a significant burden for patients and employers. Once-daily treatment with linaclotide was associated with significant reductions in overall work productivity loss and daily activity impairment compared with placebo among patients with IBSC, with significant benefits observed at all time points measured through 26 weeks of treatment. Assuming a 40-hour work week, treatment with linaclotide reduced overall work productivity loss by 2.4 hours weekly at week 12 and by 3 hours weekly by week 26.

Adding to the current body of literature on the economic burden of IBS-C in the United States, this is the first study to provide estimates of the indirect costs to employers associated with this condition. From an em-

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Funding Sources This study was funded by Forest Research Institute, LLC, a subsidiary of Actavis plc, and Ironwood Pharmaceuticals, Inc. Author Disclosure Statement Ms Buono owns stock/stock options in Actavis plc; Dr Tourkodimitris owns stock/stock options in Actavis plc; Mr Sarocco owns stock in Ironwood Pharmaceuticals, Inc; Dr Johnston has stock option holdings in Ironwood Pharmaceuticals, Inc; Ms Carson owns stock/stock options in Actavis plc.

1. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders.

Gastroenterology. 2006;130:1480-1491. Erratum in: Gastroenterology. 2006;131:688.

2. Andrews EB, Eaton SC, Hollis KA, et al. Prevalence and demographics of irritable bowel syndrome: results from a large web-based survey. Aliment Pharmacol Ther. 2005; 22:935-942.

3. Hungin AP, Chang L, Locke GR, et al. Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact. Aliment Pharmacol Ther. 2005;21: 1365-1375.

4. Saito YA, Schoenfeld P, Locke GR III. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002;97:1910-1915.

5. Talley NJ, Zinsmeister AR, Melton LJ III. Irritable bowel syndrome in a community: symptom subgroups, risk factors, and health care utilization. Am J Epidemiol. 1995; 142:76-83.

6. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al; for the American College of Gastroenterology Task Force on Irritable Bowel Syndrome. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.

7. Lovell RM, Ford AC. Effect of gender on prevalence of irritable bowel syndrome in the community: systematic review and meta-analysis. Am J Gastroenterol. 2012; 107:991-1000.

8. Nam SY, Kim BC, Ryu KH, Park BJ. Prevalence and risk factors of irritable bowel syndrome in healthy screenee undergoing colonoscopy and laboratory tests. J Neurogastroenterol Motil. 2010;16:47-51.

9. Herman J, Pokkunuri V, Braham L, Pimentel M. Gender distribution in irritable bowel syndrome is proportional to the severity of constipation relative to diarrhea.

Gend Med. 2010;7:240-246.

10. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131.

11. ParĂŠ P, Gray J, Lam S, et al. Health-related quality of life, work productivity, and health care resource utilization of subjects with irritable bowel syndrome: baseline results from LOGIC (Longitudinal Outcomes Study of GastroIntestinal Symptoms in Canada), a naturalistic study. Clin Ther. 2006;28:1726-1735.

12. Cash B, Sullivan S, Barghout V. Total costs of IBS: employer and managed care perspective. Am J Manag Care. 2005;11(1 suppl):S7-S16.

13. Levy RL, Von Korff M, Whitehead WE, et al. Costs of care for irritable bowel syndrome patients in a health maintenance organization. Am J Gastroenterol. 2001;96: 3122-3129.

14. Leong SA, Barghout V, Birnbaum HG, et al. The economic consequences of irritable bowel syndrome: a US employer perspective. Arch Intern Med. 2003;163:929-935.

15. Patel RP, Petitta A, Fogel R, et al. The economic impact of irritable bowel syndrome in a managed care setting. J Clin Gastroenterol. 2002;35:14-20.

16. Ricci JF, Jhingran P, McLaughlin T, Carter EG. Costs of care for irritable bowel syndrome in managed care. J Clin Outcomes Manag. 2000;7:23-28.

17. Doshi JA, Cai Q, Buono JL, et al. Economic burden of irritable bowel syndrome with constipation: a retrospective analysis of health care costs in a commercially insured population. J Manag Care Pharm. 2014;20:382-390.

18. American Gastroenterological Association. The burden of gastrointestinal diseases. 2001. www.lewin.com/~/media/Lewin/Site_Sections/Publications/2695. pdf. Accessed July 26, 2013.

19. DiBonaventura M, Sun SX, Bolge SC, et al. Health-related quality of life, work productivity and health care resource use associated with constipation predominant

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irritable bowel syndrome. Curr Med Res Opin. 2011;27:2213-2222.

20. Dean BB, Aguilar D, Barghout V, et al. Impairment in work productivity and health-related quality of life in patients with IBS. Am J Manag Care. 2005;11(1 suppl): S17-S26.

21. Hahn BA, Kirchdoerfer LJ, Fullerton S, Mayer E. Patient-perceived severity of irritable bowel syndrome in relation to symptoms, health resource utilization and quality of life. Aliment Pharmacol Ther. 1997;11:553-559.

22. Linzess (linaclotide) capsules [prescribing information]. St Louis, MO: Forest Laboratories, Inc; and Cambridge, MA: Ironwood Pharmaceuticals, Inc; August 2013.

23. Constella (linaclotide) hard capsules [prescribing information]. Barcelona, Spain: Almirall, SA; June 2014.

24. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107: 1714-1724; quiz 1725.

25. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012;107:1702-1712.

26. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. 1993;4:353-365.

27. Reilly MC, Bracco A, Ricci JF, et al. The validity and accuracy of the Work Productivity and Activity Impairment questionnaire–irritable bowel syndrome version (WPAI:IBS). Aliment Pharmacol Ther. 2004;20:459-467.

28. Bonomi AE, Cella DF, Hahn EA, et al. Multilingual translation of the Functional Assessment of Cancer Therapy (FACT) quality of life measurement system. Qual Life Res. 1996;5:309-320.

29. Eremenco SL, Cella D, Arnold BJ. A comprehensive method for the translation and cross-cultural validation of health status questionnaires. Eval Health Prof. 2005;

28:212-232.

30. Liljas B. How to calculate indirect costs in economic evaluations. Pharmacoeconomics. 1998;13(1 pt 1):1-7.

31. Bureau of Labor Statistics. Employer costs for employee compensation—September 2013. Press release. December 11, 2013. www.bls.gov/news.release/archives/ ecec_12112013.pdf. Accessed December 19, 2013.

32. Reilly MC, Barghout V, McBurney CR, Niecko TE. Effect of tegaserod on work and daily activity in irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2005;22:373-380.

33. Chen H, Blanc PD, Hayden ML, et al; for the TENOR Study Group. Assessing productivity loss and activity impairment in severe or difficult-to-treat asthma. Value Health. 2008;11:231-239.

34. Gibson PR, Vaizey C, Black CM, et al. Relationship between disease severity and quality of life and assessment of health care utilization and cost for ulcerative colitis in Australia: a cross-sectional, observational study. J Crohns Colitis. 2014;8:598-606.

35. Feagan BG, Reilly MC, Gerlier L, et al. Clinical trial: the effects of certolizumab pegol therapy on work productivity in patients with moderate-to-severe Crohn’s disease in the PRECiSE 2 study. Aliment Pharmacol Ther. 2010;31:1276-1285.

36. Wahlqvist P, Carlsson J, Stålhammar N-O, Wiklund I. Validity of a Work Productivity and Activity Impairment questionnaire for patients with symptoms of gastro-esophageal reflux disease (WPAI-GERD)—results from a cross-sectional study.

Value Health. 2002;5:106-113.

37. Brook RA, Wahlqvist P, Kleinman NL, et al. Cost of gastro-oesophageal reflux disease to the employer: a perspective from the United States. Aliment Pharmacol Ther. 2007;26:889-898.

38. Wahlqvist P, Reilly MC, Barkun A. Systematic review: the impact of gastro-­ oesophageal reflux disease on work productivity. Aliment Pharmacol Ther. 2006;24: 259-272.

Stakeholder Perspective Patient-Reported Outcomes Matter

By Walid F. Gellad, MD, MPH Staff Physician, VA Pittsburgh Healthcare System, Codirector, University of Pittsburgh Center for Pharmaceutical Policy and Prescribing, PA

Abdominal pain is the leading gastrointestinal (GI) symptom prompting a visit to an outpatient clinic, with almost 16 million visits nationally in 2009.1 Diarrhea and constipation are the second and third leading symptoms, respectively.1 Regardless of whether they result from diagnosed functional disorders such as irritable bowel syndrome (IBS), these GI symptoms lead to substantial reductions in quality of life and work productivity. The article by Buono and colleagues focuses on IBS with constipation (IBS-C) and examines a key patient-reported outcome: work productivity and activity impairment.2 Their study highlights the importance of understanding patient-reported outcomes that matter not only to patients, but also to employers.3 PATIENTS/PROVIDERS: There is great interest in the use of patient-reported outcomes in clinical research and performance improvement.4-6 Studies of linaclotide in patients with IBS-C exemplify the use of these patient-reported outcomes to measure key symptoms that matter to patients, including abdominal pain, number of spontaneous bowel movements, and work produc-

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tivity and activity impairment.7,8 Patients can more easily understand, and providers can more easily explain, the benefits of particular medications for symptom management when relevant symptoms are included as outcomes.

Employers also can more easily translate the potential benefits of a therapy to their bottom line, as Buono and colleagues demonstrate. It is much more difficult to articulate a clear interpretation of benefits for employers in studies using more “objective,” but perhaps more “inaccessible,” outcomes; consider, as an example, the endoscopic resolution of erosive esophagitis in clinical trials of proton pump inhibitors.9 Although the use of the Work Productivity and Activity Impairment Questionnaire for IBS-C is well validated in patients with IBS,10 in studies involving linaclotide, the questionnaire was minimally modified to remove “diarrhea” from the description of an IBS-related symptom, according to Buono and colleagues. Guidance from the US Food and Drug Administration on the use of patient-reported outcomes to support labeling indications emphasizes the importance of avoiding instrument

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Stakeholder Perspective Continued modification.11 The particular modification in the linaclotide studies is relevant, given that diarrhea is the most common side effect of linaclotide. Any improvement for patients in work productivity resulting from improvements in abdominal pain and constipation must be balanced against any potential loss related to the medication’s side effects, such as diarrhea.

EMPLOYERS/PAYERS: Taken together, the findings of studies of linaclotide demonstrate improvements in many important patient-reported domains when compared with placebo, including work productivity. However, employers need additional information to truly understand the potential benefit of providing insurance coverage for such a therapy for their employees, namely, the effectiveness of such drugs compared with older, less-expensive therapies rather than comparing them only with placebo. Employers, and payers, want to know how to maximize the benefits while minimizing treatment costs.

Other treatments, such as dietary modifications, increased physical activity, polyethylene glycol, and fiber, all have a role in the treatment of IBS-C, and linaclotide must be evaluated in the context of such therapies as well. Furthermore, only a small proportion of patients with IBS-C who receive linaclotide respond to the treatment12; therefore, there is a need to identify who is most likely to respond and who is unlikely to respond.

These questions do not take away from the impor-

tance of the study findings by Buono and colleagues, but they are emblematic of the difficulty in truly translating clinical trial findings into clinical reality. n 1. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143:1179-1187.

2. Buono JL, Tourkodimitris S, Sarocco P, et al. Impact of linaclotide treatment on work productivity and activity impairment in adults with irritable bowel syndrome with constipation: results from 2 randomized, double-blind, placebo-controlled phase 3 trials. Am Health Drug Benefits. 2014;7:289-297.

3. Leong SA, Barghout V, Birnbaum HG, et al. The economic consequences of irritable bowel syndrome: a US employer perspective. Arch Intern Med. 2003;163:929-935.

4. Basch E, Torda P, Adams K. Standards for patient-reported outcome-based performance measures. JAMA. 2013;310:139-140.

5. National Quality Forum. Patient-reported outcomes in performance measurement.

January 10, 2013. www.qualityforum.org/Publications/2012/12/Patient-Reported_ Outcomes_in_Performance_Measurement.aspx. Accessed August 1, 2014.

6. Patient Centered Outcomes Research Institute. The design and selection of patient-reported outcomes measures (PROMs) for use in patient centered outcomes research. March 22, 2012. www.pcori.org/assets/The-Design-and-Selection-of-­PatientReported-Outcomes-Measures-for-Use-in-Patient-Centered-Outcomes-­Research. pdf. Accessed August 1, 2014.

7. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012;107:1702-1712.

8. Quigley EM, Tack J, Chey WD, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C—a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment Pharmacol Ther. 2013;37:49-61.

9. Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol. 2001;96:656-665.

10. Reilly MC, Bracco A, Ricci JF, et al. The validity and accuracy of the Work Productivity and Activity Impairment questionnaire—irritable bowel syndrome version (WPAI:IBS). Aliment Pharmacol Ther. 2004;20:459-467.

11. US Food and Drug Administration. Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims. December 2009. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM193282.pdf. Accessed August 1, 2014.

12. Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med. 2011;365:527-536.

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The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important safety Information for VELCADE® (bortezomib) InDICAtIon VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

ContrAInDICAtIons VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WArnIngs, prECAutIons, AnD Drug IntErACtIons ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage A t 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1568 per 3.5-mg vial as of January 2014 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVErsE rEACtIons Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE on the next page of this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group.

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively.

The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib 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 VELCADE, 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 VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V-12-0306a

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