Journal of Managed Care Medicine Volume 14, Number 4

Vol.14, No.4, 2011

Journal of Managed Care Medicine

Advances in the Management of Type 2 Diabetes Mellitus: Integrating New Therapies to Improve Patient Outcomes Improving Patient Outcomes for the Overactive Bladder Patient Population Managing Lifetime Costs While Improving Outcomes in Bipolar Disorder Managing Multiple Sclerosis: Maximizing Diagnosis and Treatment to Improve Patient Outcomes Optimizing Treatment and Costs in the Management of Rheumatoid Arthritis Costs, Concerns and Primary Care Coordination: Behavioral Health Survey Findings Lessons Learned from Fibromyalgia: Understanding Chronic Pain Emerging Trends and Strategies in the Treatment of Breast Cancer Optimizing the Prevention and Treatment of VTE in Cancer Patients Update on Current and Novel Treatment Strategies in Non-Small Cell Lung Cancer PLUS: Fall Managed Care Forum Program Guide

JMCM Journal of Managed care Medicine 4435 Waterfront Drive, Suite 101 Glen Allen, VA 23060 (804) 527-1905 fax (804) 747-5316

editor-in-chief

Journal of Managed Care Medicine The Official Journal of the NaTiONal assOCiaTiON Of MaNaged Care PhysiCiaNs aMeriCaN assOCiaTiON Of iNTegraTed healThCare deliVery sysTeMs aMeriCaN COllege Of MaNaged Care MediCiNe aMeriCaN assOCiaTiON Of MaNaged Care Nurses a Peer-reviewed Publication

Vol. 14, No. 4, 2011

J. Ronald Hunt, MD

publisher Katie Eads

director of coMMunications

TABLE OF CONTENTS advances in the Management of type 2 diabetes Mellitus: integrating new therapies to improve patient outcomes geneva Briggs, Pharmd . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Jeremy Williams

Journal ManageMent Douglas Murphy Communications Inc. P.O. Box 71895 Richmond, VA 23255-1895 (804) 658-4253 fax (703) 997-5842

Managing editor Barry Barnum barry.barnum@douglasmurphy.com

art director Rick Gutierrez

custom article reprints High quality, custom article reprints of individual articles are available in print and electronic formats.

Contact Katie Eads, keads@namcp.org, 804-527-1905 for reprints.

ISSN: 1094-1525. The Journal of Managed Care is published by Association Services Inc. Corporate and Circulation offices: 4435 Waterfront Drive, Suite 101, Glen Allen, VA 23060; Tel (804) 527-1905; Fax (804) 747-5316. Editorial and Production offices: P.O. Box 71895, Richmond, VA 23255-1895; Tel (804) 658-4253; Fax (703) 997-5842. Advertising offices: Sloane Reed, 4435 Waterfront Drive Ste 101, Glen Allen, VA 23060 Tel (804) 527-1905, Fax (804) 7475316. Subscription Rates: one year $95 in the United States; one year $105 in Canada; one year $120 international. Back issues are available for $15 each.

All rights reserved. Copyright 2011. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage or retrieval system, without written consent from the publisher. The publisher does not guarantee, either expressly or by implication, the factual accuracy of the articles and descriptions herein, nor does the publisher guarantee the accuracy of any views or opinions offered by the authors of said articles or descriptions.

POSTMASTER: Send address changes to The Journal of Managed Care Medicine, 4435 Waterfront Drive, Suite 101, Glen Allen, VA 23060.

improving patient outcomes for the overactive bladder patient population ariana l. smith, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Managing lifetime costs While improving outcomes in bipolar disorder Jay faber, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Managing Multiple sclerosis: Maximizing diagnosis and treatment to improve patient outcomes lily Jung, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 optimizing treatment and costs in the Management of rheumatoid arthritis gary M. Owens, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 costs, concerns and primary care coordination: behavioral health survey findings danyell Jones and Mark rosenberg, Md, Phd . . . . . . . . . . . . . . . . . . . . . . . 43 lessons learned from fibromyalgia: understanding chronic pain daniel J. Clauw, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 emerging trends and strategies in the treatment of breast cancer george somlo, Md. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 optimizing the prevention and treatment of Vte in cancer patients Michael B. streiff, Md, faCP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 update on current and novel treatment strategies in non-small cell lung cancer ramaswamy govindan, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 fall Managed care forum program guide. . . . . . . . . . . . . . . . . . . . . . . . . 71 The Journal of Managed Care Medicine, including supplements, is indexed by the Cumulative index to Nursing and allied health literature (CiNahl).

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 3

Editorial Review Board alan adler, Md, Ms Medical director independence Blue Cross Paul Barry, Md, MPh Medical director, PrimeCare Novant health Madeleine Biondolillo, Md Corporate Medical director radius Management Paul Bluestein, Md Chief Medical Officer Connecticare anthony Bonagura, Md Medical director aetna inc.

Philip M. Bonaparte, Md Chief Medical Officer horizon NJ health d. Kete Cockrell, Md Medical director international Medical group Pat deverka, Md, Ms, MBe senior fellow, Center for genome ethics, law & Policy institute for genome sciences & Policy duke university Medical Center stan N. finkelstein, Md Co-director, Program on the Pharmaceutical industry director, harvard-MiT division of health sciences & Technology Massachusetts institute of Technology howard garber, Md, MPh Medical director Johns hopkins health Care Mary Parish gavinski, Md Chief Medical Officer Community Care

leo M. hartz, Md, MhM VP Clinical advocacy/Chief Medical Officer Blue Cross of Northeast Pa

Barry K. herman, Md, MMM executive Medical director Clinical research and Medical affairs sunovion Pharmaceuticals, inc.

Kathy hudson, Phd director, genetics and Public Policy Center Johns hopkins university Thomas Kaye, rPh, MBa, fashP senior Pharmacy director Passport health Plan stephen Keir, drPh Co-director, Center for Quality of life/supportive Care research robert Preston Tisch Brain Tumor Center duke university Medical Center andrei Klein, Md Physician advisor Newark, Beth israel hospital fernado C. larach, Md, faCr, MBa President a-Bay area Medical Clinics, Pa Catherine Marino, Md Chief Medical Officer MagnaCare Jeff Martin, Pharmd Clinical account director innoviant inc.

Peter W. McCauley sr., Md, CPe Medical director gottlieb/West Towns PhO inc.

Wesley Mizutani, Md Talbert Medical group

ronald Perrone, Md, MBa Chief Medical Officer MdNy healthcare gary r. Proctor, Md Chief Medical Officer, federal division ValueOptions inc.

John W. richards Jr., Md, MMM, CPe President/CeO innovative health strategies Kevin roache, Md, MMM, CPe, faCPe Vice President Medical affairs Peoples health, inc. aran ron, Md, MBa, MPh President and Chief Operating Officer group health inc.

Mark r. rosenberg, Md, Phd President/Medical director Behavioral health Management Jay schechtman, Md, MBa senior VP, Chief Medical Officer healthfirst Joseph schwerha, Md, MPh Professor & director of Occupational Medicine residency university of Pittsburgh Nancy single, Phd VP, Mission strategy and alignment american Cancer society robert h. small, Md Behavioral health Medical director TriWest healthcare alliance Jacque J. sokolov, Md Chairman ssB solutions scott spradlin, dO, faCPf, aCOi VP Medical affairs/Chief Medical Officer group health Plan

Thomas Morrow, Md director genentech

Bruce steffens, Md Market Medical director iowa–Central illinois united healthcare

uwe g. goehlert, Md, MsC, MPh, MBa, faafP staff Physician Northwestern Medical Center, department of emergency Medicine

lawrence Mullany, Md, MBa Medical director avMed health Plans

William d. strampel, dO, faCOi dean, Michigan state university College of Osteopathic Medicine

ray Mummery, Md, CMCe Chief Medical Officer dimension health

Jeff Taylor, rPh, Ms Pharmacy director aetna

atul grover, Md, Phd associate director association of american Medical Colleges

denis O’Connell, Md regional Medical director Blue Cross Blue shield of NC

humberto guerra-garcia, Md, MPh, faCP Medical director, east region ameriChoice National Medicare

a. Mark Parker, Md, MBa Medical director Quality assessment systems inc.

annetine gelijns, Phd Co-director, international Center for health Outcomes and innovation research (inChOir) Columbia university

4 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

Prentiss Taylor Jr., Md regional Medical Center director advocate health Care

Pam Thomas, Md, MPh, faCOeM Consulting Medical director Wellness, health and Productivity Management strategies

BYSTOLIC. Helping patients get the blood pressure reductions they need. h

NOW wit

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r o f r e d i even w

Important Safety Information Contraindications ■ B YSTOLIC is contraindicated in patients with severe bradycardia,

heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Please see additional Important Safety Information on the following pages and brief summary of Prescribing Information on the last page of this advertisement.

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 5

BYSTOLIC. Significant blood pressure reductions with a low incidence of side effects.

Effective as add-on therapy1* ■ In a study by Neutel et al, BYSTOLIC 5-20 mg demonstrated SBP/DBP reductions of up to -8.6/-8.6 mm Hg when

added to an ACEI, ARB, and/or diuretic vs -2.6/-3.9 mm Hg for placebo (P<0.001)1*

Low incidence of side effects and overall low discontinuation rate2 ■ Discontinuation rate due to adverse events was 2.8% for BYSTOLIC vs 2.2% for placebo2 * Results from a U.S. phase III, 3-month, multicenter, randomized, double-blind, parallel-group, placebo-controlled study of BYSTOLIC for the treatment of mild to moderate hypertension in patients already taking one or two other antihypertensives (ACEI, ARB, and/or diuretic). Primary endpoint was sitting DBP at trough. Mean values at baseline: sitting DBP at trough, 96.3 mm Hg; sitting SBP at trough, 146.0 mm Hg (N=669).

BYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be used alone or in combination with other antihypertensive agents.

Important Safety Information (continued) Adverse Reactions ■ T he most common adverse events with BYSTOLIC versus placebo (approximately ≥1% and greater than placebo) were headache, fatigue, dizziness,

diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%), and bradycardia (0.2%).

Contraindications ■ B YSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac

failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Warnings and Precautions ■ D o not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction, and

ventricular arrhythmias have been reported following the abrupt discontinuation of therapy with beta blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other beta blockers, when discontinuation of BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily.

■ B YSTOLIC was not studied in patients with angina pectoris or who had a recent MI. ■ I n general, patients with bronchospastic diseases should not receive beta blockers.

■ B ecause beta blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta blockers should generally continue treatment throughout the perioperative period. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene are used. If beta-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

The beta-blocking effects of BYSTOLIC can be reversed by beta agonists, eg, dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with beta blockers.

■ B eta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities.

■ B eta blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta blockers in these patients may be followed by an exacerbation of symptoms or may precipitate a thyroid storm.

■ B eta blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

■ Because of significant negative inotropic and chronotropic effects in patients treated with beta blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure of patients treated concomitantly with these agents.

©2011 Forest Laboratories, Inc.

44-1021004-R1

06/11

6 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

BYSTOLIC.

Widely available on managed care formularies.

MEDICARE PART D

COMMERCIAL

85%

unrestricted access3

81%

Aetna CIGNA Humana MedImpact UnitedHealthcare CVS Caremark ESI Medco

unrestricted access3 Aetna Part D CIGNA Part D Health Net Part D Humana Part D MemberHealth/CCRx SilverScript UnitedHealthcare Part D WellPoint Part D Medco Part D

Formulary status information is valid as of March 2011. Coverage is subject to change.

Important Safety Information (continued) Warnings and Precautions ■ U se caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fl uoxetine, paroxetine, etc). When BYSTOLIC is

co-administered with an inhibitor or an inducer of CYP2D6, monitor patients closely and adjust the nebivolol dose according to blood pressure response.

The dose of BYSTOLIC may need to be reduced. When BYSTOLIC is administered with fl uoxetine, signifi cant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC and a 3-fold increase in Cmax for d-nebivolol).

■ R enal clearance of nebivolol is decreased in patients with severe renal impairment. In patients with severe renal impairment (ClCr less than 30 mL/min) the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients receiving dialysis.

■ Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients with severe hepatic impairment and therefore it is not recommended in that population.

■ Patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine while taking beta blockers.

■ In patients with known or suspected pheochromocytoma, initiate an alpha blocker prior to the use of any beta blocker.

Drug Interactions ■ D o not use BYSTOLIC with other beta blockers.

■ Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

■ BYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the

phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide.

Use in Specific Populations ■ Use BYSTOLIC during pregnancy only if the potential benefi t justifi es the potential risk to the fetus.

BYSTOLIC is not recommended during nursing.

■ The safety and effectiveness of BYSTOLIC have not been established in pediatric patients.

■ In a placebo-controlled trial of 2128 patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age

with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with nebivolol compared to placebo. However, if heart failure worsens, consider discontinuation of BYSTOLIC.

Please see brief summary of full Prescribing Information on last page of this advertisement.

References: 1. Neutel JM, Smith DHG, Gradman AH. Adding nebivolol to ongoing antihypertensive therapy improves blood pressure and response rates in patients with uncontrolled stage l-ll hypertension. J Hum Hypertens. 2010;24:64-73. 2. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2010. 3. MediMedia Information Technologies, LLC, as of March 2011. Data are subject to change.

www.BYSTOLIC.com

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 7

BYSTOLIC® (nebivolol) tablets Brief Summary of full Prescribing Information Initial U.S. Approval: 2007

Rx Only

INDICATIONS AND USAGE: Hypertension - BYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS: BYSTOLIC is contraindicated in the following conditions: Severe bradycardia; Heart block greater than first degree; Patients with cardiogenic shock; Decompensated cardiac failure; Sick sinus syndrome (unless a permanent pacemaker is in place); Patients with severe hepatic impairment (Child-Pugh >B); Patients who are hypersensitive to any component of this product.

WARNINGS AND PRECAUTIONS: Abrupt Cessation of Therapy - Do not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily. Angina and Acute Myocardial Infarction - BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. Bronchospastic Diseases - In general, patients with bronchospastic diseases should not receive β-blockers. Anesthesia and Major Surgery - Because beta-blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta-blockers should generally continue treatment throughout the perioperative period. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobutamine or isoproterenol.

However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers. Diabetes and Hypoglycemia - β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities. Thyrotoxicosis - β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease - β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Non-dihydropyridine Calcium Channel Blockers - Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure in patients treated concomitantly with these agents. Use with CYP2D6 Inhibitors - Nebivolol exposure increases with inhibition of CYP2D6. The dose of BYSTOLIC may need to be reduced. Impaired Renal Function - Renal clearance of nebivolol is decreased in patients with severe renal impairment. BYSTOLIC has not been studied in patients receiving dialysis. Impaired Hepatic Function - Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. BYSTOLIC has not been studied in patients with severe hepatic impairment. Risk of Anaphylactic Reactions - While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Pheochromocytoma - In patients with known or suspected pheochromocytoma, initiate an α-blocker prior to the use of any β-blocker.

ADVERSE REACTIONS: Clinical Studies Experience - BYSTOLIC has been evaluated for safety in patients with hypertension and in patients with heart failure. The observed adverse reaction profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse reactions reported for each of these patient populations are provided below. Excluded are adverse reactions considered too general to be informative and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. The data described below reflect worldwide clinical trial exposure to BYSTOLIC in 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases.

Doses ranged from 0.5 mg to 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. HYPERTENSION: In placebo-controlled clinical trials comparing BYSTOLIC with placebo, discontinuation of therapy due to adverse reactions was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse reactions that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%) and bradycardia (0.2%).

Table 1 lists treatment-emergent adverse reactions that were reported in three 12-week, placebocontrolled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg, or 20-40 mg of BYSTOLIC and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group. Table 1. Treatment-Emergent Adverse Reactions with an Incidence (over 6 weeks) ≥1% in BYSTOLIC-Treated Patients and at a Higher Frequency than Placebo-Treated Patients are listed below in the following order: System Organ Class Preferred Term [Placebo (n = 205), Nebivolol 5 mg (n = 459), Nebivolol 10 mg (n = 461), Nebivolol 20-40 mg (n = 677)] Cardiac Disorders: Bradycardia (0, 0, 0, 1); Gastrointestinal Disorders: Diarrhea (2, 2, 2, 3); Nausea (0, 1, 3, 2); General Disorders: Fatigue (1, 2, 2, 5); Chest pain (0, 0, 1, 1); Peripheral edema (0, 1, 1, 1); Nervous System Disorders: Headache (6, 9, 6, 7); Dizziness ( 2, 2, 3, 4); Psychiatric Disorders: Insomnia (0, 1, 1, 1); Respiratory Disorders: Dyspnea (0, 0, 1, 1); Skin and Subcutaneous Tissue Disorders: Rash (0, 0, 1, 1). Listed below are other reported adverse reactions with an incidence of at least 1% in the more than 4300 patients treated with BYSTOLIC in controlled or open-label trials except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or adverse reactions unlikely to be attributable to drug because they are common in the population. These adverse reactions were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a Whole: asthenia. Gastrointestinal System Disorders: abdominal pain. Metabolic and Nutritional Disorders: hypercholesterolemia. Nervous System Disorders: paraesthesia. Laboratory Abnormalities - In controlled monotherapy trials of hypertensive patients, BYSTOLIC was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count. Postmarketing Experience - The following adverse reactions have been identified from spontaneous reports of BYSTOLIC received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal

connection to BYSTOLIC. Adverse reactions common in the population have generally been omitted. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular block (both second- and thirddegree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud’s phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.

DRUG INTERACTIONS: CYP2D6 Inhibitors - Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.). Hypotensive Agents Do not use BYSTOLIC with other β-blockers. Closely monitor patients receiving catecholaminedepleting drugs, such as reserpine or guanethidine, because the added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity. In patients who are receiving BYSTOLIC and clonidine, discontinue BYSTOLIC for several days before the gradual tapering of clonidine. Digitalis Glycosides - Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers - BYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide.

USE IN SPECIFIC POPULATIONS: Pregnancy: Teratogenic Effects, Category C - Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance. In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD). Labor and Delivery - Nebivolol caused prolonged gestation and dystocia at doses ≥5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation). No studies of nebivolol were conducted in pregnant women. Use BYSTOLIC during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers - Studies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excreted in human milk. Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended during nursing. Pediatric Use - Safety and effectiveness in pediatric patients have not been established.

Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility. Geriatric Use - Of the 2800 patients in the U.S.-sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients. Heart Failure - In a placebo-controlled trial of 2128 patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with nebivolol compared to placebo.

However, if heart failure worsens consider discontinuation of BYSTOLIC. OVERDOSAGE: In clinical trials and worldwide postmarketing experience there were reports of BYSTOLIC overdose. The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension. Other important adverse reactions reported with BYSTOLIC overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse reactions associated with β-blocker overdose include bronchospasm and heart block. The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure, and vomiting.

The patient recovered. Because of extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance. If overdose occurs, provide general supportive and specific symptomatic treatment. Based on expected pharmacologic actions and recommendations for other β-blockers, consider the following general measures, including stopping BYSTOLIC, when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously.

Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful.

Heart Block (second- or third-degree): Monitor and treat with isoproterenol infusion.

Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Congestive Heart Failure: Initiate therapy with digitalis glycosides and diuretics. In certain cases, consider the use of inotropic and vasodilating agents. Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β2-agonist and/or aminophylline.

Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required. Supportive measures should continue until clinical stability is achieved. The half-life of low doses of nebivolol is 12-19 hours. Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment.

Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA Licensed from Mylan Laboratories, Inc. Under license from Janssen Pharmaceutica N.V., Beerse, Belgium Rev. 08/10 © 2010 Forest Laboratories, Inc. Please also see full Prescribing Information at www.bystolic.com.

8 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

44-12000046-BS-A-AUG10

Advances in the Management of Type 2 Diabetes Mellitus: Integrating New Therapies to Improve Patient Outcomes geneva Briggs, Pharmd for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

summary Type 2 diabetes mellitus continues to be a major public health issue in the united states. several new agents have come to market which target previously untargeted pathophysiologic derangements in this disease. These agents are well tolerated by most patients and have some advantages over older agents. integrating these new therapies into diabetes care should lead to improvements in patient outcomes.

Key points • Many patients do not achieve and maintain appropriate glycemic goals for many different reasons.

• Clinical inertia is one major cause of failure to achieve glycemic goals.

• intensive lifestyle modifications can help patients lose weight, lower their glucose, and achieve other metabolic goals.

• The new incretin agents primarily target postprandial hyperglycemia.

• Bromocriptine resets neuroendocrine metabolic control.

• integrating these newer agents into clinical practice may help improve patient outcomes by allowing better achievement of glycemic goals with minimal adverse effects.

Diabetes prevalence has reacheD epidemic proportions in the U.s. (exhibit 1).1 it is estimated that over 8 percent of U.s. children and adults have diabetes.2 that is a total of 25.8 million people. another 79 million have pre-diabetes.2 Overall, approximately 40 percent of the U.s. population has some hyperglycemic condition.3 ninety to 95 percent of diabetes cases are type 2 diabetes mellitus (t2DM).2 as our population continues to age and increase in size, the prevalence of t2DM will continue to increase. currently, 26.9 percent of people aged 65 and older are diagnosed with type 2 disease.2 the prevalence of obesity is estimated at 32.2 percent among adult men and 35.5 percent among adult women.4 Over 60 percent of adults are considered overweight. the complications of diabetes are well known and significant. adults with diabetes have heart disease death rates two to four times higher than adults without diabetes.2 the risk for stroke is two to four times higher among people with diabetes. in 2004, heart disease was noted on 68 percent of diabetesrelated death certificates among people aged 65

years or older. stroke was noted on 16 percent.2 sixty-seven percent of adults with diabetes have blood pressure greater than or equal to 140/90 mmhg or use prescription medications for hypertension.2 Diabetes is the leading cause of new cases of blindness among adults aged 20 to 74 years.2 in 2005 to 2008, 4.2 million people with diabetes aged 40 years or older had diabetic retinopathy.2 Diabetes is also the leading cause of kidney failure, accounting for 44 percent of all new cases of kidney failure in 2008. achieving glycemic control goals with appropriate therapy can reduce complications. lowering a1c to below or around 7% has been shown to reduce microvascular and neuropathic complications of diabetes and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease.5 the american Diabetes association (aDa), american association of clinical endocrinologists (aace), and american college of endocrinologists (ace) publish guidelines on the management of diabetes. the glycemic control goals from these guidelines are given in exhibit 2.5-7 More stringent hemoglobin a1c (a1c) goals

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exhibit 1: age-adjusted percentage of u.s. adults Who Were obese or Who had diagnosed diabetes1 1994

<14.0%

2000

14.0-17.9%

18.0-21.9%

1994

<4.5%

2009

22.0-25.9%

2000

4.5-5.9%

6.0-7.4%

>26% 2009

7.5-8.9%

>9.0%

exhibit 2: glycemic control goals5-7 parameter

normal

ada goal

ace/aace goal

fasting (or pre-prandial) glucose

<100 mg/dl

90-130 mg/dl

<110 mg/dl

Postprandial glucosev

<120 mg/dl

100-140 mg/dl

<140 mg/dl

a1C

<6%

<7%

<

6.5%

Preprandial, before meal; postprandial, 1-2 hours after beginning a meal; a1 C, hemoglobin a1C ada, american diabetes association aCe, american College of endocrinologists aaCe, american association of Clinical endocrinologists

for selected individual patients may be set, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. conversely, less stringent a1c goals may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain despite maximized therapy.5-7 Unfortunately, 43 to 67 percent of patients do not meet a1c goals.8-10 there are many reasons why patients do not achieve and maintain appropriate goals (exhibit 3).11-13 One major reason is clinical inertia. this is defined as lack of treatment intensification in

a patient not at evidence-based goals for a chronic disease such as diabetes, hypertension, or hyperlipidemia. clinical inertia, which has also been called therapeutic inertia, has been implicated as a major factor that contributes to inadequate a1c, blood pressure, and lipid control in t2DM. Only 7 percent of adults with diabetes have simultaneously achieved a1c less than 7%, systolic blood pressure less than 130 mm hg, and low density lipoprotein cholesterol less than 100 mg/dl.14 clinical inertia has been documented to occur in all types of settings, including outpatient, inpatient, and specialist care.15-18 clinical inertia is a problem of the health care professional and the health care system, and it is separate from patient-related issues of adherence, weight gain, and

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access to care. clinical inertia has been postulated to predominantly occur due to three problems: overestimation of care provided; use of “soft” reasons to avoid intensification of therapy; and lack of education, training, and practice organization focused on achieving therapeutic goals.12 a decline in efficacy with long-term traditional oral agent therapy is another reason for poor longterm control. in one study, only one-third of patients maintained goal a1c after three years of therapy on a sulfonylurea and metformin.19 in one trial, a cumulative incidence of monotherapy failure at five years was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide.20 nonadherence with lifestyle change recommendations for diet, exercise, and weight control are another significant reason for failure to achieve glycemic and other goals, such as cholesterol and blood pressure. this can be both a health care provider issue for not providing adequate education and support to the patient or a patient issue with implementation, adherence, and/or persistence. self management training and lifestyle interventions are vital to optimizing therapeutic outcomes. the recently published fouryear findings from the look ahead trial found that intensive lifestyle intervention can produce sustained weight loss and improvements in fitness, glycemic control, and cvD risk factors in individuals with type 2 diabetes when compared with support and education alone (exhibit 4).21 the interventions in this trial consisted of at least 175 minutes of physical activity per week (intensity of brisk walking), a portion-controlled diet using liquid meal replacements, monthly follow-up, and education.

Many therapies are associated with weight gain, which worsens insulin resistance and glucose con-

exhibit 3: reasons for poor glycemic control in type 2 diabetes Mellitus11-13 • Clinical inertia • delayed diagnosis and initiation of treatment • failure to make and adhere to lifestyle changes • Weight gain from medications (i.e., secretagogues, insulin) • Medication nonadherence • loss of durability of antidiabetic medications • Caution about using “too many” medications • underuse of insulin in poorly controlled patients • failure to address pathophysiologic abnormalities beyond insulin secretion and resistance • Progressive beta cell loss despite antidiabetic therapy

trol. insulin, insulin secretagogues (sulfonylureas and meglitinides), and thiazolidinediones are known to lead to weight gain. Weight gain can also lead patients to be nonadherent. insulin and insulin secretagogue therapies are associated with significant risk for hypoglycemia. Other adverse effects with some therapies include gastrointestinal side effects and edema. adverse effects are a common reason patients stop therapy. another reason target goals are not meet is that conventional oral agents have not addressed all the metabolic needs of t2DM patients. insulin and insulin secretagogues primarily target insulin secre-

exhibit 4: look ahead: 4-Year results21

intensive lifestyle intervention

diabetes support & education

Weight loss

6.15%

0.88%

hemoglobin a1C

-0.36%

-0.09%

systolic BP (mm hg)

-5.33

-2.97

diastolic BP (mm hg)

-2.92

-2.48

hdl Cholesterol (mg/dl)

3.67

1.97

Triglycerides (mg/dl)

-25.56

-19.75

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 11

exhibit 5: comparison of incretin agents for type 2 diabetes

Medication

dosing

average decrease in a1C

impact on Weight

Most Common adverse effects

sitagliptin (Januvia®)*

Once daily oral

0.6 - 0.8%

Neutral

Nausea diarrhea

saxagliptin (Onglyza®)*

Once daily oral

0.5 - 0.8%

Neutral

Nausea diarrhea

exenatide (Byetta®)

Twice daily, sQ injection

0.8 - 1.0%

reduction

Nausea diarrhea

liraglutide (Victoza®)

Once daily sQ injection

1-1.2%

reduction

Nausea diarrhea

DPP-4 Inhibitors

GLP-1 Agonists

* also available in combination with metformin (Janumet® and Kombiglyze Xr®) sQ, subcutaneous

tory defects. Metformin and thiazolindinediones primarily target insulin resistance. the unmet needs are alpha cell dysfunction (unsuppressed glucagon secretion) and accelerated gastric emptying with subsequent quick delivery of glucose to the gastrointestinal tract resulting in postprandial hyperglycemia. an additional unmet pathophysiologic need is progressive pancreatic beta cell dysfunction. so far, medications have not been proven to slow loss of beta cells.

Many of the underlying pathophysiologic abnormalities of t2DM are related, in part, to the impaired incretin effect. incretin-based therapies are a new approach to help fill the current gaps in the management of t2DM. these agents primarily target postprandial hyperglycemia, an often-overlooked element of t2DM management that contributes to increasing insulin resistance, poor glycemic control, and failure to achieve a1c goals. the major target of incretin-based therapy is glucagon-like peptide one (Glp-1). numerous ways to supplement endogenous Glp-1 have been studied. because Glp-1 is rapidly degraded by dipeptidyl peptidase 4 (Dpp-4), subcutaneous or intravenous infusions are necessary for delivery. because of the impracticality of Glp-1 infusions, longer acting analogues of Glp-1 that possess stability in the presence of Dpp-4 (Glp-1 agonists) and agents which

block the action of Dpp-4 were developed (Dpp-4 inhibitors). exhibit 5 summarizes the properties of the currently available incretin agents. these agents restore glucose dependent insulin secretion and suppress glucagon levels resulting in decreases in a1c, postprandial glucose, and fasting glucose. reduced appetite, enhanced satiety, slowed gastric emptying, and weight loss have also been observed with Glp-1 enhancement. Many other agonists and Dpp-4 inhibitors are under development. the incretin agents have some advantages over sulfonylureas. they generally do not cause hypoglycemia when used alone, yet produce similar decreases in a1c. When combined with other therapies such as sulfonylureas, rates of hypoglycemia increase. these agents are weight neutral or lead to modest weight loss compared with the significant weight gain and subsequent loss of glycemic control that can occur with sulfonylureas. compared to each other, Glp-1 agonists lower a1c more and promote more weight loss than Dpp-4 inhibitors but require injection and cause a higher rate of nausea which can lead to therapy discontinuation.22 post-marketing, a few uncommon but significant adverse effects have been reported with the incretin agents. hypersensitivity reactions in patients treated with sitagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions, including stevens-

12 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

Johnson syndrome have been reported. pancreatitis has been reported with all the incretin agents. pancreatitis does not appear to occur more often in patients treated with incretin agents than in patients treated with other antidiabetic therapies. pancereatitis is more common among patients with diabetes compared to those without.23 another new agent for t2DM is actually an old agent – bromocriptine – in a new quick- release formulation (cycloset ®). it appears to improve glycemic control through stimulation of dopamine 2 receptors in the hypothalamus. taken orally, within two hours of waking, it is thought to reset neuroendocrine metabolic control and thus decreases insulin resistance, reduces day-long postprandial glucose levels, decreases elevated lipolysis in adipose tissue, and improves glycemia. it lowers a1c approximately 1.2% and fasting glucose 54 mg/dl.24 cardiovascular and overall safety have been demonstrated with bromocriptine in the t2DM population.25 the quick release formulation is FDa approved as monotherapy or as add on therapy. because these agents have been marketed for less than 10 years, there are no long-term data on adherence rates and duration of efficacy compared to older agents. hopefully in the future, we will have data on the impact of these agents to solidify their place in therapy.

5. american Diabetes association. standards of Medical care in Diabetes 2011.

Diabetes care. 2011; 34(supplement 1):s11-s61.

6. handelsman Y, Mechanick Ji, blonde l. american association of clinical endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. endocr pract. 2011;17(suppl 2):1-53.

7. rodbard hW, blonde l, braithwaite ss, et al. american association of clinical endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. endocr pract. 2007;13(suppl 1):1-68.

8. Koro ce, bowlin sJ, bourgeois n, Fedder DO. Glycemic control from 1988 to 2000 among U.s. adults diagnosed with type 2 diabetes: a preliminary report.

Diabetes care. 2004;27:17-20.

9. harris Mi, eastman rc, cowie cc, et al. racial and ethnic differences in glycemic control of adults with type 2 diabetes. Diabetes care. 1999;22:403-8.

10. cheung bM, Ong Kl, cherny ss, et al. Diabetes prevalence and therapeutic target achievement in the United states, 1999 to 2006. Am J Med. 2009;122:443-53.

11. eknoyan G. a history of obesity, or how what was good became ugly and then bad. adv chronic Kidney Dis. 2006;13:421-7.

12. phillips ls, branch Wt, cook cb, et al. clinical inertia. ann intern Med. 2001;135:825-34.

13. barnett ah. treating to goal: challenges of current management. eur J endocrinol. 2004;151(suppl 2):t3-7; discussion t29-30.

14. saydah sh, Fradkin J, cowie cc. poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA. 2004;291:335-42.

15. Ziemer Dc, Miller cD, rhee MK, et al. clinical inertia contributes to poor diabetes control in a primary care setting. Diabetes educ. 2005;31:564-71.

16. cook cb, castro Jc, schmidt re, et al. Diabetes care in hospitalized noncritically ill patients: more evidence for clinical inertia and negative therapeutic momentum. J hosp Med. 2007;2:203-11.

17. Grant r, adams as, trinacty cM, et al. relationship between patient

conclusion

medication adherence and subsequent clinical inertia in type 2 diabetes glyce-

type 2 diabetes has become a devastating epidemic.

While lifestyle measures remain a cornerstone of prevention and therapy, most t2DM patients will require pharmacologic therapy. Most t2DM patients should be able to achieve desired glycemic targets by thoughtful application of presently available pharmacologic agents. the newer agents have a place in therapy to help achieve glycemic goals. JMCM

mic management. Diabetes care. 2007;30:807-12.

18. shah br, hux Je, laupacis a, et al. clinical inertia in response to inadequate glycemic control: do specialists differ from primary care physicians? Diabetes care. 2005;28:600-6.

19. UK prospective Diabetes study (UKpDs) Group. UKpDs 28: a randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. Diabetes care. 1998;21:87-92.

20. Kahn se, haffner sM, heise Ma, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. n engl J Med. 2006;355:2427-43.

geneva Briggs, Pharmd is President of Briggs and associates in

21. look aheaD research Group, Wing rr. long-term effects of a lifestyle

richmond, Va.

intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the look aheaD trial. arch intern

references

Med. 2010;170:1566-75.

1. cDc’s Division of Diabetes translation. national Diabetes surveillance sys-

22. pratley re, nauck M, bailey t, et al. liraglutide versus sitagliptin for pa-

tem. available at http://www.cdc.gov/diabetes/statistics

tients with type 2 diabetes who did not have adequate glycaemic control with

2. centers for Disease control and prevention. national diabetes fact sheet:

metformin: a 26-week, randomised, parallel-group, open-label trial. lancet.

national estimates and general information on diabetes and pre-diabetes in the

2010;375(9724):1447-56.

United states, 2011. atlanta, Ga: U.s. Department of health and human ser-

23. Garg r, chen W, pendergrass M. acute pancreatitis in type 2 diabetes

vices, centers for Disease control and prevention, 2011. available at http://

treated with exenatide or sitagliptin: a retrospective observational pharmacy

www.cdc.gov/diabetes/pubs/estimates11.htm#1.

claims analysis. Diabetes care. 2010;33:2349-54.

3. cowie cc, rust KF, Ford es, et al. Full accounting of diabetes and pre-di-

24. pijl h, Ohashi s, Matsuda M, et al. bromocriptine: a novel approach to the

abetes in the U.s. population in 1988-1994 and 2005-2006. Diabetes care.

treatment of type 2 diabetes. Diabetes care. 2000;23:1154-61

2009;32:287-94.

25. Gaziano JM, cincotta ah, O’connor cM, et al. randomized clinical trial

4. Flegal KM, carroll MD, Ogden cl, curtin lr. prevalence and trends in

of quick-release bromocriptine among patients with type 2 diabetes on overall

obesity among Us adults, 1999-2008. JaMa. 2010 ;303:235-41.

safety and cardiovascular outcomes. Diabetes care. 2010;33:1503-8.

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 13

Improving Patient Outcomes for the Overactive Bladder Patient Population ariana l. smith, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

summary Overactive bladder (OaB) has a significant impact on the quality of life of affected patients. data has shown that quality of care is inadequate in many patients. Managed care plans can improve patient outcomes by instituting screening programs and targeting quality indicators for this condition.

Key points • OaB has a significant impact on quality of life.

• urgency is the most bothersome symptom of OaB and causes behavioral changes.

• One in six adults have symptoms suggestive of OaB. • One simple screening question - “do you have bladder problems that are troublesome or do you ever leak urine?” – can help identify these patients.

• Behavioral modifications, pelvic floor exercises, biofeedback, pharmacologic therapy, neural modulation, correction of significant pelvic floor dysfunction, and surgical augmentation cystoplasty are all treatment options.

• Combination of behavioral modification and antimuscarinic agents provides significant improvement in incontinence.

• agents are under study targeting pathways beyond antimuscarinics.

• Current data indicates quality of care for urinary incontinence is inadequate.

Overactive blaDDer (Oab) is DeFineD by the international continence society as a “symptom syndrome” of urgency, with or without urge incontinence, usually with frequency and nocturia.1 there has always been considerable confusion on the part of patients and among experts regarding the meaning of urgency. the urgency portion of the definition of Oab has also undergone revision. in 1998, the definition of urgency was a strong desire to void accompanied by fear of leakage or pain.

Many people did not like this definition due to confusion with painful bladder syndrome. in 2002, it was revised as the sudden, compelling desire to pass urine that is difficult to defer.1 some people argue that this is not quite right either and should really include the phrase “fear of leakage”. however, as of today, this is the definition that stands.

Urgency, which is pathologic, has to be differentiated from urge, which is a normal physiological desire to void. Urge usually has a gradual onset, increases as a function of bladder volume, and can usually be deferred with various strategies. in pa-

tients with Oab, much lower volumes of urine trigger bladder sensation and urgency and little warning precedes severe urgency. as a result, the patient voids at a much earlier time point at much lower volumes.

Urgency drives behavioral adaptations of Oab, including fluid restriction, toilet mapping, and restriction of activities and intentionally increased voiding frequency. toilet mapping is when a person knows the location of every possible toilet. Urgency is the most bothersome symptom of Oab. When Oab is treated, quality of life gains come from controlling urgency above those from reducing incontinence.2 about one-third of Oab patients experience urge related incontinence. a different type of incontinence, stress urinary incontinence (sUi), can coexist in Oab patients. When a patient has both urge and stress incontinence, this is called mixed incontinence. sUi occurs when a patient coughs, laughs, sneezes, exercises or lifts something heavy, essentially putting physical stress on their bladder.

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exhibit 1: impact of oab on Qol

psYchological • guilt/depression • loss of self-respect and dignity • fear of: - being a burden - lack of bladder control - urine odor • apathy/denial

phYsical • limitations or cessation of physical activities

sexual • avoidance of sexual contact and intimacy

QualitY of life

occupational • absence from work • decreased productivity

social • reduction in social interaction • alteration of travel plans • increased risk of institutionalization of frail older persons

doMestic • requirements for specialized underwear, bedding • special precautions with clothing

Differentiating Oab from stress incontinence usually only requires a few directed questions. the key differences are sUi patients rarely complain of urgency or frequency and generally report leakage with physical activity. they tend to have small volume urine loss as opposed to Oab with urge incontinence episodes where patients report large volume loss, often the whole bladder contents. patients with sUi can generally reach the toilet with an urge to urinate and rarely experience nocturia or nighttime leakage. painful bladder syndrome, previously known as interstitial cystitis, is often confused with Oab, but it is a separate entity and is treated differently. patients have some similar symptoms as Oab, including urinary frequency which is generally the result of discomfort that is partially relieved or lessened by voiding. painful bladder patients generally have pelvic, vaginal, urethral, or bladder pain. these patients do not generally have fear of leakage or urgency incontinence. the key symptoms that differentiate Oab and painful bladder syndrome are urinary incontinence which is almost exclusive of Oab and bladder pain which is almost exclusive of painful bladder syndrome. Urgency, frequency and nocturia are generally seen with both conditions.

Over 16 percent or approximately one in six adults have symptoms suggestive of Oab.3 it has been long

appreciated that the prevalence of Oab syndrome increases with age. recent studies have shown a similar prevalence of Oab in men and women, with men having a much greater prevalence of disease than previously appreciated.3 in the United states, the prevalence of Oab is greater than that of diabetes and ulcers and as common as asthma, chronic bronchitis, and hypercholesterolemia.4,5 the topic of quality of life (QOl) in Oab is really an important one because treatment of this condition does not prolong life, in the way that treating cancer or htn generally does, and we have never been able to show that treating Oab decreases disease severity over time. it may lead to less complications of conditions like skin breakdown or falls en route to the toilet, but our primary objective with treatment is to improve QOl. the impact of Oab on health related-quality of life is profound. Many QOl domains are affected with limitation of activity, avoidance of sex, decreased work productivity, increased housekeeping burden, avoiding travel, and loss of dignity (exhibit 1). people with Oab score worse than the general population in all domains of functioning, including physical and social functioning, general and mental health, and vitality.6 the control of micturition is complex and involves both the autonomic and somatic nervous systems. the sympathetic and parasympathetic systems

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 15

exhibit 2: oab pathology and symptoms pathophysiologic Mechanism

associated symptom

involuntary detrusor contractions during filling phase

urgency

frequency reduced functional bladder capacity

urge incontinence

detrusor pressure overcomes sphincteric outflow resistance

work in tandem to allow simultaneous smooth muscle contraction of the bladder and smooth muscle relaxation of the urethra for efficient voiding to take place. the somatic nerves allow voluntary control over the sphincter. normal neurologic innervation permits normal bladder function which is comprised of a filling/ storage phase and an emptying phase. in the filling/storage phase, the elastic smooth muscle of the bladder muscle stretches to maintain low pressure as the bladder fills with urine. at the same time, the urethral sphincter is under high pressure, preventing leakage. Once capacity is reached and the individual makes a decision to void, the emptying phase begins. First, the urethral sphincter relaxes, then the detrusor contracts and micturition occurs. in an Oab, there is urgency which can be a sensory or motor response. Motor urgency results from inappropriate contraction of the bladder muscle during the storage phase. these unpredictable bladder contractions produce a strong desire to urinate. these contractions can be measured on urodynamic testing. the origin of involuntary contractions is not completely understood but several theories have been proposed, the most common being a combination of neurogenic and myogenic origin. Urgency in the absence of involuntary contractions, otherwise known as sensory urgency, is believed to be secondary to afferent nerve stimulation in the bladder. the pathophysiology of Oab and the resulting symptoms are best understood as involuntary bladder contractions leading to the patient experiencing urgency, then because the bladder cannot fill completely, bladder capacity is reduced, resulting in urinary frequency. the most severe form of overactive bladder occurs when detrusor muscle pressure during these contractions overcomes sphincteric resistance, resulting in urinary incontinence (exhibit 2).

the major risk factors for Oab are neurologic disease, multiple sclerosis, stroke, spinal cord injury, back surgery, back injury, pelvic organ prolapse, chronic bladder outlet obstruction from bph, fecal impaction, and aging. providers can identify patients with one simple screening question - â&#x20AC;&#x153;Do you have bladder problems that are troublesome or do you ever leak urine?â&#x20AC;?. it is important that patients be asked about this because many are reluctant to discuss their symptoms due to embarrassment or lack of awareness that there are effective treatments. if patients answer yes, they should have additional screening.

Most cases can be diagnosed based on patient history, pelvic and rectal examination, neurologic examination, a cough stress test, and urinalysis and culture to rule out a urinary tract infection. Urologists may have the patient complete a three-day voiding diary (intake, output, accidents) and may conduct additional testing, including voided urine cytology, uroflowmetry and post-void residual urine, cystoscopy, and urodynamics. Urodynamics are especially valuable in patients with persistent or refractory symptoms and young men and women in whom neurologic diseases may present with Oab symptoms. the goal of urodynamic studies is to reproduce the symptoms that the patient experiences at home. everyone who wants treatment should and can be offered some method of treatment. short of identifying reversible causes, there is no cure for Oab. the ultimate goal is symptom resolution but a realistic goal is symptom improvement, not cure. patient expectations must be realistic. in increasing order of invasiveness, the treatment options are behavioral modifications, pelvic floor exercises, biofeedback, pharmacologic therapy, neural modulation, correction of significant pelvic floor dysfunction, and sur-

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exhibit 3: behavioral Modification is effective; combination with drug therapy is better7 group 1

Mean reduction in ui (%)

initial behavioral

group 2

drug added

initial drug

Behavioral added

0 -20 -40 -60 -80 -100

-57.5 -72.7 -84.3

-88.5

P=.034

P=.001

ui, urinary incontinence

gical augmentation cystoplasty. behavioral modifications include lifestyle changes, fluid restriction within two hours of bedtime, dietary changes, elimination of caffeine, changing timing of diuretic administration to the morning, and timed voiding. timed voiding is a technique to try to prevent urgency and incontinence episodes by emptying the bladder regularly around the clock, usually every two hours. these behavioral modifications may seem like common sense, but many patients donâ&#x20AC;&#x2122;t realize the implications of these things and require education. there is a lot of room for improvement in this area of treatment. patients require strong educational effort to recognize and isolate the pelvic musculature for pelvic floor exercises. after instruction, it requires daily commitment to be able to resist leakage and to suppress the voiding reflex. there are definitely problems with patient compliance and these exercises are probably not a long-term cure. biofeedback is primarily used as an adjunct to pelvic floor exercises. it utilizes vaginal, rectal, or bladder probes to monitor pressure. essentially, biofeedback heightens the patientâ&#x20AC;&#x2122;s awareness of the bladder, pelvic floor, and urethra through feedback, allowing the patient to manipulate these areas at will. studies have shown that pelvic floor exercises plus biofeedback are more effective than exercises alone. the ideal medication for Oab would block urgency, block involuntary contractions, have no effect on voluntary voiding, minimal adverse effect and no major safety issues. Unfortunately, this does not yet exist. antimuscarinic agents have been the mainstay of

exhibit 4: how do we improve outcomes for overactive bladder?

1. understand the symptoms that comprise the condition 2. understand the difference between similar disease states 3. understand the prevalence and co-morbid diseases that may predispose our patients 4. understand the pathophysiology 5. understand the treatment options and their rationale 6. sCreeN our patients 7. Offer treatment 8. refer when refractory ...This is providing high Quality Care

pharmacologic treatment for Oab. these are also known as anticholinergics. the traditional teaching was that these agents mitigated bladder contractility via blockage of muscarinic receptors in the detrusor muscle. recent scientific advances suggest that the mechanism of action of antimuscarinics is much more complex than previously thought. basic science research has identified muscarinic (M2 and M3) receptors on detrusor myocytes and other bladder structures (i.e., urothelium/suburothelium/afferent nerves). the major portion of the neurohumoral stimulus for involuntary bladder contractions comes from acetylcholine-induced stimulation of muscarinic receptors in the detrusor muscle during filling. recent data support antimuscarinic

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sensory effects which may in fact have a significant impact on bladder storage variables. there is no data to support a significant reduction in detrusor contraction, except in patients with neuropathic bladders. voiding variables (pressure/flow) are not significantly changed. thus, the available data do not support the conclusion that antimuscarinics exert their effect by inhibiting detrusor contractility, but they suggest effects on variables associated with sensation during filling and storage.

Male patients with lower urinary tract symptoms and confirmed outflow obstruction are generally treated first for prostate-related conditions. an antimuscarinic can be added if Oab symptoms persist. antimuscarinics, when used in patients who do not have a significant residual urine volume, are not associated with an increased risk for acute urinary retention. antimuscarinic agents are effective for Oab. they reduce urge incontinence by 70 to 85 percent, frequency by 20 to 30 percent, and urgency by 40 to 50 percent. the volume voided increases by 10 to 20 percent. Quality of life improves. efficacy does come with a price of adverse effects. the reason is muscarinic receptors are all over the body and bladder selectivity has not yet been achieved. the common side effects include dry eyes, dry mouth, constipation, decreased cognition from penetration of the blood brain barrier, blurry vision, and tachycardia. Many patients discontinue antimuscarinic use because of these side effects. there are many options on the market today. extended-release oxybutynin was introduced in the late 1990s and improved convenience with once daily dosing. extended-release oxybutynin also produced fewer side effects by eliminating the peaks and troughs compared with immediate release three times a day dosing. several new drugs and novel delivery systems of old drugs (like oxybutynin patch and gel) came on the market, all looking for a piece of the Oab market. claims of receptor selectivity, cleaner metabolism, no penetration of the brain, and time-release action were made by the drug companies. currently, there are multiple antimuscarinic options, none of which have shown clinical superiority despite their slightly different pharmacologic properties. there is no agreed upon “best drug in class” and the most cost-effective way to choose from the available drugs will likely depend on contract price. there are very few head-to-head trials looking at these medications. some agents have slight theoretical advantages, primarily having to do with pharmacologic properties. For example, M3 or muscarinic subtype 3 selectivity is greater for some agents, but it has never been shown that increased

selectivity translates to greater efficacy or improved tolerability.

Different patients respond to different antimuscarinic agents for unknown reasons. as such, patients often require trial of multiple antimuscarinic agents to attain maximum efficacy with tolerable side effects. trials of two or three of these drugs seem reasonable. the best data for improving the symptoms of Oab come from treatment with two modalities behavioral modification and pharmacologic therapy (exhibit 3). as shown in exhibit 3, combination therapy results in a significant reduction in incontinence episodes.7 Despite efficacy in studies, patients tend not to be persistent nor adherent with antimuscarinics. rates of discontinuation found in medical claims studies range from 43 to 83 percent of patients discontinuing medication within the first 30 days and rates continuing to rise over time.8 Findings from medical claims studies also suggest that over half of patients never refill their initial prescription and that adherence levels tend to be low, with mean/median medication possession ratio (Mpr) values ranging from 0.30 to 0.83.8 this indicates that the medications are either not well tolerated, not effective, or the patients have unrealistic expectations for efficacy. if an initial medication fails to control symptoms, the dose can be maximized, medication can be changed, or an additional medication can be added. Medication doses that exceed the recommended maximum generally produce side effects that are intolerable. persistent symptoms despite pharmacologic therapy and well-followed behavior modifications are considered refractory Oab. in refractory Oab, a urology evaluation with urodynamics and cystoscopy to rule out another cause or missed diagnosis may be necessary.

When patients have clearly failed pharmacologic therapy, neuromodulation is an option. the interstim® neuromodulation device is FDa approved for refractory Oab. botulinum a toxin (botox ®), which is not FDa approved, has significant data to support its off-label use. the final option, should all else fail, is augmentation cystoplasty, which is making the bladder bigger by adding a segment of small intestine. this is rarely performed since the advent of neuromodulation. neuromodulation implies modification of sensory and/or motor function through electrical stimulation. it involves stimulation of sacral nerves to modulate the neural reflexes that influence the bladder, sphincter, and pelvic floor. the exact mode of action is still unclear. there are several techniques, but the best studied is the interstim® device using the

18 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

third sacral nerve (s3). this device includes a tined lead placed near the sacral nerve and programmable implantable neurostimulator. the system provides stimulation to the sacral nerve via electrodes that are floating next to the s3 nerve root. the tines prevent displacement of the lead. after placement of the stimulator, the patient goes home with an external battery for one week and completes regular voiding diaries. if there is better than 50 percent improvement in Oab symptoms, they move on to the second stage. if not, the stimulator lead is removed. if the test phase was successful, an internal stimulator is placed at stage two. the system is programmed by the physician who can stimulate a combination of the four electrodes on the lead. even after implantation, reprogramming is easily achieved. the patients also have a controller, which allows them to optimize settings within physician-specified limits. it also allows the patient to turn up, turn down or turn off the device should they wish.

Outcomes with sacral stimulation have consistently been good. in one study of 76 patients with refractory urge incontinence, 47 percent were completely dry and 29 percent had a 50 percent reduction in symptoms.9 long-term data are being accrued. some patients do fail neurostimulation, others do not like the idea of implantation of a device, and some patients have contraindications to use, including the need for serial Mri. For those patients, botulinum a toxin is tried. botulinum a toxin is a potent inhibitor of acetylcholine release at the neuromuscular junction of autonomic nerves in smooth muscle and somatic nerves in striated muscle. it does this by interacting with the protein complex necessary for vesicle docking and release. intra-detrusor injection can result in chemical denervation that has been shown to improve symptoms in patients with refractory Oab. this reversible denervation will last for three to nine months (mean six months). Generally, between 100 units and 300 units are injected into the bladder at 10 to 30 sites depending on the patient’s condition and severity. the injections can be repeated once the effects wear off. the most common side effect with these injections is urinary retention, especially in neurogenic patients already on intermittent catheterization. there are potential side effects from spread by diffusion to nearby muscles, particularly with high doses.

Minimal complications have been reported despite increasing use and dose. a major issue with using botulinum toxin for Oab is lack of FDa approval for this indication. thus, third-party payers do not reimburse for its use. ad-

ditionally, there is no standardization of technique or dose and no studies on long-term sustainability. currently, if a patient fails interstim® and botox®, the only option is major surgery to enlarge the bladder. in theory, there are several possibilities to improve Oab symptoms targeting alternative pathways other than the muscarinic receptor. agents targeting these other pathways are under study. the potential targets include the central nervous system and peripheral nerves that control motor and sensory response. although the parasympathetic system is important in filling and storage of the bladder, it has yet to be proven whether the sympathetic nervous system plays an active role. Functional evidence for the role of beta-adrenergic receptors in human bladder suggests that relaxation induced by adrenergic stimulation is mediated mainly through beta-3 (ß3) receptor activation. the development of ß3 agonists came after the discovery that the human bladder contains a predominance of ß3 subtype receptors.

One ß3 receptor antagonist, mirabegron, is in the advanced stages of development. clinical trials with this agent are finding a significant reduction in frequency, urgency, urge incontinence and increase in volume voided and safety appears good so far. the best part about this possible new class of medications is the mechanism of action is different from antimuscarinics so they could be used in combination. another treatment being studied for Oab is an oral tackykinin (nK-1) receptor antagonist that is currently available as an antiemetic. this drug works via afferent peripheral mechanism as a substance p antagonist. nK-1 antagonists may inhibit input from the bladder to the spinal cord. another area of important research for the future is quality of care indicators for Oab. in general, there is a paucity of quality care data for Oab, but health services research is gaining popularity in urology. Many things go into improving outcomes in patients with Oab (exhibit 4). One published study of quality indicators among 372 randomly selected patients enrolled in two managed care plans found that quality of care for urinary incontinence was inadequate. Only 20 percent of the women with incontinence had undergone pelvic examination.

Only 50 percent were offered medication therapy for their symptoms and only 13 percent were prescribed behavioral interventions.10 several projects are underway including the Urologic Diseases of america project specifically looking at outcomes and quality of care indicators for Oab. this is an area ripe for managed care programs to improve care. conclusion

Oab has a significant impact on the quality of life

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of affected patients. there are numerous treatment options, but patients must first be identified and correctly diagnosed. combination of behavioral modification and antimuscarinic agents is the most effective treatment. agents are under study targeting pathways beyond antimuscarinics. current data indicate quality of care for urinary incontinence is inadequate and could be improved by managed care. JMCM

4. collins, JG. prevalence of selected chronic conditions: United states, 1990â&#x20AC;&#x201C; 1992. national center for health statistics. vital health stat 10 (194). 1997.

5. Fantl Ja, newman DK, colling J, et al. Urinary incontinence in adults: acute and chronic Management. clinical practice Guideline, no. 2, 1996 Update. rockville, MD: Us Dept. Of health and human services. public health service, agency for health care policy and research. ahcpr publ. #960682. March 1996.

6. Kobelt G, Kirchberger i, Malone-lee J. review. Quality-of-life aspects of the overactive bladder and the effect of treatment with tolterodine. bJU int.

ariana l. smith, Md is an assistant Professor of urology and direc-

1999;83: 583-90.

tor of Pelvic reconstructive surgery at the university of Pennsylvania

7. burgio Kl, locher Jl, Goode ps. combined behavioral and drug therapy for

school of Medicine.

urge incontinence in older women. J am Geriatr soc. 2000;48:370-4.

references

treatment of overactive bladder syndrome with anticholinergic therapy: a sys-

8. sexton cc, notte sM, Maroulis c, et al. persistence and adherence in the 1. abrams p, cardozo l, Fall M, et al. the standardization of terminology in

tematic review of the literature. int J clin pract. 2011;65:567-85.

lower urinary tract function: report from the standardization sub-committee of

9. schmidt ra, Jonas U, Oleson Ka, et al. sacral nerve stimulation for treat-

the international continence society. Urology. 2003;61:37-49.

ment of refractory urinary urge incontinence. sacral nerve stimulation study

2. coyne Ks, payne c, bhattacharyya sK, et al. the impact of urinary urgency

Group. J Urol. 1999;162:352-7.

and frequency on health-related quality of life in overactive bladder: results

10. Gnanadesigan n, saliba D, roth cp, et al. the quality of care provided to

from a national community survey. value health. 2004;7:455-63.

vulnerable older community-based patients with urinary incontinence. J am

3. stewart WF, van rooyen Jb, cundiff GW, et al. prevalence and burden of

Med Dir assoc. 2004;5:141-6.

overactive bladder in the United states. World J Urol. 2003;20:327-36.

20 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

For patients with severe COPD associated with chronic bronchitis and a history of exacerbations

COPD EXACERBATIONS are serious events...

Reducing Patient Risk Is Critical

INDICATIONS AND USAGE DALIRESP is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

Please see Important Safety Information and Brief Summary of full Prescribing Information on the following pages and at www.DALIRESP.com.

COPD=chronic obstructive pulmonary disease.

DALIRESP does not completely eliminate exacerbations or signs and symptoms of COPD.

IMPORTANT SAFETY INFORMATION Contraindications

DALIRESP is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C).

Warnings and Precautions

• DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Prescribers should advise patients, their caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, 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 if such events occur. Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP. – Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In controlled clinical trials 5.9% of patients treated with DALIRESP reported psychiatric adverse reactions vs 3.3% treated with placebo. The most common psychiatric adverse reactions were insomnia (2.4% vs 1.0%), anxiety (1.4% vs 0.9%), and depression (1.2% vs 0.9%).

– Three patients treated with DALIRESP experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) compared to one patient (suicidal ideation) treated with placebo.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information on the following pages and at www.DALIRESP.com.

For patients with severe COPD associated with chronic bronchitis and a history of exacerbations

INTRODUCING DALIRESP

®

The first and only selective PDE4 inhibitor to reduce the risk of COPD exacerbations1,2 • Reduces moderate or severe exacerbations by 17% vs placebo 1,3,4 • Effective alone or in combination with a bronchodilator 1,3 • Effective in older and younger patients (>65 and 40-65 years) 1,3 • Statistically significant increase in lung function (pre-bronchodilator FEV1) of 48 mL vs placebo 1,4 – DALIRESP is not a bronchodilator; this increase was not clinically significant 1,3 • The first new class of drugs for COPD in 25 years 2,5

• Patients should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated and treatment discontinuation considered.

– In addition to weight loss being reported as a common adverse reaction (7.5% of patients treated with DALIRESP vs 2.1% placebo), weight was prospectively assessed in two 1-year clinical trials. In these studies that compared DALIRESP to placebo, 20% vs 7% experienced moderate weight loss (5-10% of body weight) and 7% vs 2% experienced severe weight loss (>10% body weight).

– During the follow-up period after discontinuing DALIRESP, the majority of patients regained some of the weight they had lost.

• Use with strong cytochrome P450 enzyme inducers (eg, rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended, as they decrease the exposure and may reduce the therapeutic effectiveness of DALIRESP.

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 23

For patients with severe COPD associated with chronic bronchitis and a history of exacerbations

DALIRESP significantly reduces exacerbations REDUCTION IN THE RATE OF MODERATE OR SEVERE EXACERBATIONS3,4

Mean Number of Exacerbations per Patient per Year

2.0

17

1.5

%

REDUCTION

1.37 1.0

1.14

0.5

0 Placebo

DALIRESP

(n=1554)

(n=1537)

P=0.0003 vs placebo

Study design: A pre-specified pooled analysis from 2 identical, 52-week, double-blind, placebo-controlled trials in patients with severe COPD associated with chronic bronchitis and a history of exacerbations (N=3091). Median patient age was 64 years; 76% male, 84% Caucasian. LABAs or short-acting anticholinergics were allowed as concomitant treatment. The reduction in the rate of moderate (requiring treatment with systemic glucocorticosteroids) or severe (resulting in hospitalization and/or leading to death) exacerbations and change in lung function (pre-bronchodilator FEV1) were primary endpoints. Each study met both co-primary endpoints.

• Moderate exacerbations were defined as those requiring treatment with systemic corticosteroids1 • Severe exacerbations were defined as resulting in hospitalization and/or death1

Indications and Usage

DALIRESP is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

IMPORTANT SAFETY INFORMATION Warnings and Precautions

• Prescribers should advise patients, their caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, 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 if such events occur. Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP. References: 1. DALIRESP (roflumilast) Prescribing Information. Forest Pharmaceuticals, Inc. St. Louis, MO. 2. US Food and Drug Administration. FDA approves new drug to treat chronic obstructive pulmonary disease. March 1, 2011. http://www.fda.gov/NewsEvents/newsroom/PressAnnouncements/ucm244989.htm. Accessed June 22, 2011. 3. Data on file. Forest Laboratories, Inc. 4. Calverley PMA, Rabe KF, Goehring U-M, Kristiansen S, Fabbri LM, Martinez FJ; for the M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet.

2009;374:685-694. 5. US Food and Drug Administration. Atrovent approval history (NDA 019085, 1986). Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed July 21, 2011.

For patients with severe COPD associated with chronic bronchitis and a history of exacerbations

Effective with LABAs or short-acting anticholinergics In the same studies:

DALIRESP significantly reduced the rate of exacerbations vs placebo in patients using a bronchodilator1,3 CONSISTENT EFFECT WITH A CONCOMITANT BRONCHODILATOR1,3

DALIRESP with LABAs (Long-acting ß2 Agonists) DALIRESP with Short-acting Anticholinergics

Study design: A pre-specified pooled analysis from 2 identical, 52-week, double-blind, placebo-controlled trials in patients with severe COPD associated with chronic bronchitis and a history of exacerbations (N=3091). Median patient age was 64 years; 76% male, 84% Caucasian. LABAs and short-acting anticholinergics were allowed and were used by 44% and 35% of patients treated with DALIRESP and 45% and 37% of patients treated with placebo, respectively. The reduction in the rate of moderate (requiring treatment with systemic glucocorticosteroids) or severe (resulting in hospitalization and/or leading to death) exacerbations and change in lung function (pre-bronchodilator FEV1) were primary endpoints. Each study met both co-primary endpoints.

• The effect with concomitant LABAs or short-acting anticholinergics was similar to that seen in the overall population1,3

IMPORTANT SAFETY INFORMATION Warnings and Precautions

• Patients should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated and treatment discontinuation considered.

Adverse Reactions

In clinical trials the most common adverse reactions (≥2% and greater than placebo) were diarrhea (9.5% vs 2.7%), weight loss (7.5% vs 2.1%), nausea (4.7% vs 1.4%), headache (4.4% vs 2.1%), back pain (3.2% vs 2.2%), influenza (2.8% vs 2.7%), insomnia (2.4% vs 1.0%), dizziness (2.1% vs 1.1%), and decreased appetite (2.1% vs 0.4%).

Please see additional Important Safety Information on the previous pages and Brief Summary of full Prescribing Information on the following page and at www.DALIRESP.com.

DALIRESP is a registered trademark of Nycomed GmbH. © 2011 Forest Laboratories, Inc.

84-12000140

08/11

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 25

DALIRESP™ (roflumilast) tablets Brief Summary of Full Prescribing Information Initial U.S. Approval: 2011

Rx Only

INDICATIONS AND USAGE DALIRESP™ is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

Limitations of Use DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

CONTRAINDICATIONS The use of DALIRESP is contraindicated in the following conditions: Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3)and Use in Special Populations (8.6)].

WARNINGS AND PRECAUTIONS Treatment of Acute Bronchospasm DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm.

Psychiatric Events including Suicidality Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of patients treated with DALIRESP 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo.

The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with DALIRESP 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo, respectively) [see Adverse Reactions (6.1)]. Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving DALIRESP compared to one patient (suicidal ideation) who received placebo.

Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, 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 DALIRESP if such events occur.

Weight Decrease Weight loss was a common adverse reaction in DALIRESP clinical trials and was reported in 7.5% (331) of patients treated with DALIRESP 500 mcg once daily compared to 2.1% (89) treated with placebo [see Adverse Reactions (6.1)]. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss.

During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving DALIRESP. Patients treated with DALIRESP should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of DALIRESP should be considered.

Drug Interactions A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure, which may result in a decrease in the therapeutic effectiveness of DALIRESP. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with DALIRESP is not recommended. [see Drugs That Induce Cytochrome P450 (CYP) Enzymes (7.1) and Clinical Pharmacology (12.3)].

ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: • Psychiatric Events Including Suicidality [see Warnings and Precautions (5.2)] • Weight Decrease [see Warnings and Precautions (5.3)] Adverse Reactions in Clinical Studies Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described below reflect exposure of 4438 patients to DALIRESP 500 mcg once daily in four 1-year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials [see Clinical Studies (14.1)]. In these trials, 3136 and 1232 COPD patients were exposed to DALIRESP 500 mcg once daily for 6 months and 1-year, respectively.

The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean prebronchodilator forced expiratory volume in one second (FEV1) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with DALIRESP reported an adverse reaction compared with 65.3% treated with placebo.

The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for DALIRESP-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of DALIRESP were diarrhea (2.4%) and nausea (1.6%).

Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in DALIRESPtreated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.

Table 1 summarizes the adverse reactions reported by ≥ 2% of patients in the DALIRESP group in 8 controlled COPD clinical trials.

Table 1: Adverse Reactions Reported by ≥ 2% of Patients Treated with DALIRESP 500 mcg daily and Greater Than Placebo Treatment Adverse Reactions DALIRESP Placebo (Preferred Term) (N=4438) (N=4192) n (%) n (%) Diarrhea 420 (9.5) 113 (2.7) Weight decreased 331 (7.5) 89 (2.1) Nausea 209 (4.7) 60 (1.4) Headache 195 (4.4) 87 (2.1) Back pain 142 (3.2) 92 (2.2) Influenza 124 (2.8) 112 (2.7) Insomnia 105 (2.4) 41 (1.0) Dizziness 92 (2.1) 45 (1.1) Decreased appetite 91 (2.1) 15 (0.4) Adverse reactions that occurred in the DALIRESP group at a frequency of 1 to 2% where rates exceeded that in the placebo group include: Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting Infections and infestations - rhinitis, sinusitis, urinary tract infection, Musculoskeletal and connective tissue disorders - muscle spasms Nervous system disorders - tremor Psychiatric disorders - anxiety, depression DRUG INTERACTIONS A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [see Clinical Pharmacology (12.3)].

Drugs That Induce Cytochrome P450 (CYP) Enzymes Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of DALIRESP. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with DALIRESP is not recommended [see Drug Interactions (5.4) and Clinical Pharmacology (12.3)].

Drugs That Inhibit Cytochrome P450 (CYP) Enzymes The co-administration of DALIRESP (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit. [see Clinical Pharmacology (12.3)].

Oral Contraceptives Containing Gestodene and Ethinyl Estradiol The co-administration of DALIRESP (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic effects: Pregnancy Category C: There are no adequate and well controlled studies of DALIRESP in pregnant women.

DALIRESP was not teratogenic in mice, rats, or rabbits. DALIRESP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

DALIRESP induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the maximum recommended human dose (MRHD) (on a mg/m2 basis at maternal doses > 2 mg/kg/day and 6 mg/kg/day, respectively). DALIRESP induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD (on a mg/m2 basis at maternal doses ≥ 0.6 mg/kg/day). No treatment-related effects on embryo-fetal development were observed in mice, rats, and rabbits at approximately 12, 3, and 26 times the MRHD, respectively (on a mg/m2 basis at maternal doses of 1.5, 0.2, and 0.8 mg/kg/day, respectively).

26 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

Nonteratogenic effects: DALIRESP has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice. These studies found that DALIRESP decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/mg2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. DALIRESP also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m2 basis at a maternal dose of 12 mg/kg/day) during pregnancy and lactation.

Labor and Delivery DALIRESP should not be used during labor and delivery. There are no human studies that have investigated effects of DALIRESP on preterm labor or labor at term; however, animal studies showed that DALIRESP disrupted the labor and delivery process in mice.

DALIRESP induced delivery retardation in pregnant mice at doses greater than or equal to approximately 16 times the MRHD (on a mg/m2 basis at a maternal dose of > 2 mg/kg/day).

Nursing Mothers Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human milk is probable. There are no human studies that have investigated effects of DALIRESP on breast-fed infants. DALIRESP should not be used by women who are nursing.

Pediatric Use COPD does not normally occur in children. The safety and effectiveness of DALIRESP in pediatric patients have not been established.

Geriatric Use Of the 4438 COPD subjects exposed to DALIRESP for up to 12 months in 8 controlled clinical trials, 2022 were > 65 years of age and 471 were > 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].

Hepatic Impairment Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh A subjects and by 92% and 41%, respectively in ChildPugh B subjects, as compared to age-, weight- and gender-matched healthy subjects. The Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) [see Contraindications (4) and Clinical Pharmacology (12.3)].

Renal Impairment In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and roflumilast N-oxide were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment [see Clinical Pharmacology (12.3)].

OVERDOSAGE Human Experience No case of overdose has been reported in clinical studies with DALIRESP. During the Phase I studies of DALIRESP, the following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and arterial hypotension.

Management of Overdose In case of overdose, patients should seek immediate medical help.

Appropriate supportive medical care should be provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether roflumilast is dialyzable by peritoneal dialysis.

Manufactured by: Nycomed GmbH Production Site Oranienburg Lehnitzstrasse 70 – 98 16515 Oranienburg Germany Manufactured for: Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA © 2010 Forest Laboratories, Inc. 84-1020598-BS-RMC17137-FEB11 Please also see full Prescribing Information at www.daliresp.com

Managing Lifetime Costs While Improving Outcomes in Bipolar Disorder Jay faber, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

summary Bipolar disorder is a costly disease from a social, work, and medical perspective.

Managed care can have an impact on the lifetime costs of this disease by instituting disease management or other programs that target appropriate management.

Quality of life for these patients can also be improved by appropriate therapies.

Key points • Bipolar disorder is costly due to significant direct and indirect costs.

• appropriate medications should be used to aggressively treat both depressive and manic symptoms.

• appropriate treatment improves quality of life and reduces health care costs.

• Treatment adherence is especially important to achieving good outcomes.

• disease management programs have significant potential for improving adherence, reducing hospitalization, and reducing overall costs.

bipOlar DisOrDer is a brain DisOrDer characterized by extreme shifts in mood, energy, and functioning. there are two types of bipolar disorder (bpD). in bpD i, the patient has had at least one manic or mixed episode and in bpD ii, the patient has had one or more depressive episodes and at least one hypo-manic episode.1 symptoms usually emerge in late adolescence or early adulthood. this is a severe condition that affects nearly 2 percent of the U.s. population. because diagnostic assessment methods and criteria vary broadly from study to study, lifetime prevalence estimates of any type of bpD worldwide are 0.5 percent to over 5 percent.2 the epidemiologic catchment area study in the U.s. found a bpD i prevalence of 0.8 percent, bpD ii of 0.5 percent, and any bipolar disorder of 1.3 percent.2 in that study, the bpD i average age of onset was 18 years and 22 years for bpD ii. bipolar i occurred equally in men and women, whereas bpD ii was more common in women. the U.s. national co-morbidity survey which only examined bpD i found a prevalence of 0.45 percent and manic episode prevalence of 1.6 percent.4 in this study, the average age of onset was 21 years and the disease

occurred equally in men and women.

Misdiagnosis of bpD is common. a national Depressive and Manic-Depressive association (nDMDa) survey revealed 69 percent of patients were initially misdiagnosed.5 in more than one-third of cases, 10 years passed before a correct diagnosis.

Many patients are initially misdiagnosed with major depression. this leads to inappropriate treatment, loss of productivity, and lowered quality of life. Up to 15 percent of individuals with bpD eventually commit suicide compared with 10 percent of patients with depression.6 bpD is the most expensive behavioral health diagnosis for both individuals and their insurance providers. the total lifetime costs for patients with bpD in the U.s. are estimated to be $24 to $48 billion.7-9 hospitalization is a significant part of the direct costs. seventy-five percent of bpD patients are hospitalized at least once. Other direct costs include nursing home care, outpatient treatment, prescription and treatment costs, and nonmedical support costs. lost productivity is the largest portion of indirect costs. Disability and premature mortality are other significant indirect costs. bpD is ranked as the

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 27

exhibit 1: health benefits cost comparison insured employees with and without bpd10

Workersâ&#x20AC;&#x2122; Comp long-term dis short-term dis sick leave Pharmacy Medical 0

2000 4000 6000 emp with no BPd (n=229,145) emp with BPd (n=761)

sixth leading cause of disability worldwide. in a study of insured employees, claims, payroll, and demographic data from several large U.s.-based employers were examined for costs related to medical, pharmacy, workers compensation, short- and long-term disability, and sick leave costs. Using data from 761 employees with bpD versus 229,145 employees without bpD, the mean difference in annual cost of the bpD group compared with control was $6,836. this was a 217 percent difference. the employees with bpD had higher costs in all areas (exhibit 1).10 Delays in diagnosis can be a reason for increased costs. treatment delay worsens disease outcome. inadequate treatment is another cause of increased costs.

Work-related absenteeism is common among persons with bpD. a primary care study showed a sevenfold increased likelihood of missing work. in the nDMDa survey, 88 percent of patients reported occupational difficulties.5 in one study, six months after hospitalization for a manic episode 43 percent of patients were unemployed, although 80 percent had mild to no symptoms. One point seven years after hospitalization for mania, 23 percent were unemployed for the entire period. Factors influencing employment include total symptom severity, history of psychiatric hospitalization, and maternal education. between 30 and 60 percent of persons with bpD do not regain full social or occupational functioning after the onset of illness. after diagnosis, treatment often falls short of treatment guidelines. in an analysis of hospitalized persons with bpD, five in six were discharged from hospital with medications inconsistent with national treatment guidelines. in a study of outpatients with bpD, one-third were not receiving mood stabilizers. in a Med-cal 1994-1998 analysis of persons diagnosed with bpD, 58 percent did not receive mood stabilizers in the first year after diagnosis.9 Direct health care costs were significantly higher for those who did not use mood-stabilizing agents during the first year. treatment has improved since the introduction of second-generation antipsychotic agents. appropriate treatment improves quality of life (QOl) and reduces health care costs. in a literature review on bpD health-related QOl and health care resource utilization/cost, patients who achieved standard lithium serum levels had better work performance than patients with low lithium serum lev-

exhibit 2: comparison of bipolar vs. unipolar disorder1 bipolar

unipolar

substance abuse

Very high

Moderate

family history

Common

less common

first episode < 25 years

Very common

less common

seasonality

Common

Occasional

highly recurrent depression

More common

less common

antidepressant â&#x20AC;&#x153;Misadventuresâ&#x20AC;?

Common

usually absent

rapid On/Off Pattern

Typical

unusual

Postpartum depression/Psychosis

More common

less common

Mixed depression/hypomania/Mania

Common

absent

28 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

exhibit 3: example disease Management intervention goal: the member will understand how to recognize and manage a manic episode > intervention #1: the disease management specialist will teach the warning signs of a manic episode > intervention #2: the disease management specialist will teach the member why they need to control manic episode Measurable outcome: the member will articulate at least 3 warning signs of a manic episode When all the goals are achieved as evidenced by the measurable outcome, the patient can be discharged for the dM program

exhibit 4: difference in total cost of care in adherent versus nonadherent patients19 bipolar disorder total cost 10,000

regular $1657

8,000

irregular $9701

6,000 Cost

4,000 2,000 0 regular irregular

els.11 patients who receive higher doses of quetiapine may have reduced utilization of mental health resources. Olanzapine treatment results in a slight improvement in work impairment and health-related QOl compared with haloperidol. bpD recognition and treatment by primary care providers (pcps) is uncommon. Forty-one percent of primary care providers in one survey did not screen patients with major depression for bpD.12 additionally, only 57 percent knew that antidepressants can increase cycling in bpD. symptoms that prompt pcps to refer patients for psychiatric care include suicidality, symptoms resistant to antidepressant treatment, and manic symptoms. educating pcps on appropriate diagnosis and management of this disorder would improve recognition and treatment. accurate diagnosis requires ruling out other medical or psychiatric conditions that could be accounting for the symptoms. in addition to substance abuse, other comorbid conditions such as obsessive compulsive disorder and panic disorder are also common. exhibit 2 provides a comparison between characteristics of bipolar disorder and unipolar depression.1 Forty percent of patients with bpD i experience mixed states (mania and major depression). sixty percent of bpD i patients experience co-mor-

bid substance abuse. in other studies, rates of alcohol abuse range as high as 69 percent and drug abuse as high as 60 percent. patients with bpD ii present diagnostic challenges because hypomania is often not experienced as â&#x20AC;&#x153;abnormalâ&#x20AC;?. additionally, prior hypomania is often underreported. recognition of mania or hypomania is essential in distinguishing unipolar depression from bipolar depression. accurate diagnosis requires active inquiry regarding past mania or hypomania. primary care providers can use a simple screening questionnaire to help with diagnosis. in a managed care population, a health risk assessment and claims data can be used to identify people who potentially have bpD but are not being treated.

Disease management programs for bpD have significant potential for improving adherence, reducing hospitalization, and reducing overall costs. an example disease management intervention is given in exhibit 3. treatment of bpD includes pharmacotherapy and psychotherapy. there are many treatment challenges in this group of patients, including medication tolerability, acceptance of treatment, insight into illness, and need to manage acute symptoms such as agitation and insomnia with adjuncts. treatment

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 29

exhibit 5: treatment adherence strategies for adults with bpd • Prescribe once-daily dosing if possible • use adherence-enhancing aids (eg, weekly pill boxes, daily mood charting) • ask family members to supervise medication use • Monitor closely medication blood levels • include depot antipsychotic if appropriate in treatment regimen

adherence is a major issue.

Mood stabilizers are used for treatment of bpD manic episodes. these include lithium and anticonvulsants such as valproic acid, carbamazepine, and lamotrigine. lithium in acute mania results in response rates of 49 to 70 percent in multiple randomized, placebocontrolled trials.13 higher plasma concentrations are often needed for acute efficacy. psychosis in these patients will improve in tandem with mania. lithium is also effective for bpD i patients who are depressed with no history of rapid cycling. the suggested lithium level for ideal antidepressant response is 0.8-1.2 meq/l. the need for blood levels can be an issue for treatment adherence. the suicide rate is 8.6-fold higher in individuals not receiving lithium versus those receiving it.14 atypical antipsychotics at low doses are used for treating acute manic episodes. newer generation atypical antipsychotics offer tolerability benefits over conventional antipsychotics. compared with first-generation antipsychotics, second-generation antipsychotics improve medication adherence behavior, quality of life, and subjective tolerability.15 For treatment of bpD depressive episodes, quetiapine, olanzapine and fluoxetine in combination, or lamotrigine can be used. combining olanzapine with fluoxetine results in better outcomes than olanzapine alone.16 Olanzapine and fluoxetine combination has also been compared with lamotrigine.17 the combination provided a greater improvement in depressive and manic symptoms but caused more treatment-emergent adverse events, including greater weight gain and elevated metabolic factors. antidepressants alone are also used for some patients. they lower risk of acute depressive episode relapse by 70 percent but can increase cycling.18 continued antidepressant treatment is beneficial for patients with recurrent depressive episodes. patients will need to be monitored for possible mania. several interventions can help optimize outcomes

in bpD. the primary therapeutic agents used should be known to be efficacious for bpD. Depressive and manic episodes both need to be managed with the least number of medications. polypharmacy may be necessary, but should be supported by evidencebased guidelines. treatments should be customized based upon prior response, patient preference, comorbidities, and co-prescribed medications. adherence with therapy should be monitored on a regular basis. symptoms that destabilize the illness such as sleep disturbances, anxiety, psychosocial stressors, and comorbid conditions need to be identified and managed. education of the patient and significant others is also important. lastly, recognizing that the course of illness may change over time is important because therapy may have to change over time. treatment adherence is very important to outcomes. in one study, 75 percent of patients with irregular medication use required hospitalization for an average of 37.2 total days.19 Only 31 percent of the regular medication users required hospitalization for an average of 4.4 days. Maintaining adherence can result in significantly lower costs (exhibit 4).19 several factors are known to negatively impact treatment adherence. these include younger age, single status, male gender, lower educational level, hypomanic denial, psychosis, co-morbid substance abuse, medication adverse effects, and unfavorable personal attitudes toward treatment.20 ability to afford care can also impact ability to adhere. Given the high rate of unemployment with this group of patients, they may not have the money to pay for medication. adherence can be monitored in numerous ways, including self-report, family report, serum lithium levels/rbc lithium levels, microelectronic devices (MeMs), and claims data review. Multiple complementary interventions, particularly if customized for the individual, are likely to be more successful than any one intervention in improving adherence. exhibit 5 lists some adherence improvement strategies. randomized trials have shown the value of structured forms of psychotherapy as adjunct to mood stabilizers.21 cognitive-behavioral therapy, interpersonal and social rhythm therapy, family-focused therapy, and group psychoeducation are all useful. some of the benefits of combining psychotherapy with medication maintenance include delay in recurrences, stabilization of symptoms, and improved medication adherence. conclusion

Optimizing outcomes in bpD may include many interventions. appropriate medications should be used to aggressively treat the underlying mood dis-

30 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

order. treatment adherence is especially important to achieving good outcomes. JMCM

10. Gardner hh, Kleinman nl, brook ra, et al. the economic impact of bipolar disorder in an employed population from an employer perspective. J clin psychiatry. 2006;67:1209-18.

Jay faber, Md is Medical director for lifesync, a behavioral health

11. bowden, cl. bipolar disorder and work loss. am J Manag care. 2005;11(3

subsidiary for humana health, in dallas, TX.

suppl):s91-4.

12. stang p, Frank c, Yood MU, et al. bipolar Disorder Detection, ascertain-

references

ment, and treatment: primary care physician Knowledge, attitudes, and

1. american psychiatric association: Diagnostic and statistical Manual of Men-

awareness. prim care companion J clin psychiatry. 2006;8:147-152.

tal Disorders, Fourth edition, text revision. Washington, Dc: american psy-

13. Yildiz a, vieta e, leucht s, baldessarini rJ. efficacy of antimanic treat-

chiatric association; 2000:345-428.

ments: meta-analysis of randomized, controlled trials. neuropsychopharmacol-

2. Kleinman l, lowin a, Flood e, et al. costs of bipolar disorder. pharmaco-

ogy. 2011;36:375-89.

economics. 2003;21:601-22.

14. M端ller-Oerlinghausen b. arguments for the specificity of the antisuicidal

3. regier Da, narrow We, rae Ds, et al. the de facto Us mental and addic-

effect of lithium.

tive disorders service system. epidemiologic catchment area prospective

eur arch psychiatry clin neurosci. 2001;251 suppl 2:ii72-5.

1-year prevalence rates of disorders and services. arch Gen psychiatry.

15. bipolar Disorder: Quality of life and the impact of atypical antipsychotics.

1993;50:85-94.

am J Manag care 2005;11:s275-s280.

4. Kessler rc, chiu Wt, Demler O, Walters ee. prevalence, severity, and co-

16. tohen M, vieta e, calabrese J, et al. efficacy of olanzapine and olanzapine-

morbidity of twelve-month DsM-iv disorders in the national comorbidity

fluoxetine combination in the treatment of bipolar i depression. arch Gen psy-

survey replication (ncs-r). arch Gen psychiatry. 2005;62:617-27.

chiatry. 2003;60:1079-88.

5. hirschfeld rM, lewis l, vornik la. perceptions and impact of bipolar dis-

17. brown eb, Mcelroy sl, Keck pe Jr, et al. a 7-week, randomized, double-

order: how far have we really come? results of the national Depressive and

blind trial of olanzapine/fluoxetine combination versus lamotrigine in the

Manic-Depressive association 2000 survey of individuals with bipolar disorder.

treatment of bipolar i depression. J clin psychiatry. 2006;67:1025-33.

J clin psychiatry. 2003;64:161-74.

18. Geddes Jr, carney sM, Davies c, et al. relapse prevention with antide-

6. american psychiatric association. practice guideline for the treatment of pa-

pressant drug treatment in depressive disorders: a systematic review. lancet.

tients with bipolar disorder (revision). am J psychiatry. 2002;159(4 suppl):1-50

2003;361(9358):653-61.

7. begley ce, annegers JF, swann ac et al. the lifetime cost of bipolar disorder in

19. svarstad bl, shireman ti, sweeney JK. Using drug claims data to assess the

the Us: an estimate for new cases in 1998. pharmacoeconomics. 2001;19:483-495.

relationship of medication adherence with hospitalization and costs. psychiatr

8. Dean bb, Gerner D, Gerner rh. a systematic review evaluating health-re-

serv. 2001;52:805-11.

lated quality of life, work impairment, and healthcare costs and utilization in

20. berk M, berk l, castle D. a collaborative approach to the treatment alli-

bipolar disorder. curr Med res Opin. 2004;20:139-154.

ance in bipolar disorder. bipolar Disord. 2004;6:504-18.

9. li J, Mccombs Js, stimmel Gl. cost of treating bipolar disorder in the

21. Miklowitz DJ. an update on the role of psychotherapy in the management

california Medicaid (Medi-cal) program. J affect Disord. 2002;71:131-139.

of bipolar disorder. curr psychiatry rep. 2006;8:498-503.

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 31

Managing Multiple Sclerosis: Maximizing Diagnosis and Treatment to Improve Patient Outcomes lily Jung, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

summary Multiple sclerosis is a disease in which permanent neurologic damage accumulates with each attack of symptoms. disease modifying therapy reduces the rate of relapse and thus decreases the amount of accumulated disability. early initiation of therapy is key to maximizing the ultimate amount of disability a person will have.

Key points • Multiple sclerosis is a neurodegenerative disease.

• diagnosis is made clinically based on lesions separated in time and in space.

• Clinically isolated syndrome is a marker for risk of developing clinically definite multiple sclerosis.

• Other risk factors include genetics, viral exposure, Northern european descent, and vitamin d deficiency.

• Treatment of Ms includes acute attack management, disease modification, and symptom management.

• early treatment with disease modifying agents decreases the amount of accumulated disability.

• Oral and injectable disease modifying agents reduce relapse rate and Mri evidence of disease.

MUltiple sclerOsis (Ms) is an attacK on the myelin sheath orchestrated by blood-borne immune cells invading the brain through the bloodbrain barrier with associated loss of neurons. it is primarily a t cell mediated phenomenon. permanent neurological damage is directly correlated to axonal damage. With each attack or relapse, the patient accumulates more damage. thus, Ms is a neurodegenerative disease. approximately 400,000 americans have Ms. the disease affects 2.5 million people worldwide. there appears to be a worldwide increase in Ms for which no one knows the cause. accurate data on incidence in the U.s. is difficult to obtain because it is not a cDc reportable disease. the incidence of Ms is high in canada, scandinavia, United Kingdom, and the northern U.s. Other areas with high rates are russia, eastern europe, new Zealand, and southeastern australia. risk for developing Ms is multifactorial. there is a genetic component, but genes are not the primary

risk factor. viral exposure, northern european descent, and vitamin D deficiency are all risk factors. there is no single test for Ms diagnosis. Diagnosis is still made clinically based on lesions separated in time and in space.1 Other mimickers need to be ruled out. Magnetic resonance imaging (Mri) is used to help with diagnosis but not everything that looks like Ms, even on Mri, is actually Ms. in the majority of patients with Ms, the first clinical neurological manifestation is a clinically isolated syndrome (cis). cis can be defined as a solitary, inflammatory, demyelinating syndrome of acute onset in the central nervous system (cns) in an individual with no prior history of demyelination and in whom alternative diagnoses have been excluded with appropriate clinical and laboratory investigations. individuals who experience a cis may or may not go on to develop multiple sclerosis. an Mri with findings consistent with Ms can be used to diagnose someone with cis at high risk for developing clinically definite Ms (cDMs). the diagnostic

32 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

exhibit 1: a Window of opportunity3-5

Window of opportunity disability

Natural Course of Ms later Treatment early Treatment

TiMe

criteria do allow for the diagnosis of Ms based on Mri and one clinically consistent episode.1 based on clinical trials in cis, several of the Ms medications are FDa approved for use in this population to prevent cDMs development. a new phenomenon is radiologically isolated syndrome. in this case, a patient has had an Mri scan for another reason which shows lesions suspicious for Ms. in one study, the presence of contrast enhancing lesions was predictive for development of cis or cDMs.2 For patients with serendipitously discovered lesions, serial Mris should be obtained to watch for changes. exhibit 1 shows what happens if patients with early lesions are treated.3-5 treatment during the early “window of opportunity” will affect the progression of disability over time. a patient treated early will never become as disabled as those who are treated later. Disease modifying therapy even started late can reduce the ultimate amount of disability. treatment of Ms is mainly in three areas: acute attack management, disease modification, and symptom management. health maintenance through appropriate immunizations, smoking cessation, vitamin D supplementation, and bone density monitoring are also important. because patients live a long life with Ms and do not generally die from their disease, regular health maintenance is important. smoking worsens Ms so cessation should be encouraged. Ms and the medications used to manage the disease increase risk for osteoporosis so bone density should be monitored.

Glucocorticosteroids are used to manage acute attacks.6 however, there does not appear to be any long-term functional benefit of these agents beyond brief use during a clinical attack. eight medications are currently approved as disease

modifying agents in Ms: interferon beta-1b (betaseron® and extavia®), interferon beta-1a (avonex ® and rebif ®), glatiramer (copaxone®), mitoxantrone (novantrone®), natalizumab (tysabri®), and fingolimod (Gilenya®). all of these are injectable agents with the exception of fingolimod. Mitoxantrone is a chemotherapy agent that is rarely used because of toxicities such as leukemia. natalizumab is a humanized monoclonal antibody that attaches to white blood cells. it is primarily used in patients with relapsing remitting Ms who have failed another disease modifying therapy because of the potential of adverse effects which includes progressive multifocal leukoencephalopathy (pMl). it may be used in some cases as initial therapy in a patient who presents with very aggressive disease. the risk of pMl is approximately one in 1000. the risk of developing pMl is lower in the U.s. compared with the european Union. prior exposure to John cunningham virus ( Jc virus) increases risk of developing pMl with natalizumab use because the virus reactivates when the infected person is immunocompromised. testing for prior exposure to this virus is being studied as a means to identify those patients at risk for pMl.7 Fingolimod is the first oral disease modifying agent for Ms which costs approximately $3,700/ month. it has been compared with placebo and interferon (iFnß-1a) compared with placebo, fingolimod reduced annualized relapse rate by 54 to 60 percent, reduced Mri inflammatory activity by 74 to 85 percent, reduced risk of disability progression by 37 to 40 percent for six months, and reduced brain atrophy by 32 to 36 percent. Oral fingolimod demonstrated superiority over iFnß-1a, a standard of care for Ms, at 12 months. Fingolimod 0.5 mg significantly reduced annualized relapse rate by 52

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 33

exhibit 2: primary endpoint: annualized relapse rate8

annualized relapse rate

-52% vs ifNß -1a p<0.0001 0.4

0.33

0.3 0.2

0.16

0.1 0.0

ifNß-1a iM (n=431)

exhibit 3: patient considerations lifestyle expectations Capabilities support system

Medical considerations Burden of disease enhancing lesions disease course Number of relapses

safety considerations

percent versus iFnß-1a (exhibit 2).8 Fingolimod 1.25 mg significantly reduced annualized relapse rate by 38 percent, but this dose was not approved by the FDa. both oral fingolimod doses significantly reduced Mri detected inflammatory activity compared with iFnß-1a iM. the major adverse effects are first dose bradycardia, increase in blood pressure over time, and decreases in respiratory function. cladrabine is a synthetic purine nucleoside analog that causes apoptosis of cD4+ and cD8+ lymphocytes and b cells with relatively transient effects on neutrophils and monocytes. the injectable form of this agent is currently FDa-approved for treatment of leukemias and lymphomas. Five days of oral treatment twice a year with this agent results in sustained immunomodulation. a two-year study found a reduction in annualized relapse rate compared to placebo.9 this agent decreases the white blood cell count which can be significant. the FDa rejected

fingolimod 0.5 mg (n=429)

the new drug application for oral cladribine in early 2011, but this agent may still make it to market as more data becomes available. numerous agents are under study for Ms treatment. these include alemtuzumab, bG12, teriflunomide, laquinomod, daclizumab, and rituxamab. alemtuzumab is a monoclonal antibody that may “reset” the bone marrow so the immune system no longer attacks the nervous system. it has been studied against interferon and reduces risk of relapse by 74 percent compared with interferon, reduced risk for sustained accumulation of disability and reduced mean disability. there are numerous choices in disease modifying agents. the choice of agent will depend on patient, disease, and safety considerations (exhibit 3). if the patient is doing well, usually a change in medication will not be made.

One questionable therapy for Ms is endovascular treatment of chronic cerebrospinal venous insufficiency (ccvi). ccvi is supposedly associated with Ms and doing percutaneous transluminal angioplasty of the azygous and internal jugular veins is proposed to alleviate symptoms. Many patients with Ms are looking for miracles, but this is a dangerous procedure that is not clearly of value. there are many symptoms of Ms that can and should be treated. this includes cognitive dysfunction, fatigue, depression, numbness/tingling/pain, weakness, bowel dysfunction, bladder dysfunction, sexual dysfunction, and tremor. these symptoms contribute significantly to the quality of life impairment related to Ms. Fampridine (ampyra) is an oral agent FDa approved to improve walking in patients with Ms. it is not a disease modifying agent and is rather expensive. For 20 to 25 percent of patients, this agent can make a difference in the distance a patient can walk

34 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

and how fatigued they get with walking. exercise is another important intervention in Ms. previously, it was believed that exercise worsened the disease but this has been disproven. all patients should be encouraged to exercise.

sclerosis: 2005 revisions to the â&#x20AC;&#x153;McDonaldâ&#x20AC;? criteria. ann neurol.

2005;58:840-6.

2. Okuda Dt, Mowry eM, beheshtian a, et al. incidental Mri anomalies suggestive of Ms. the radiologically isolated syndrome. neurology. 2009;72:800-5.

3. trapp bD, ransohoff r, rudick r. axonal pathology in multiple sclerosis: relationship to neurologic disability. curr Opin neurol. 1999;12:295-302.

conclusion

4. Jeffery Dr. early intervention with immunomodulatory agents in the treat-

the treatment of Ms continues to evolve. Disease modifying therapy is now available as an oral agent, which is an improvement over injectable agents. in addition to disease modifying therapy, many symptoms will also require management. because people with Ms live long lives, preventative medicine is also important to maintain their quality of life. JMCM

ment of multiple sclerosis. J neurol sci. 2002;197:1-8.

5. cohen Ja, carter Jl, Kinkel rp, schwid sr. therapy of relapsing multiple sclerosis. treatment approaches for nonresponders. J neuroimmunol. 1999;98:29-36.

6. Goodin Ds, Frohman eM, Garmany Gp Jr, et al. Disease modifying therapies in multiple sclerosis: subcommittee of the american academy of neurology and the Ms council for clinical practice Guidelines. neurology. 2002;58:169-78.

7. Gorelik l, lerner M, bixler s, et al. anti-Jc virus antibodies: implications for pMl risk stratification. ann neurol. 2010;68:295-303.

lily Jung, Md was recently named the Chief of staff at the new swedish/

8. cohen Ja, barkhof F, comi G, et al. Oral fingolimod or intramuscular inter-

issaquah Medical Center in issaquah, Wa. Previously, she was the

feron for relapsing multiple sclerosis. n engl J Med. 2010;362:402-15.

Medical director of the Neurology clinic and interim director of the

9. Giovannoni G, comi G, cook s, et al. clinical outcomes with cladribine

Multiple sclerosis clinic at swedish Neuroscience institute at swedish

tablets in the 96-week, phase iii, double-blind, placebo-controlled claritY

hospital in seattle.

study in patients with relapsing-remitting multiple sclerosis. program and abstracts of the 25th congress of the european committee for treatment and

references

research in Multiple sclerosis; september 9-12, 2009; Dusseldorf, Germany.

1. polman ch, reingold sc, edan G, et al. Diagnostic criteria for Multiple

abstract p470.

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 35

Optimizing Treatment and Costs in the Management of Rheumatoid Arthritis gary M. Owens, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

summary early intervention with disease modifying medications in most patients with rheumatoid arthritis (ra) is important to optimizing management. given the development of biologic agents, rheumatoid arthritis can be an expensive disease to manage.

There are steps managed care can take to ensure the appropriate use of biologic agents and manage costs related to these agents.

Key points • The course of the disease varies among patients.

• early intervention and therapy tailored to the aggressiveness of the presentation are key to managing ra.

• The medications used to treat ra all have significant adverse effects which should be prevented if possible.

• Biologic dMards have revolutionized treatment of ra but are not curative.

• Optimizing adherence and persistence with dMards are important in managing ra.

• agents from all mechanism of action categories should be included on the managed care formulary.

• One option for controlling TNf inhibitor costs is to consider limiting the number of switches between drugs in the same category.

• Plans should measure outcomes of care.

rheUMatOiD arthritis (ra) is a chrOnic inflammatory disease that involves both the articular joints and major organs.1,2 it is the most common inflammatory disease in humans, affecting about 1 percent of the population.2,3 it causes disability in approximately 50 percent of patients within 10 years of diagnosis.1 ra is a disease that reduces life expectancy.4 First-degree relatives of people with ra have double the risk of developing the disease. it occurs more commonly in women (3:1 compared with men). ra most commonly begins in ages 30 to 60. the most common symptoms are joint pain, fatigue, loss of appetite, nodules under the skin (painless), skin redness or inflammation, swollen glands, eye burning and itching, and deformities of hands and feet. ra affects many organ systems beyond the joints, including lungs bones, cardiovascular, and blood. Multisystem problems in ra include interstitial lung disease, osteoporosis, cardiovascu-

lar disease, thrombocytosis, anemia, fever, pleural inflammation, inflammatory vasculitis, cachexia, autoantibody production, increase in gammaglobulins, and abnormal blood counts. On a cellular level, this is a disease that involves various immune (b cells, t cells, and monocytes) and connective tissue (fibroblasts, synovial, and endothelial) cells.

Key diagnostic features are symptoms greater than six-week duration, inflammatory synovitis, palpable synovial swelling, morning stiffness for greater than one hour, and fatigue. it typically presents as a symmetrical and polyarticular (>3 joints) process. it typically involves wrists, metacarpophalangeal (Mcp) joints, and proximal interphalangeal (pip) joints of the hands and usually spares certain joints (i.e., thoracolumbar spine, distal interphalangeal (Dip) joints of the fingers and interphalangeal joints of the toes). patients may have subcutaneous or periosteal nodules at pressure points. rheumatoid factor is positive in 45 percent in first six months. eighty-five percent

36 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

exhibit 1: clinical course of ra5

severity of arthritis

4 type 1 3

type 2

2

type 3

1 0 0

0.5

1

2

3

4

6

8

16

Years Type 1 = self-limited—5% to 20% Type 2 = Minimally progressive—5% to 20% Type 3 = Progressive—60% to 90%

are positive with established disease. rheumatoid factor is not specific for ra, but a high titer early in the disease is a prognostic factor for progressive course. X-ray can show marginal erosions and joint space narrowing. exhibit 1 shows how not all ra patients are alike.5 some patients with ra have a self-limited course, whereas others will have minimally progressive or progressive disease. Joint damage occurs early in most patients. Fifty percent will show joint space narrowing or erosions in the first two years. by 10 years, 50 percent of young working patients are disabled. Many people do not think of ra as a fatal disease, but it does shorten life span related to complications. compared to the general population, women with ra lose 10 years and men lose four years. early intervention and therapy tailored to the aggressiveness of the presentation are key to managing ra. the sicker the patient is and the faster they get that way, the worse the future will be. early intervention can make a difference in the degree of disability accumulation. it is essential to establish a treatment plan early in the disease. the treatment principles in ra are: confirm the diagnosis.

• Determine where the patient stands in the spectrum of disease.

• When damage begins early, start aggressive treatment early.

• Use the safest treatment plan that matches the aggressiveness of the disease.

• Monitor treatment for adverse effects.

• Monitor disease activity and revise treatment as needed. assessment should include current disease activity,

degree of damage, functional status, extra-articular manifestations, and prior medication responses and side effects. the critical elements of the treatment plan are nonpharmacologic and pharmacologic therapies. nonpharmacologic therapy includes education, assistive devices such as splits and braces, exercise, and physical and/or occupational therapy. education is important for building a cooperative long-term relationship. treatment will almost always be required for a lifetime. the arthritis Foundation has many different programs which can be valuable for patients and can be a tremendous resource for managed care. exercise helps patients maintain range of motion and manage pain.

Medications that up or down regulate parts of the immune system’s inflammatory pathway are useful in ra. pharmacologic options for pain control include non-narcotic analgesics, narcotic analgesics, and nonsteroidal anti-inflammatory drugs (nsaiDs). nsaiDs are indicated for symptomatic relief and improved function. they do not change disease progression. the smallest dose of the agents with the least cardiovascular impact (i.e., ibuprofen, naproxen) should be used. Gastropathy secondary to nsaiDs is common. Gastric ulcers are more common than duodenal ulcers. there are no reliable warning signs – 80 percent of serious events occur without prior symptoms. the risk of hospitalization for nsaiD ulcers in ra is 2.5 to 5.5 times higher than the general population. Over 100,000 patients are hospitalized and 16,000 deaths occur annually in the U.s. because of nsaiD-induced gastrointestinal complications.6 the risk factors for having nsaiDinduced ulcers include older age (> 60), prior history of peptic ulcer or gastrointestinal symptoms with

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 37

exhibit 2: cost of therapy (Based upon WaC) generic

brand

Yearly cost

abatacept

Orencia

$20,500

adalimumab

humira

$20,800

certolizumab

Cimzia

$21,000

etanercept

enbrel

$21,200

golimumab

simponi

$20,800

infliximab

remicade

$21,100

rituximab

rituxan

$21,500

tocilizumab

actemra

$20,800

nsaiDs, concomitant use of prednisone, higher doses of nsaiD, and higher disability level. steroids can be used to manage inflammation and treat disease flares. low-dose prednisone (<10 mg daily) may substitute for nsaiDs and is used as bridge therapy until disease modifying anti-rheumatic drugs (DMarDs) begin to work. if steroids are used long term, prophylactic treatment for osteoporosis should be considered. intra-articular steroids are useful for disease flares. small molecule, immunosuppressive, and biologic DMarDs have been shown to slow progression of damage and development disability in ra. the small molecule DMarDs include minocycline, sulfasalazine, hydroxychloroquine, and intramuscular gold. because of modest efficacy and/or adverse effects, most of these are used very little for ra. immunosuppressive DMarDs include methotrexate, azathioprine, cyclophosphamide, and cyclosporine.

Methotrexate is the most effective single DMarD, is inexpensive, and should be the mainstay of therapy. the other agents are used less frequently and in patients who do not tolerate methotrexate. all the DMarDs have serious adverse effects.

For example, methotrexate can cause liver, lung, and bone marrow disease. Methotrexate lung is commonly overlooked. it first presents as a dry cough with shortness of breath and fever. it is most often seen in the first six months of treatment. the acute mortality is 17 percent and 50 to 60 percent of patients with ra have recurrence with retreatment, which carries the same mortality.7 the risk factors are older age, ra lung, prior use of DMarD, low

albumin, and diabetes. biologic DMarDs have revolutionized treatment of ra. although these agents do not cure the disease, they do provide dramatic improvements in symptoms and quality of life. they include tumor necrosis factor inhibitors [etanercept (enbrel®),infliximab (remicade®), adalimumab (humira®), certolizumab (cimzia®), golimumab (simponi®)], interleukin-1 seceptor antagonists [anakinra (Kineret ®)], interleukin 6 inhibitor [tocilizumab (actemra®)], t cell modulator [abatacept (Orencia®)], and b-cell killer [rituximab (rituxan®)]. these agents are all expensive and generally have about the same annual cost (exhibit 2). the available therapies for ra are not curative.8 For all the currently approved biologics, roughly 50 percent of patients will respond at an acr20 to acr50 level, which is a 20 to 50 percent reduction in symptoms.9 Other issues with biologics are that the dose of most is fixed within a narrow range.8,10 the injectable agents, particularly the anti-tnF agents, have reached top 20 status for spending on ra medications in managed care prescription data. certain employer demographics will have very high spend for ra agents, such as employers who primarily have younger, female employees. typically, therapy starts with a tnF inhibitor. if one does not work, patients may be switched to another one or have the dose escalated. there are limited data from randomized controlled trials to support switching between the various approved tnF-a antagonist drugs.11,12 a good general rule is to try two tnF inhibitors and then move on to an-

38 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

other class of biologic DMarD. all of the biologic DMarDs need frequent monitoring. blood, liver, lung, and kidney are frequent sites of adverse effects. the interval of laboratory testing varies with the medication. Most patients need to be seen three to six times a year. ra management to a great degree hinges on therapy adherence and persistence. Over the course of a year, a large number of patients will stop taking their ra therapy. in addition to general reasons such as lack of understanding and inability to pay, poor adherence and persistence may indicate suboptimal therapy. suboptimal therapy may be caused by inadequate relief of symptoms and disease progression. the benefits of the medication should be addressed with members in disease management or case management programs. Members need to know how to determine efficacy and how to communicate lack of efficacy to their providers. some example ways for ra include a decrease in pain, improvement in function, less morning stiffness, and few adverse drug events.

Managing biologic DMarDs can be an issue for health plans. agents from all mechanism of action categories should be included on the formulary. the plan can have preferred products within the classes that have more than one agent. One option for controlling tnF inhibitor costs is to consider limiting the number of switches between drugs in the same category. plans should design a disease management or case management approach to measure outcomes of care. plans should follow costs and help patients maintain adherence and persistency.

rheumatoid arthritis. lancet. 2007;370:1861-74.

conclusion

matoid arthritis after treatment with tumour necrosis factor alpha inhibitors

significant risk. treatment will need to change over time based on disease activity. Managed care can control the costs of biologic therapy with selected interventions. JMCM gary M. owens, Md is President of gary Owens associates.

references 1. World health Organization. chronic rheumatic conditions. available at http://www.who.int/chp/topics/rheumatic/en.

2. Firestein Gs. evolving concepts of rheumatoid arthritis. nature.

2003;423:356-61.

3. Olsen nJ, stein cM. new drugs for rheumatoid arthritis. n engl J Med. 2004;350:2167-79.

4. symmons D, Mathers c, pfleger b. the global burden of rheumatoid arthritis in the year 2000. available at http://www.who.int/healthinfo/statistics/ bod_rheumatoidarthritis.pdf.

5. pincus t. assessment of long-term outcomes of rheumatoid arthritis. how choices of measures and study designs may lead to apparently different conclusions. rheum Dis clin north am. 1995;21:619-54 6. singh G. recent considerations in nonsteroidal anti-inflammatory drug gastropathy. am J Med. 1998;105(suppl b):31s-38s.

7. Kremer JM, alarc贸n Gs, Weinblatt Me, et al. clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review. arthritis rheum. 1997;40:1829-37.

8. smolen Js, steiner G. therapeutic strategies for rheumatoid arthritis. nat rev Drug Disc. 2003;2:473-88.

9. smolen Js, Maini rn. interleukin-6: a new therapeutic target. arthritis res ther. 2006;8 suppl 2:s5.

10. smolen Js, aletaha D, Koeller M, et al. new therapies for treatment of 11. smolen Js, Kay J, Doyle MK, et al. Golimumab in patients with active rheu-

because joint damage begins early, effective treatment should begin early in most patients and should be targeted to aggressiveness of the disease. treatment with enough power to match the disease should be chosen. new classes of medications and biologics offer new opportunities but do come with

(GO-aFter study): a multicentre, randomised, double-blind, placebo-controlled, phase iii trial. lancet. 2009;374(9685):210-21.

12. voll re, Kalden Jr. Do we need new treatment that goes beyond tumor necrosis factor blockers for rheumatoid arthritis? ann n Y acad sci.

2005;1051:799-810.

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 39

moving millimeters

See how many millimeters you can move with EDARBI EDARBI 80 mg was statistically superior to DIOVAN® 320 mg and BENICAR® 40 mg in reducing 24-hr mean ambulatory and clinic SBP1 ReDUCTIONs IN 24-hR MeAN AMBUlATORy sBP AT Week 61,2 Mean ambulatory baseline: Study 1=144.9 mm Hg

STUDY sTUDy 11

t Similar results were observed across two other comparator studies: Study 2 vs BENICAR 40 mg and Study 3 vs DIOVAN 320 mg t Clinic SBP differences between EDARBI and active comparators were consistent with mean ambulatory results Study 1 Design: A 6-week, randomized, double-blind, placebo-controlled, forced-titration study in patients (N = 1,291) with clinic SBP ≥150 mm Hg and ≤180 mm Hg and 24-hr mean SBP ≥130 mm Hg and ≤170 mm Hg. The primary endpoint was change in 24-hr mean ambulatory SBP. Placebo lowered 24-hr mean ambulatory SBP by 0.3 mm Hg. Data shown are placebo corrected.

IMPORTANT sAfeTy INfORMATION WARNING: AVOID Use IN PReGNANCy When pregnancy is detected, discontinue eDARBI as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. t Avoid fetal or neonatal exposure.

DIOVAN 320 mg

-10.0 mm Hg

BENICAR 40 mg

-11.7 mm Hg

EDARBI 80 mg

-14.3 mm Hg

P<0.001 vs DIOVAN 320 mg P=0.009 vs BENICAR 40 mg References: 1. EDARBI Prescribing Information. 2. White WB, Weber MA, Sica D, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension.

Hypertension. 2011;57:413-420.

t Correct volume or salt depletion prior to administration of EDARBI. t Monitor for worsening renal function in patients with renal impairment. t In patients with an activated renin-angiotensin system, as by volume or salt depletion, reninangiotensin-aldosterone system (RAAS) blockers such as azilsartan medoxomil can cause excessive hypotension. In patients whose renal function may depend on the activity of the reninangiotensin system, e.g., with renal artery stenosis, treatment with RAAS blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. t Monitor renal function periodically in patients receiving EDARBI and NSAIDs who are also elderly, volume-depleted, or who have compromised renal function. t The most common adverse reaction in adults was diarrhea (2%). for further information, please see adjacent Brief summary of Prescribing Information.

INDICATIONs AND UsAGe EDARBI is an angiotensin II receptor blocker indicated for the treatment of hypertension in adults to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. There are no controlled trials demonstrating risk reduction with EDARBI, but at least one pharmacologically similar drug has demonstrated such benefits.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. EDARBI may be used either alone or in combination with other antihypertensive agents.

EDARBI is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

Trademarks the property of their respective ©2011 Takeda America, Inc. All rights reserved. LXA-00482 09/11 40 are Journal of Managed Careowners.

Medicine | Vol.Pharmaceuticals 14, No. 4 | North www.namcp.org

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for Edarbi (azilsartan medoxomil) tablets WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue Edarbi as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function.

Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbi.

Correct volume or salt depletion prior to administration of Edarbi, or start treatment at 40 mg. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Impaired Renal Function As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbi.

In patients whose renal function may depend on the activity of the reninangiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death.

Similar results may be anticipated in patients treated with Edarbi.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of Edarbi in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

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

A total of 4814 patients were evaluated for safety when treated with Edarbi at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least 6 months; of these, 588 were treated for at least 1 year.

Treatment with Edarbi was well-tolerated with an overall incidence of adverse reactions similar to placebo. The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2.4% (19/801) for placebo, 2.2% (24/1072) for Edarbi 40 mg, and 2.7% (29/1074) for Edarbi 80 mg. The most common adverse event leading to discontinuation, hypotension/orthostatic hypotension, was reported by 0.4% (8/2146) patients randomized to Edarbi 40 mg or 80 mg compared to 0% (0/801) patients randomized to placebo. Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race.

In placebo controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with Edarbi 80 mg daily compared with 0.5% of patients on placebo.

Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of â&#x2030;Ľ0.3% and greater than placebo in more than 3300 patients treated with Edarbi in controlled trials are listed below: Gastrointestinal Disorders: nausea General Disorders and Administration Site Conditions: asthenia, fatigue Musculoskeletal and Connective Tissue Disorders: muscle spasm Nervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal Disorders: cough Clinical Laboratory Findings In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommon with administration of Edarbi.

Serum creatinine: Small reversible increases in serum creatinine are seen in patients receiving 80 mg of Edarbi. The increase may be larger when coadministered with chlorthalidone or hydrochlorothiazide.

In addition, patients taking Edarbi who had moderate to severe renal impairment at baseline or who were >75 years of age were more likely to report serum creatinine increases.

Hemoglobin/Hematocrit: Low hemoglobin, hematocrit, and RBC counts were observed in 0.2%, 0.4%, and 0.3% of Edarbi-treated subjects, respectively.

None of these abnormalities were reported in the placebo group. Low and high markedly abnormal platelet and WBC counts were observed in <0.1% of subjects.

DRUG INTERACTIONS No clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, and warfarin. Therefore, Edarbi may be used concomitantly with these medications.

INDICATIONS AND USAGE Edarbi is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Edarbi.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Programâ&#x20AC;&#x2122;s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Edarbi may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women during the second and third trimester. When pregnancy is detected, Edarbi should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Edarbi as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system is available. In these rare cases, the mother should be apprised of the potential hazards to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Edarbi should be discontinued unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 41 irreversible injury.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving azilsartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including azilsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C (first trimester) and D (second and third trimesters).

There is no clinical experience with the use of Edarbi in pregnant women.

Nursing Mothers It is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in pediatric patients under 18 years of age have not been established.

Geriatric Use No dose adjustment with Edarbi is necessary in elderly patients. Of the total patients in clinical studies with Edarbi, 26% were elderly (65 years of age and older); 5% were 75 years of age and older. Abnormally high serum creatinine values were more likely to be reported for patients age 75 or older. No other differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment Dose adjustment is not required in patients with mild-to-severe renal impairment or end-stage renal disease. Patients with moderate to severe renal impairment are more likely to report abnormally high serum creatinine values.

Hepatic Impairment No dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Edarbi has not been studied in patients with severe hepatic impairment.

OVERDOSAGE Limited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once daily doses up to 320 mg of Edarbi were administered for 7 days and were well tolerated. In the event of an overdose, supportive therapy should be instituted as dictated by the patientâ&#x20AC;&#x2122;s clinical status. Azilsartan is not dialyzable.

CLINICAL PHARMACOLOGY Pharmacokinetics Special Populations The effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 1 as change relative to reference (test/reference). Effects are modest and do not call for dosage adjustment.

Figure 1 Impact of intrinsic factors on the pharmacokinetics of azilsartan Population Description

PK

Fold Change and 90% CI

Recommendation

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and 2-year rat studies. The highest doses tested (450 mg azilsartan medoxomil/kg/day in the mouse and 600 mg azilsartan medoxomil/kg/day in the rat) produced exposures to azilsartan that are 12 (mice) and 27 (rats) times the average exposure to azilsartan in humans given the maximum recommended human dose (MRHD, 80 mg azilsartan medoxomil/day). M-II was not carcinogenic when assessed in 26-week Tg.rasH2 mouse and 2-year rat studies. The highest doses tested (approximately 8000 mg M-II/kg/day (males) and 11,000 mg M-II/kg/day (females) in the mouse and 1000 mg M-II/kg/day (males) and up to 3000 mg M-II/kg/day (females) in the rat) produced exposures that are, on average, about 30 (mice) and 7 (rats) times the average exposure to M-II in humans at the MRHD. Mutagenesis: Azilsartan medoxomil, azilsartan, and M-II were positive for structural aberrations in the Chinese Hamster Lung Cytogenetic Assay. In this assay, structural chromosomal aberrations were observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan was also positive in this assay both with and without metabolic activation. The major human metabolite, M-II was also positive in this assay during a 24 hr assay without metabolic activation.

Azilsartan medoxomil, azilsartan, and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay.

Impairment of Fertility: There was no effect of azilsartan medoxomil on the fertility of male or female rats at oral doses of up to 1000 mg azilsartan medoxomil/kg/day [6000 mg/m2 (approximately 122 times the MRHD of 80 mg azilsartan medoxomil/60 kg on a mg/m2 basis)]. Fertility of rats also was unaffected at doses of up to 3000 mg M-II/kg/day.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).

General Information Pregnancy: Female patients of childbearing age should be told that use of drugs like Edarbi that act on the renin-angiotensin system during pregnancy can cause serious problems in the fetus and infant including low blood pressure, poor development of skull bones, kidney failure, and death. These consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Discuss other treatment options with female patients planning to become pregnant. Women using Edarbi who become pregnant should notify their physicians as soon as possible.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 For more detailed information, see the full prescribing information for Edarbi at www.edarbi.com or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327.

Edarbi is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Š2011 Takeda Pharmaceuticals America, Inc. April 2011 AZL074 R2 L-LXA-0411-4

AGE

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

No dose adjustment

Severe/Normal

Cmax AUC

No dose adjustment

ESRD/Normal

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

>65y/18-45y GENDER Females/Males RACE Whites/Blacks RENAL IMPAIRMENT

HEPATIC IMPAIRMENT

No dose adjustment

Severe/Normal

NO EXPERIENCE

PEDIATRIC

NO EXPERIENCE

0.5

1.0

1.5

2.0

Change relative to reference

2.5

3.0

42 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

Costs, Concerns, and Primary Care Coordination: Behavioral Health Survey Findings danyell Jones and Mark rosenberg, Md, Phd

summary: NaMCP/aaMCM Behavioral health survey findings: Behavioral health integration in Primary Care has recently been the focus of legislators, executives, and health care professionals. This article will reveal the findings of a NaMCP member survey related to these topics, and open dialogue about the topic of integration and coordination across Behavioral health and Primary Care Providers Key points: • survey results indicate that there is a new awareness in how Behavioral health issues can affect the overall health of a patient, as well as care costs.

• ineffective or inadequate treatment of mental health and substance abuse issues can significantly increase the cost of overall health care.

• Conversely, adequate treatment of Behavioral comorbidities in patients presenting with Primary Care issues can decrease costs of health care and increase overall health.

• Behavioral health/Primary Care integration is currently an important topic, and integration models continue to evolve. With changing legislation opening the doors to Behavioral health Care access, providers and organizations should look to what they can do from an integration perspective.

naMcp/aaMcn survey

the recognition, diagnosis, and treatment methodologies surrounding behavioral health have been changing in recent years. the field of behavioral health has benefited greatly from increased general awareness, decreased stigmatization, new legislation, and evolving models of integration between behavioral health and primary care, but there are still some areas of discrepancy regarding the impact that behavioral health is having on both patients and the health care industry from a financial perspective. in May 2011, the national association of Managed care physicians (naMcp) and the american association of Managed care nurses (aaMcn) conducted a member survey which questioned 142 respondents about the topic of behavioral health. the goal of this survey was to identify how members gauged the importance of behavioral health care in the overall treatment of patients, address the most impactful comorbidities, and determine the perceived cost impact of mental health and sub-

stance abuse on overall health care costs. this article will reveal the findings of that survey and discuss in more detail the results and the future of behavioral health integration.

Methodology and results respondent information

the respondents of the aaMcn/naMcp were a group comprised of individuals involved in various levels of health care, and representative of individuals employed by providers (14.6 percent), insurance companies/health plans (77.2 percent), employers/ purchasers (3.3 percent), and governmental entities (4.9 percent). their positions within these organizations ranged from Medical Directors (11.9 percent), to nurse Managers (30.2 percent) and case Mangers (9.8 percent), to Directors (4.9 percent) and executives (4.2 percent). Other positions represented included utilization reviewers, consultants, and clinicians. the survey respondents worked in a variety of health care areas with the majority of them serving

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exhibit 1: respondent distribution based on Work area

Behavioral health Management 4% utilization Management 47%

Case Management 38%

Quality Management 11%

exhibit 2: percentage of primary care Visits related to a Mental health/substance abuse issue

greater than 76%

1.5%

61% to 75%

6.2%

46% to 60%

16.2%

31% to 45%

28.5%

16% to 30%

33.1%

less than 15%

14.6% 0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

response percentage

functional roles in case management (37.8 percent) and utilization review (46.8 percent)(exhibit 1.)

Overall, a striking majority of the respondents recognized the importance of behavioral health in the overall health of their respective populations served with 93.6 percent of respondents rating behavioral health services as important or very important to the overall population served. regarding the importance of behavioral health, 5.7 percent of respondents were neutral, and less than 1 percent of respondents (.7 percent) believed that behavioral health was an unimportant factor when it came to serving the overall health care needs of their patient population. survey participants were also asked to identify the percentage of primary care visits which are related to a mental health or substance abuse issue. the survey findings revealed that 14.6 percent of respondents felt that less than 15 percent of visits

to a primary care provider were related to behavioral health issues, 33.1 percent of respondents, and the majority in this category, believed that 16 to 30 percent of visits to primary care were related to mental health or substance abuse and 28.5 percent of respondents believed that mental health or substance abuse issues were related to 46 to 60 percent of primary care visits. Of the respondentsâ&#x20AC;&#x2122; total, 7.7 percent believed that primary care visits related to behavioral health accounted for more than 61 percent of all visits overall(exhibit 2). cost

cost was a primary focus of the naMcp/aaMcn survey. basic determinations were sought to gauge how respondents valuated the impact of behavioral health comorbidities on the overall cost of health care, and whether or not effective treatment of men-

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responses percent

exhibit 3: diseases, When presented with a behavioral health comorbidity, Most dramatically increase health care cost

100.0% 90.0% 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0%

90.8% 66.9% 50.7%

diabetes

Coronary artery disease (Cad)

autoimmune disease

44.4%

Cancer

disease

tal health/substance abuse disorders would result in a decrease of overall health care costs. an overwhelming 95.7 percent of respondents stated that they believed that mental health/substance abuse co-morbidity either increases, significantly increases, or dramatically increases the overall cost of health care. interestingly, 97.1 percent of respondents felt that effective treatment of major mental health and/or substance abuse would result in an overall decrease in health care costs. these results indicate that behavioral health is a driving financial factor in the cost of health care and the financial standings of provider, insurer, employer, and government organizations. Furthermore, these findings illustrate the point that ineffective treatment of behavioral health issues can dramatically increase cost, while effective treatment can decrease overall health care cost. a number of specific diseases were identified as having the most dramatic impact in increasing overall health care costs, when presented with behavioral health co-morbidity. these diseases include diabetes, with 90.8 percent of respondents citing it as resulting in a dramatic cost increase, followed by coronary artery disease (66.9 percent), autoimmune disease (50.7 percent), and cancer (44.4 percent).(exhibit 3) correlation with educational Questions

there was some interest in the correlation between these diseases and behavioral health comorbidities expressed in an open-ended survey question. this question asked respondents to identify one area of behavioral health that should be addressed by the naMcp. several respondents stated that they would like more information assessing and address-

ing behavioral health issues while in a primary care setting. Others stated that they would be interested in learning more about facilitating coordination between medical providers and behavioral health providers. the co-management of behavioral health and primary care issues from a business and operational perspective was also a frequently requested inquiry. One survey participant stated that it would be beneficial to address behavioral health and the total cost of care as â&#x20AC;&#x153;it is not uncommon for patients with behavioral health co-morbidities to have nearly twice the annual total cost of care. Finding a way to more effectively manage the behavioral health issues will be a win for all parties-patients, employers, and health plans.â&#x20AC;? discussion

in summation, the findings of the naMcp and aaMcn behavioral health survey indicate that the majority of individuals within the health care industry realize the benefit of integrating behavioral health and primary care. additionally, the respondents are aware of the positive cost impact that this integration can have if behavioral health issues are effectively addressed and the negative cost impact of failing to treat behavioral health comorbidities. however, there are still questions as to how to most successfully implement integration from a patient care and financial management perspective, and the burdens to integration remain substantial. a recent report released by the Milbank Memorial Fund states that the four most predominant challenges to overcoming behavioral health/primary care coordination, or integration are: 1. behavioral and physical health providers have

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long operated in their separate areas.

2. cross coordination of efforts, and sharing of patient information between behavioral health providers and primary care providers rarely occurs.

3. confidentiality laws pertaining to substance abuse and mental abuse are generally more restrictive than those pertaining to physical health.

4. payment and mental health parity issues are prevalent.1 though these challenges to integration may at first glance seem daunting, there are currently hundreds of integrated care initiatives being put into place across the United states, including two large scale integration programs; the california integrated behavioral health project, and a care coordination program in the United states air Force. Many additional models for integrated care have also been emerging, making it more probable that a variety of organizations will be able to find an integration model which will best meet the needs of their business, and their patient base. in addition to the development of medium to large scale integration projects, a substantial number of initiatives have begun to target specific behavioral health comorbidities in primary care. Depression has been a frequent choice for these smaller initiatives due to the prevalence of the disease and the impact it has been shown to have on a number of physical disorders.

Despite the differing targets and goals of these integration models, it is generally agreed that there are four commonalities inherent in all integrated care models. “these concepts are the medical home, the health care team, stepped care, and the fourquadrant clinical integration.”2 clinics, hospitals, and providers across the country are beginning to experiment with these models, adapting mixtures of one or more model to better serve and reflect specific circumstances. some of the circumstances which may impact the design and implementation of a program model are patient population, population density, capacity, and regulatory and compliance issues. additionally, the level of coordination, or integration, can vary greatly between one organization and another, and as more research is conducted experts are now delineating between the definitions of care coordination and care integration. care coordination is generally referred to as coordination of patient care between primary care providers, and behavioral health specialists. the fundamentals of care coordination include screening for behavioral health issues in a primary care setting, developing a complex referral relationship between primary care providers and behavioral specialists, and encouraging the dissemination of information

between multiple providers for the optimal patient outcome. in the care coordination model primary care providers most often deliver behavioral health services, and referrals are made for more severe or advanced issues. care coordination services may be co-located, or conducted between providers and specialists at different locations. care integration, by comparison, is when overall care of the patient in all aspects has been integrated “as part of primary care and patients perceive it as a routine part of their health care.”2 in the integrated care model there is a single treatment plan for a patient, and care is delivered via a team comprised of primary care clinicians, case Managers, and behavioral health specialists. it is encouraging from a health care perspective that there is an almost unanimous realization of the benefits of integration and coordination, which only leaves the question of implementation and overcoming barriers to implement the most advantageous model for a practice. Finding unique ways to overcome the barriers to integration/coordination implementation should be a priority for all health care professionals moving forward, especially considering the prevalence of behavioral health disorders in the population, and the growing number of americans who will be eligible for services under proposed health care reform. according to a statistical report produced by the national institute of Mental health (niMh), it is estimated that over a quarter (26.2 percent) of americans over the age of 18 suffer from a diagnosable mental disorder in the course of a year.2 in addition, the substance abuse and Mental health services administration estimates that “32 million more americans will be covered in 2014. between 20 to 30 percent of these (6 to 10 million people) will have a mental or substance use disorder.3 Furthermore, it has been stated that the Mental health parity and addiction equity act will impact 140 million individuals participating in group health plans4, and that the affordable care act will increase the number of people who are insured, of which more than half are expected to have a mental disorder.5 this potentially large influx of newly covered individuals means that now is the time to plan for integration. there are a number of things which should be taken into consideration when identifying an integration model that will best meet the needs of your organization. From a patient care perspective, the goal should always be to reduce the associated stigma of behavioral health care, follow best practices for patients with comorbidities, and encourage care coordination and communication. additionally,

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assisting those individuals who present with more complex issues, or require chronic care should be a priority as these individuals tend to have the greatest cost impact on health care.

From an organizational and planning perspective, providers should determine their catchment area and examine the services offered in the area, as well as capacity for care. training and education for both behavioral health specialists, and primary care providers should be ongoing, and should be encouraged in a cross-disciplinary manner that facilitates coordination. Operational impact should be gauged to judge financial ramifications of integration, potential coding/billing issues that may arise, and regulatory/compliance risks that providers need to be aware of, and any potential reimbursement factors which will impact integration. the new emergence of multiple integration and coordination models, along with a multitude of mean of variation means that with the right research nearly every health care practice should be able to

find a model which allows for adaptable solutions to meet their individual needs. JMCM Mark rosenberg, Md, phd is the President of BhM healthcare solutions, a nationally recognized healthcare consulting firm and director of aaMCN/NaMCP Behavioral health institute. danyell Jones is the director of Customer solutions at BhM healthcare solutions.

We would also like to thank the Behavioral health executive leadership Committee for assistance gathering this data.

references 1. collings, chris, et al. evolving Models of behavioral health integration in primary care. health policy. new York: Millibank Memorial Fund, 2010.

2. national institute of Mental health. â&#x20AC;&#x153;niMh/nih/gov/statistics.â&#x20AC;? 2008. 2011 <http://www.nimh.nih.gov/statistics/pdf/ncs-r-any_Disorder.pdf>.

3. congressional budget Office. March 3, 2010 4. advocate for human potential. (2010). special report: Mhpaea regulations. issue paper number 4, 3.

5. Mechanic, D. (2001). closing Gaps in Mental health care. health services research 36:6.

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DEXILANT WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

DEXILANT works to effectively maintain EE healing and heartburn relief Median percentage of 24-hour heartburn-free periods of the maintenance of healed EE study—overall treatment1,2

96% %* 29% efficacy endpoint, 0*Secondary20 40 p<0.0025 60

DEXILANT 30 mg (n=132) Placebo 80 (n=141)100

24

HRS

DEXILANT 30 mg provides effective maintenance of EE healing • 66% of patients remained healed over 6 months with DEXILANT 30 mg (n=125) vs 14% with placebo (n=119; p<0.00001).

Study primary endpoint.1,2 Results of a 6-month, multicenter, double-blind, placebo-controlled, randomized study of patients who had successfully completed an EE study and showed endoscopically confirmed healed EE. Based on crude rate estimates, patients who did not have endoscopically documented relapse and prematurely discontinued were considered to have relapsed.

Conclusions of comparative efficacy cannot be drawn from this information.

Indications

DEXILANT is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE and relief of heartburn for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

Important Safety Information

DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.

Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Hypomagnesemia has been reported rarely with prolonged treatment with PPls. Most commonly reported adverse reactions were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).

Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations.

Please see adjacent brief summary of prescribing information for DEXILANT. ‡ Wolters Kluwer Pharma Solutions, Dynamic Claims, ≤30 days supply, commercial plans only, September 2010–March 2011. §Average commercial patient cost for a 30-day prescription represents patient out-of-pocket expenses after use of programs such as electronic vouchers and Instant Savings cards.

Average patient costs for DEXILANT are less than all other branded Rx PPIs†‡§

†Based on average out-of-pocket costs for commercially insured patients.

Cost comparisons do not imply comparable safety, efficacy, or FDA-approved indications.

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BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed-release capsules for oral use INDICATIONS AND USAGE DEXILANT is indicated for: · the healing of all grades of erosive esophagitis (EE) for up to 8 weeks · maintaining healing of EE and relief of heartburn for up to 6 months · the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

CONTRAINDICATIONS DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Gastric Malignancy Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.

Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Adverse Reactions].

Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions].

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

The safety of DEXILANT was evaluated in 4548 patients in controlled and uncontrolled clinical studies, including 863 patients treated for at least 6 months and 203 patients treated for one year. Patients ranged in age from 18 to 90 years (median age 48 years), with 54% female, 85% Caucasian, 8% Black, 4% Asian, and 3% other races. Six randomized controlled clinical trials were conducted for the treatment of EE, maintenance of healed EE, and symptomatic GERD, which included 896 patients on placebo, 455 patients on DEXILANT 30 mg, 2218 patients on DEXILANT 60 mg, and 1363 patients on lansoprazole 30 mg once daily.

Most Commonly Reported Adverse Reactions The most common adverse reactions (≥2%) that occurred at a higher incidence for DEXILANT than placebo in the controlled studies are presented in Table 2.

Table 2: Incidence of Adverse Reactions in Controlled Studies Placebo DEXILANT DEXILANT DEXILANT Lansoprazole 30 mg 60 mg Total 30 mg (N=896) (N=455) (N=2218) (N=2621) (N=1363) Adverse Reaction % % % % % Diarrhea 2.9 5.1 4.7 4.8 3.2 Abdominal Pain 3.5 3.5 4.0 4.0 2.6 Nausea 2.6 3.3 2.8 2.9 1.8 Upper Respiratory 0.8 2.9 1.7 1.9 0.8 Tract Infection Vomiting 0.8 2.2 1.4 1.6 1.1 Flatulence 0.6 2.6 1.4 1.6 1.2 Adverse Reactions Resulting in Discontinuation In controlled clinical studies, the most common adverse reaction leading to discontinuation from DEXILANT therapy was diarrhea (0.7%).

Other Adverse Reactions Other adverse reactions that were reported in controlled studies at an incidence of less than 2% are listed below by body system: Blood and Lymphatic System Disorders: anemia, lymphadenopathy; Cardiac Disorders: angina, arrhythmia, bradycardia, chest pain, edema, myocardial infarction, palpitation, tachycardia; Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo; Endocrine Disorders: goiter; Eye Disorders: eye irritation, eye swelling; Gastrointestinal Disorders: abdominal discomfort, abdominal tenderness, abnormal feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breath odor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis,

gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal blistering, painful defecation, proctitis, paresthesia oral, rectal hemorrhage, retching; General Disorders and Administration Site Conditions: adverse drug reaction, asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation, nodule, pain, pyrexia; Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly; Immune System Disorders: hypersensitivity; Infections and Infestations: candida infections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, viral infection, vulvo-vaginal infection; Injury, Poisoning and Procedural Complications: falls, fractures, joint sprains, overdose, procedural pain, sunburn; Laboratory Investigations: ALP increased, ALT increased, AST increased, bilirubin decreased/increased, blood creatinine increased, blood gastrin increased, blood glucose increased, blood potassium increased, liver function test abnormal, platelet count decreased, total protein increased, weight increase; Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia; Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, muscle cramps, musculoskeletal pain, myalgia; Nervous System Disorders: altered taste, convulsion, dizziness, headaches, migraine, memory impairment, paresthesia, psychomotor hyperactivity, tremor, trigeminal neuralgia; Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido changes; Renal and Urinary Disorders: dysuria, micturition urgency; Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia, menstrual disorder; Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis, cough, dyspnoea, hiccups, hyperventilation, respiratory tract congestion, sore throat; Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritis, rash, skin lesion, urticaria; Vascular Disorders: deep vein thrombosis, hot flush, hypertension Additional adverse reactions that were reported in a long-term uncontrolled study and were considered related to DEXILANT by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity, cholecystitis acute, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gout, herpes zoster, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, rectal tenesmus, restless legs syndrome, somnolence, tonsillitis.

Other adverse reactions not observed with DEXILANT, but occurring with the racemate lansoprazole can be found in the lansoprazole prescribing information, ADVERSE REACTIONS section.

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

Blood and Lymphatic System Disorders: autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura Ear and Labyrinth Disorders: deafness Eye Disorders: blurred vision Gastrointestinal Disorders: oral edema, pancreatitis General Disorders and Administration Site Conditions: facial edema Hepatobiliary Disorders: drug-induced hepatitis Immune System Disorders: anaphylactic shock (requiring emergency intervention), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal) Metabolism and Nutrition Disorders: hypomagnesemia, hyponatremia Musculoskeletal System Disorders: bone fracture Nervous System Disorders: cerebrovascular accident, transient ischemic attack Renal and Urinary Disorders: acute renal failure Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness Skin and Subcutaneous Tissue Disorders: generalized rash, leucocytoclastic vasculitis DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics DEXILANT causes inhibition of gastric acid secretion. DEXILANT is likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, DEXILANT should not be co-administered with atazanavir.

DEXILANT may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).

Warfarin Co-administration of DEXILANT 90 mg and warfarin 25 mg did not affect the pharmacokinetics of warfarin or INR [see Clinical Pharmacology]. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with DEXILANT and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Tacrolimus Concomitant administration of dexlansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

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USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed.

A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9 times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole [see Nonclinical Toxicology].

Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Nonclinical Toxicology], 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 Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established.

Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole.

Hepatic Impairment No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. However, serious adverse events of hypertension have been reported in association with twice daily doses of DEXILANT 60 mg. Non-serious adverse reactions observed with twice daily doses of DEXILANT 60 mg include hot flashes, contusion, oropharyngeal pain, and weight loss. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive.

CLINICAL PHARMACOLOGY Pharmacodynamics Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment.

Enterochromaffin-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months.

During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology].

Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day.

Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology].

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended human lansoprazole dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.

In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 to 600 mg per kg per day, 2 to 80 times the recommended human lansoprazole dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg lansoprazole per kg per day (40 to 80 times the recommended human lansoprazole dose based on BSA) and female mice treated with 150 to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human lansoprazole dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice.

Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended human lansoprazole dose based on BSA).

A 26-week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not positive.

Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test.

Dexlansoprazole was positive in the Ames test and in the in vitro chromosome aberration test using Chinese hamster lung cells. Dexlansoprazole was negative in the in vivo mouse micronucleus test.

The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

PATIENT COUNSELING INFORMATION To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved Patient Information Leaflet should be discussed with the patient.

Inform the patient to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued.

Advise the patient to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see Warnings and Precautions].

Advise the patient to tell their health care provider if they take atazanavir, tacrolimus, warfarin and drugs that are affected by gastric pH changes [see Drug Interactions].

Advise the patient to follow the dosing instructions in the Patient Information Leaflet and inform the patient that: · DEXILANT is available as a delayed release capsule. · DEXILANT may be taken without regard to food. · DEXILANT should be swallowed whole. · Alternatively, DEXILANT capsules can be administered as follows: – Open capsule; – Sprinkle intact granules on one tablespoon of applesauce; – Swallow immediately. Granules should not be chewed.

– Do not store for later use.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. Trademark registered with the U.S. Patent and Trademark office.

All other trademark names are the property of their respective owners. ©2009, 2011 Takeda Pharmaceuticals America, Inc. DEX006 R14_BS Revised: June 2011 L-LPD-0611-2

References: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. 2. Metz DC, Howden CW, Perez MC, et al. Aliment Pharmacol Ther. 2009;29:742-754.

DEXILANT and DEXILANT (with design) are trademarks of Takeda Pharmaceuticals North America, Inc., registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Dual Delayed Release is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc.

©2011 Takeda Pharmaceuticals North America, Inc. LPD-01866 7/11 Printed in U.S.A.

Lessons Learned from Fibromyalgia: Understanding Chronic Pain daniel J. Clauw, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

summary fibromyalgia, a predominately centrally medicated chronic pain state, can be used to illustrate the advances that have been made in understanding and treating chronic pain. Because central chronic pain is caused by alterations in pain perception and modulation, therapy needs to target central nervous system neurotransmitters. Therapy with nonpharmacologic interventions also is necessary to manage the functional consequences of pain and psychological factors.

Key points • Current paradigms for diagnosing and treating chronic pain are obsolete and need to change.

• Central neuronal factors play a prominent role in inter-individual differences in pain sensitivity and are present in all chronic pain states.

• Central mechanisms of pain are prominent in fM, irritable bowel syndrome, temporomandibular joint disease, and tension headache.

• Central pain is typically characterized by multifocal pain, high current and lifetime history of pain, and multiple somatic symptoms.

• Chronic pain mechanisms are totally different from those of acute pain.

• Treatment should be dually focused using pharmacologic and nonpharmacologic therapies.

• Cognitive behavioral therapy and exercise programs are effective, inexpensive treatments for chronic pain that should be covered by managed care plans.

• Nsaids, opioids, and injections are not effective treatments for central chronic pain.

• There should be barriers to using ineffective treatments in chronic pain.

there is nO chrOnic pain state Where the degree of damage or inflammation in the periphery (i.e., nociceptive input) correlates well with level of pain, predicts severity of pain, or predicts who will have chronic pain. Our diagnostic paradigms - and terms we use to describe chronic pain states - imply otherwise. Until recently, many assumed that when there was a disparity between peripheral findings and pain, that this was primarily due to psychological factors. Our current paradigms for diagnosing and treating chronic pain are obsolete and need to change. historically, if the medical examination and multitude of tests could not find a reason for the patient’s pain, it was blamed on the patient. Fibromyalgia (FM) is one such disease that has no outward objective evidence of pain. FM can be used as an example

of a centrally-based chronic pain state to describe the advances in knowledge regarding chronic pain. there are a multitude of nonpsychological, neurobiological factors that can increase or decrease sensitivity to pain, and these are operative in many chronic pain states. because these central factors play prominent roles in most individuals with chronic pain, it is imperative that we modify our diagnostic and therapeutic paradigms to better identify and treat “central pain”. a contemporary view of chronic pain is that it can originate from three different sources: peripheral nociceptive input from damaged or inflamed tissues, nerve damage or dysfunction (neuropathic pain), and central spinal and supraspinal mechanisms (exhibit 1). We have had a historical tendency to put different “diseases” in different pain categories,

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exhibit 1: Mechanistic characterization of pain any combination may be present in a given individual

peripheral

(nonciceptive) • inflammation or mechanical damage in tissues • Nsaid, opioid responsive • responds to procedures • Classic examples – acute pain due to injury – Osteoarthritis – rheumatoid arthritis – Cancer pain

neuropathic

• damage or dysfunction of peripheral nerves • responds to both peripheral (Nsaids, opioids, Na channel blockers) and central (TCa’s, neuroactive compounds) pharmacological therapy • Classic examples - diabetic neuropathic pain - Post-herpetic neuralgia

but this is overly simplistic, because it appears central neuronal factors play a prominent role in leading to tremendous inter-individual differences in pain sensitivity that seem to be closely associated with clinical outcomes in nearly any chronic pain state. the central factors can be best thought of as a volume control on what happens to peripheral nociceptive input. For example, population-based studies show that 30 to 40 percent of individuals with significant radiographic osteoarthritis joint damage are pain-free. Only about 20 percent of individuals with diabetic neuropathy have pain. thus, there must be significant central influences on pain processing. central pain features occur across all chronic pain syndromes but occur over a wide continuum Until relatively recently, these central influences were felt to primarily be psychological, but now it is clear that chronic pain is a complex experience. central factors such as augmented pain and sensory processing are playing significant roles in subsets of individuals in any chronic pain state. thus, most individuals with osteoarthritis and rheumatoid arthritis have evidence of peripheral nociceptive input, and most with FM have prominent central factors, but no chronic pain state is solely due to any one of these

central

(non-nociceptive) • Characterized by central disturbance in pain processing (diffuse hyperalgesia/ allodynia) • responsive to neuroactive compounds altering levels of neurotransmitters involved in pain transmission • Classic examples - fibromyalgia - irritable bowel syndrome - TMJd - Tension headache

mechanisms. Diagnostic labels (e.g., fibromyalgia, ibs, tMJD) are largely historical and irrelevant.1 Wolfe has shown that degree of “fibromyalgia-ness” predicts pain intensity, symptoms and disability over a wide range of rheumatic disorders.2 central mechanisms of pain are prominent in FM, irritable bowel syndrome, temporomandibular joint disease, and tension headache. central pain is typically characterized by multifocal pain, high current and lifetime history of pain, and multiple somatic symptoms (e.g., fatigue, memory difficulties, sleep disturbances). patients with chronic pain syndromes generally have a normal physical examination except for diffuse tenderness and nonspecific neurological signs.3 central pain syndromes are one and a half to two times more common in females. the fact that FM is almost exclusively a female condition is an artifact of the diagnostic criteria, which requires not only widespread pain but also tender points. Women tend to be tenderer than men. chronic pain syndromes have strong familial/genetic underpinnings. it is important in a chronic pain patient to take a family history of pain. specifically looking at the genetics of FM, recent work

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exhibit 2: overlap between pain syndromes and psychiatric conditions 4,16

psychiatric disorders

chronic widespread pain (cWp)

• 10% of population • fibromyalgia defined

by CWP plus tenderness

pain and/or sensory amplification

regional pain syndromes

• 20 - 30% of population • subsets of individuals with any regional pain syndrome display hyperalgesia

• Nearly every type of psychiatric disorder is more common in any type of chronic pain syndrome, and vice-versa – depression – Bipolar – PTsd – gad – Panic attack somatoform disorders

• 4% of population • multiple unexplained symptoms – no “organic” findings

suggests a greater than eight odds ratio for first-degree relatives.4 some of the genes that may be involved include serotonin receptor polymorphism t/t phenotype, serotonin transporter, dopamine D4 receptor exon iii repeat polymorphism, and catecholamine o-methyl transferase (cOMt).5-8 identifying the specific genetic mutations that lead to altered pain processing in an individual patient may help in selection of appropriate therapy. cOMt mutations have recently been shown to be associated with increased pain, especially in females, in osteoarthritis, dyspepsia, and shoulder pain. these mutations have been shown to be predictive of responsiveness to drugs for certain chronic pain states – the first step in “personalized analgesia”.9-10 as various genetic mutations that lead to altered pain processing are discovered, genetic testing in chronic pain patients will become more common. Managed care will have to develop reimbursement policies for these tests. the mechanisms that underlie chronic pain are totally different from those of acute pain. chronic pain syndromes are characterized by augmented pain processing and sensory amplification identifiable via experimental pain and sensory testing and functional neuroimaging. chronic pain is in part due to alterations in central nervous system levels of neurotransmitters involved in controlling descending facilitatory and inhibitory pathways. like most other physiological processes, humans have a “volume control” setting for how our brain and spinal cord processes pain and other sensory information.11 this is likely set by genes and modified

by neurohormonal factors and neural plasticity. the higher the volume control setting, the more pain we will experience, irrespective of peripheral nociceptive input. this volume control setting will determine whether someone will have chronic pain irrespective of whether they damage a joint or have an autoimmune inflammatory disease. allodynia or hyperalgesia is the term for heightened pain sensitivity. chronic pain may be a neurodegenerative disease. the longer it is present, the harder it is to treat. the brain regions involved in pain processing atrophy over time.12,13 this is a reason to aggressively manage chronic pain from the beginning. there are a number of stressors capable of triggering central pain states. these include early life events such as institutionalization, peripheral pain syndromes (e.g., rheumatoid arthritis, lupus, osteoarthritis), physical trauma (e.g., automobile accidents), certain catastrophic events (war but not natural disasters), infections, and psychological stress/ distress.14,15 there is overlap between chronic pain states and other comorbid pain syndromes, psychiatric disorders, somatoform disorders, and regional pain syndromes (exhibit 2).4,16. it is likely that the observed overlap between individuals who have one type of chronic pain and another centrally medicated disorder occurs because the mechanisms that underlie any chronic pain state are similar. Depression and central chronic pain have overlapping neurobiological processes. some neurotransmitters such as serotonin and norepinephrine are involved, albeit in dif-

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exhibit 3: essential hypertension of pain processing pathways

facilitation

inhibition

• substance P

• descending anti-nociceptive pathways

• glutamate and eaa • serotonin (5hT2a, 3a)

+

–

• Norepinephrineserotonin (5hT1a,b), dopamine

• Nerve growth factor

• Opioids

• CCK

• gaBa • Cannabanoids • adenosine arrows indicate changes shown in fM

ferent brain regions, in pain and sensory processing, as well as in mood. thus, patients with depression, chronic pain, or both will respond to medications that alter these brain neurotransmitters. how individuals think about their pain can affect both the sensory and affective processing of pain. this has been shown on functional Mri. this is also why cognitive behavioral therapy (cbt) works well across a number of chronic pain states. a major problem with reimbursement across all chronic pain states is preferential reimbursement for medications, procedures, and devices over cbt. a chronic pain physician can easily order an expensive test like an Mri or get approval for a spinal stimulator but cannot get approval for six one-hour sessions of cbt that cost $300 and have been shown to be broadly efficacious. reimbursement for physical therapybased exercise programs is also an issue. Most benefits are for 12 weeks of therapy, which is sufficient for acute pain. a better approach for chronic pain is a series of once a month visits as a booster to help patients stick with an exercise routine. lack of reimbursement is the major reason cbt and exercise programs are not utilized in routine clinical practice. changing benefit structure to allow people to get the same number of physical therapy visits over a one-year period instead of just 12 weeks and covering cbt for chronic pain conditions could lead to dramatic cost savings across all chronic pain states. chronic pain is not much different from other com-

plex medical illnesses. chronic pain can be thought of like essential hypertension of pain processing pathways. patients with chronic pain have an imbalance between substances that facilitate pain and those that inhibit pain processing (exhibit 3). as shown in exhibit 3, the only inhibitor neurotransmitter that patients with FM have in a heightened state is endogenous opioids. this is likely why opioid medications are not effective in central chronic pain states.

Unfortunately, opioids are heavily used. not only do they not work, they may be making patients worse by superimposing opioid-induced hyperalgesia on top of disease-related hyperalgesia. Getting patients off opioids can dramatically improve their pain. there need to be barriers to using opioids in chronic pain states. the use of the wrong medications, injections, and surgical procedures in routine clinical practice for FM is a significant problem. nsaiDs are the number two prescribed class of medications for FM, yet they are not effective. Opioids are number four. there is no evidence that the overwhelming majority of injection procedures such as nerve blocks have any demonstrated efficacy in the setting in which they are being used. the same could be said for many surgical procedures for chronic pain. because descending analgesic pathways mediated by serotonin and norepinephrine are attenuated in FM and other chronic pain states, tricyclic antidepressants and dual reuptake inhibitors (duloxetine, milnacipran) work well. pentanoids (gabapetin, pre-

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gabalin) modulate substance p and glutamate, other affected neurotransmitters. combination of an agent that targets serotonin and norepinephrine with an agent that targets substance p and glutamate will improve the likelihood of a good improvement compared with either agent alone. this is moving therapy for chronic pain closer to similar therapies utilized to treat hypertension and other chronic medical diseases. there are two markedly different domains that must be addressed in chronic pain patients –cause of the pain and functional consequences of pain. the cause of the pain may be nociceptive processes (damage or inflammation of tissues) or disordered sensory processing (volume control issue). Functional consequences of pain include increased distress, decreased activity, isolation, poor sleep, and maladaptive illness behaviors. the functional issues worsen pain and lead to a spiraling process. the best treatments for the functional consequences are exercise, education, and cbt. patients with chronic pain need dually focused treatment using pharmacologic and nonpharmacologic therapies. the nonpharmacologic therapies are inexpensive but underutilized. nonpharmacologic therapies need to come before surgical procedures and expensive diagnostic testing. these should especially be promoted for use early in the disease process when the person is beginning to move from acute to chronic pain. it might prevent the development of chronic pain. For those patients who do develop chronic pain, early treatment will result in more success. now that we know central pain mechanisms affect pain perception in many chronic pain states, medications are being developed to target the mechanisms.

One agent under study that acts on volume control of pain processing is tanezumab, a monoclonal antibody against nerve growth factor. it has shown efficacy in chronic low back pain. agents like this will be coming to market in a few years and will be expensive.

rheum Dis clin north am. 2009;35:233-51.

2. Wolfe F, rasker JJ. the symptom intensity scale, fibromyalgia, and the meaning of fibromyalgia-like symptoms. J rheumatol. 2006;33:2291-9.

3. Watson nF, buchwald D, Goldberg J, et al. neurologic signs and symptoms in fibromyalgia.arthritis rheum. 2009;60:2839-44.

4. arnold lM, hudson Ji, hess ev, et al. Family study of fibromyalgia. arthritis rheum. 2004;50:944-52.

5. bondy b, spaeth M, Offenbaecher M, et al.the t102c polymorphism of the 5-ht2a-receptor gene in fibromyalgia. neurobiol Dis. 1999;6:433-9.

6. Offenbaecher M, bondy b, de Jonge s, et al. possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. arthritis rheum. 1999;42:2482-8.

7. buskila D, cohen h, neumann l, ebstein rp. an association between fibromyalgia and the dopamine D4 receptor exon iii repeat polymorphism and relationship to novelty seeking personality traits. Mol psychiatry. 2004;9:730-1.

8. Gürsoy s, erdal e, herken h, et al. significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. rheumatol int. 2003;23:104-7.

9. clauw DJ, Witter J. pain and rheumatology: thinking outside the joint. arthritis rheum. 2009;60:321-4.

10. George sZ, Dover Gc, Wallace Mr, et al. biopsychosocial influence on exercise-induced delayed onset muscle soreness at the shoulder: pain catastrophizing and catechol-o-methyltransferase (cOMt) diplotype predict pain ratings. clin J pain. 2008;24:793-801.

11. Mogil Js. the genetic mediation of individual differences in sensitivity to pain and its inhibition. proc natl acad sci U s a. 1999;96:7744-51.

12. apkarian av, sosa Y, sonty s, et al. chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J neurosci. 2004;24:10410-5.

13. Kuchinad a, schweinhardt p, seminowicz Da, et al. accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J neurosci.

2007;27:4004-7.

14. clauw DJ, chrousos Gp. chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. neuroimmunomodulation. 1997;4:134-53.

15. Mclean sa, clauw DJ. predicting chronic symptoms after an acute “stressor”-lessons learned from 3 medical conditions. Med hypotheses. 2004;63:653-8.

16. Kato K, sullivan pF, evengård b, pedersen nl. a population-based twin study of functional somatic syndromes. psychol Med. 2009;39:497-505.

conclusion

new paradigms need to be applied to the diagnosis and treatment of chronic pain states. Managed care can be instrumental in improving care for patients with chronic pain by covering appropriate nonpharmacologic therapies and by implementing barriers to inappropriate medication and procedure use. JMCM daniel J. clauw, Md is a Professor of anesthesiology, Medicine (rheumatology) and Psychiatry and director, Chronic Pain and fatigue research Center at The university of Michigan

references 1. ablin K, clauw DJ. From fibrositis to functional somatic syndromes to a bellshaped curve of pain and sensory sensitivity: evolution of a clinical construct.

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Emerging Trends and Strategies in the Treatment of Breast Cancer george somlo, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

summary although the death rate has been declining, breast cancer still has a significant impact on women. Because breast cancer is not one single disease, therapy needs to be individualized. Treatment decision making advances include the use of computer models and tumor gene expression testing to better target therapy. Therapeutic advances include therapies to target certain tumor gene expression.

Key points • Breast cancer is the second leading cause of death in women, but the death rate has been declining.

• Breast cancer is not one single disease, thus treatment decisions are based on tumor and prognostic factors.

• several tools are available to assist in treatment decision making.

• Treatment guidelines also provide assistance in making treatment decisions.

• estrogen receptor-positive patients receive antiestrogen therapy after surgical treatment with individual agents chosen based on menopausal status.

• her2 over-expression accounts for about 25 percent of cases of primary breast cancer.

• Trastuzumab use in the her2-positive patients results in clear improvement in relapse and survival.

• Breast cancer in which hormone receptors and her2 are negative is treated with chemotherapy.

• The use of bevacizumab in metastatic breast cancer is controversial.

breast cancer is the secOnD leaDinG cause of death in women. approximately 200,000 women in the United states are diagnosed with breast cancer annually and more than 40,000 will die from breast cancer.1 Overall, one in eight women will develop breast cancer and one in 30 will die from the disease. the death rate from this disease has been declining during the last 25 years.2 reasons for this decline include earlier diagnosis, better adjuvant therapies, and decreased use of hormone replacement therapy.

Once breast cancer is diagnosed, treatment decisions are made based on the stage of disease based on tumor size and degree of lymph node involvement and prognostic factors. these include estrogen/progesterone receptor status, tumor histopathology, and other molecular markers such as human epidermal growth

factor receptor 2 (her2). there are many other molecular markers currently under development. there are several tools oncologists are using to assist in treatment decision making. One of these is a computer program, adjuvant Online (adjuvantonline.com), which can give an estimated risk of relapse based on patient specific data. this is a rough estimate. it does not tell the oncologist which patients do not need intervention. treatment decision making has been moving more into molecular-based, evidence- supported decision making. Oncotype DX is an example test which examines the patient’s tumor for the expression of 21 different genes and provides a score which identifies which patients would or would not have benefit from the addition of chemotherapy to hormone therapy.

Oncotype DX testing is only relevant for patients

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exhibit 1: advanced breast cancer is treated based on the biology of the tumor

advanced breast cancer requiring therapy

er and/or pr positive hormonal treatments

refractory to hormonal therapy

chemorx anti-angiogenetic and investigational agents

er and/or negative chemotherapy

her2 positive chemotherapy + trastuzumab

chemotherapy, dual inhibitors investigational agents

with estrogen receptor-positive disease. chemotherapy in addition to adjuvant hormone therapy can reduce risk of recurrence about 25 percent in patients with an Oncotype DX score of greater than 31. this tool is still being validated in studies. Using this type tool will hopefully allow patients to avoid getting chemotherapy when they would not benefit. the alternative approach to trying to figure out predictors in primary breast tumors is Mammaprint. in the U.s., breast tissue samples are fixed with formalin before testing. in europe, Mammaprint is conducted using fresh tissue. this test checks for 70 different gene expressions.3 even at the gene level, we are still looking at estrogen receptor negative or positive and her2 over-expression. this test is the equivalent of immunohistochemical analysis, although it is more sophisticated and is not 100 percent overlapping. it can be used for all patients with breast cancer unlike the Oncotype DX. there are preliminary data from europe suggesting that this assay can identify patients at high risk for relapse. validation trials are underway. these new assays are providing better selection of patients for potentially toxic chemotherapy. We are getting more sophisticated in figuring out prognostic markers but are still not ideal. estrogen receptor status is the primary decision

her2 negative chemotherapy

chemorx anti-angiogenetic investigational agents

maker in what treatment will be given after primary surgery. about 55 percent of patients with primary breast cancer will be estrogen receptor positive. adjuvant hormone therapy significantly reduces relapse. in the setting of estrogen receptorpositive breast cancer, the choice of adjuvant hormone therapy depends on the menopausal status of the patient.4 premenopausal women should receive tamoxifen. postmenopausal women can receive either an aromatase inhibitor or tamoxifen. aromatase inhibitors therapy leads to lower rate of distal recurrences, disease in the contralateral breast, and disease-free survival when compared to tamoxifen in postmenopausal women but do not result in significant increases in overall survival. the adverse effect rates of the aromatase inhibitors are somewhat lower compared with tamoxifen. switching to an aromatase inhibitor in postmenopausal women after five years of adjuvant tamoxifen is an option. there is no proof that any of the aromatase inhibitors are better than the others. in the premenopausal patient who is a candidate for anti-estrogen therapy, bone health, hot flashes, cardiovascular effects, and compliance are all issues which must be considered. compliance is a major issue with getting someone to take a medicine for five to seven years to prevent a relapse. Data suggest

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exhibit 2: antibody conjugates

drug

linker

compliance falls off to about 60 percent within the first couple of years of therapy.

Medical, surgical or radiologic ovarian ablation and chemotherapy will put premenopausal women into menopause. the consequences of early menopause are multi-fold, including hot flashes, osteopenia, and osteoporosis. Zoledronic acid has been studied in combination with ovarian suppression with gosrelin or adjuvant hormone therapy.5 Data from one study favored zoledronic acid with a lower rate of relapse, a 3.2 percent absolute benefit in reducing recurrence. in addition to building bone, bisphosphonates may interfere with the metastatic process. the unanswered question is what are the consequences of starting a bisphosphonate in relatively young patients and continuing it for years. the her2 over-expression population accounts for about 25 percent of cases of primary breast cancer. her2 over-expression is identified by immunohistochemistry or fluorescence in situ hybridization (Fish). there have been at least five trials examining the use of trastuzumab in addition to chemotherapy in the her2-positive patient population. patients with her2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence from the addition of trastuzumab to adjuvant chemotherapy.6-12 the standard of care is one year of trastuzumab. the most benefit occurs when it is given concomitantly with taxane-based chemotherapy rather than before or after chemotherapy. this agent can result in partially reversible cardiac toxicity in 2 to 4 percent of patients. cardiac toxicity is lessened by anthracycline-free therapy, shorter duration, or sequencing after chemotherapy. breast cancer in which estrogen receptors and her2 are negative (triple-negative disease) is treated with chemotherapy. Docetaxel, doxorubicin, cyclophosphamide, and paclitaxel are preferred agents. the inclusion of anthrocyclines is important to op-

antibody

timal response, but there is a slight increase in risk for secondary leukemia. based on new trial data, the nccn guidelines are updated yearly and specify the preferred regimens and dosing intervals.

When we treat breast cancer, all patients are not alike. a 38-year-old with triple-negative disease is not the same as a 65-year-old with estrogen receptor-positive disease. in stage iv breast cancer (widely metastatic disease), the median survival for triple-negative breast cancer is eight months and 36 months for her2 + breast cancer.13,14 again, this is not one disease, and therapy needs to be based on the tumor biology and needs to be individualized. exhibit 1 outlines the treatment of advanced disease. the majority of advances in the cancer therapy have come about because of clinical trials. Only 5 to 8 percent of patients go on studies. Managed care can play a role by allowing patients to participate in appropriate studies. bevacizumab, a vascular endothelial growth factor (veGF) receptor inhibitor, is a controversial therapy in metastatic breast cancer. this agent was given accelerated approval (but not final approval) for treating metastatic breast cancer by the FDa based on improvements in progression-free survival but not overall survival.15 in July 2010, the Oncologic Drugs advisory committee (ODac) of the FDa voted in favor of withdrawing the indication of bevacizumab in combination with paclitaxel for metastatic breast cancer, a recommendation that the FDa proposed to follow, and against a potential new indication for bevacizumab, in combination with other chemotherapy drugs, as first-line treatment for her2-negative metastatic breast cancer. this decision was based on the results of newer studies that demonstrated no clinically significant improvement in progression-free survival, no difference in overall survival, and a poor safety profile for bevacizumab.15 the issue of FDa approval for breast cancer is still under review.16 at this time, the nccn guidelines

58 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

include bevacizumab and paclitaxel as an acceptable combination in stage iv breast cancer while noting that there is no proven difference in overall survival.4 Duration of treatment in stage iv cancer is another issue. a complete response is relatively rare; it occurs in about 15 percent of cases. there are no randomized studies proving survival benefit when continuing therapy after maximum response. the treatment team needs to be pragmatic and assess the impact of side effects on quality of life and risk of inducing resistance with continuing therapy versus fear of relapse. there are no established tools to trigger either stopping or reinstating therapy; circulating tumor cells, tumor markers, symptoms, radiographic findings all play or may play a role. it is unknown if different rules for different types of breast cancer are needed. there is an ongoing intergroup trial examining the use of circulating tumor cells. how to measure response is another controversial issue. there is much debate as to whether progression-free survival or overall survival should be the final endpoint. patients who are living without growing disease and have good quality of life make the argument for using progression-free survival even if in the end they do not live any longer. the latest advance in breast cancer therapy is linking chemotherapy agents to an antibody such as trastuzumab in order to transport the chemotherapy agent into individual cancer cells. When an antibody binds to a receptor on the cancer cell, the receptorantibody conjugate is internalized in the cell. an example is the antibody conjugate shown in exhibit 2. this conjugate provides intracellular delivery of mertansine, a derivative of maytansine, a naturalproduct microtubule polymerization inhibitor that is significantly more potent than vincristine.

references 1. U.s. cancer statistics Working Group. United states cancer statistics: 1999– 2007 incidence and Mortality Web-based report. atlanta (Ga): Department of health and human services, centers for Disease control and prevention, and national cancer institute; 2010. available at: http://www.cdc.gov/uscs.

2. berry Da, cronin Ka, plevritis sK, et al. effect of screening and adjuvant therapy on mortality from breast cancer. n engl J Med. 2005;353:1784-92.

3. sørlie t, perou cM, tibshirani r, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. proc natl acad sci U s a. 2001;98:10869-74.

4. nccn clinical practice Guidelines in Oncology. breast cancer. version 2.2011. available at www.nccn.org.

5. Gnant M, Mlineritsch b, schippinger W, et al. endocrine therapy plus zoledronic acid in premenopausal breast cancer. n engl J Med. 2009;360:679-91.

6. Yin W, Jiang Y, shen Z, et al. trastuzumab in the adjuvant treatment of her2-positive early breast cancer patients: a Meta-analysis of published randomized controlled trials. plos One. 2011;6(6):e21030.

7. vogel cl, cobleigh Ma, tripathy D, Gutheil Jc, harris ln, et al. efficacy and safety of trastuzumab as a single agent in first-line treatment of her2overexpressing metastatic breast cancer. J clin Oncol. 2002;20:719–726.

8. romond eh, perez ea, bryant J, suman vJ, Geyer ce, Jr, et al. trastuzumab plus adjuvant chemotherapy for operable her2-positive breast cancer. n engl J Med. 2005;353:1673–84.

9. smith i, procter M, Gelber rD, Guillaume s, Feyereislova a, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in her2-positive breast cancer: a randomised controlled trial. lancet. 2007;369:29–36.

10. Gianni l, Dafni U, Gelber rD, azambuja e, Muehlbauer s, et al. treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with her2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. lancet Oncol. 2011;12:236–44.

11. Joensuu h, bono p, Kataja v, alanko t, Kokko r, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the Finher trial. J clin Oncol. 2009;27:5685–92.

12. spielmann M, roche h, Delozier t, canon Jl, romieu G, et al. trastuzumab for patients with axillary-node-positive breast cancer: results of the Fnclcc-pacs 04 trial. J clin Oncol. 2009;27:6129–34.

13. Dent r, trudeau M, pritchard Ki, et al. triple-negative breast cancer:

conclusion

clinical features and patterns of recurrence. clin cancer res. 2007;13(15 pt

breast cancer is not one disease, thus treatment needs to be personalized. tools that are currently available help to refine prognosis and assess the benefit of treatment options. Ongoing studies of these tools and their integration into clinical decision making is clearly essential in order to improve our therapies. treatment guidelines are available for managing breast cancer but are constantly changing. Managed care needs to support patient participation in research trials to further refine therapy. as we make improvements in managing this disease, new challenges continue to arise. JMCM

1):4429-34.

14. robert n, leyland-Jones b, asmar l, et al. randomized phase iii study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with her-2-overexpressing metastatic breast cancer. J clin Oncol. 2006;24:2786-92.

15. D’agostino rb. changing end points in breast-cancer Drug approval — the avastin story. new engl J Med. (online) June 27, 2011.

16. avastin (bevacizumab) information. http://www.fda.gov/Drugs/Drugs a fet y/ po s t m a r ket D r u g s a fet yi n for m a t ion forpa t ient s a nd p r ov id er s / ucm193900.htm.

george somlo, Md is director, Breast Oncology in the department of Medical Oncology and Therapeutics research and Co-director, of the Breast Cancer Program at City of hope Comprehensive Cancer Center.

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 59

Optimizing the Prevention and Treatment of VTE in Cancer Patients Michael B. streiff, Md, faCP for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

summary Venous thromboembolism (VTe) is a major problem in many different patient populations but especially affects patients with cancer. unless contraindicated, all hospitalized patients and certain outpatients with cancer should receive prophylaxis to prevent thrombolic events. health systems can improve their compliance with prophylaxis guidelines by instituting mandatory risk assessment for all cancer patients.

Key points • VTe is a major problem in many cancer patients, resulting in morbidity and mortality.

• Cancer patients develop VTe for both intrinsic and extrinsic reasons.

• VTe is preventable.

• all hospitalized cancer patients need to be risk assessed and should receive inpatient VTe prophylaxis, unless contraindicated.

• Pharmacologic prophylaxis is preferred over mechanical.

• high-risk cancer surgery patients and certain myeloma patients should receive outpatient prophylaxis.

• improving compliance with prophylaxis guidelines requires a mandatory assessment process for all patients.

venOUs thrOMbOeMbOlisM (vte) is a major public health problem with increasing rates (exhibit 1).1 it is especially an issue with cancer patients. at least 900,000 events occur in cancer patients annually and the incidence has been increasing since the early 1990s.2 the risk for vte is four to sevenfold higher in cancer patients compared to those without cancer. twenty percent of cancer patients will suffer a vte. vte is deadly, accounting for 10 percent of hospital deaths. in one-third of patients, the first sign of a vte is death. cancer patients have a two to threefold higher risk of dying related to vte. if the patient survives the episode, vte causes long-term morbidity. post-thrombotic syndrome occurs in 50 percent by 10 years. recurrent vte occurs in 40 percent of patients by 10 years. cancer patients develop vte for both intrinsic and extrinsic reasons.3 patient specific factors include increasing age, african american and caucasian ethnicity, and thrombophilia. the cancer itself influences risk. solid tumors such as pancreatic malignancies and malignant gliomas are commonly

recognized to be associated with a very high risk of vte. Other cancers result in intermediate risk, such as lung cancer. breast and prostate cancer are all low-risk cancers for developing vte. Metastatic cancer results in higher risk as do adenocarcinomas compared with squamous cell histology. it has more recently been recognized that lymphomas and leukemias are not uncommonly associated with symptomatic vte.2 high-risk cancers often express tissue factor, a key initiator of coagulation activation. host response to the tumor can also result in tissue factor expression by monocytes and endothelial cells promoting clot formation. extrinsic factors include certain chemotherapy agents, surgery, hospitalization, central venous catheters, infections, and erythropoietic stimulatory agents (esa). vte is preventable. When assessing efficacy data of vte prophylaxis in cancer patients, there are limited data. Only 5 to 15 percent of patients in the trials of lMWh and dabigatran (pradaxa®) had cancer. even considering the rate of bleeding, vte prophylaxis is worth the risk with approximately a 60 percent decrease in risk (exhibit 2).4 One hun-

60 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

exhibit 1: Venous thromboembolism is a Major public health problem1

VTe (per 100,000 population)

dVT 180 160 140 120 100 80 60 40 20 0

Pe

N=8,621,000

1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005

Year

dred percent of events probably cannot be prevented so health systems and practitioners should not be penalized if patients received guideline-based prophylaxis, yet had an event. the national comprehensive cancer center network (nccn) and american society of clinical Oncology (ascO) guidelines recommend that all hospitalized adult patients with cancer be risk assessed for the presence of contraindications to pharmacological prophylaxis.5,6 all patients without contraindications should receive anticoagulant prophylaxis with unfractionated heparin (UFh), low molecular weight heparin (lMWh) or fondaparinux. For patients with a contraindication to pharmacologic anticoagulation treatment, mechanical prophylaxis (sequential compression devices or compression stockings) is recommended. pharmacologic therapy is more efficacious than mechanical therapy and should be used if at all possible. patients with contraindications should be regularly reassessed for suitability for pharmacologic prophylaxis. contraindications for prophylaxis are active or high risk of bleeding, therapeutic anticoagulation, thrombocytopenia (platelets < 50, 000), elevated inr or aptt ratio greater than 1.3 (excluding lupus inhibitor), and heparin-induced thrombocytopenia (UFh or lMWh are contraindicated).

Dosing of heparin may need to be different in patients with cancer. based on a meta-analysis, three times daily UFh reduces deep vein thrombosis (Dvt) rates compared to twice daily dosing but also increases risk of bleeding.7 three times a day dosing should be targeted to the patient with higher risk of vte which includes those with cancer.

Mechanical Dvt prophylaxis does have an advantage of no bleeding risk related to the therapy. Un-

fortunately, the major disadvantage is that continuous application is necessary for efficacy. compliance has been shown to be problematic. in one study, full compliance only occurred in 19 percent of patients.8 contraindications for mechanical therapy include a Dvt within the previous three months, arterial insufficiency, and open leg wounds. some cancer patients require anticoagulation be continued at hospital discharge. in one large trial, the mean time to Dvt after surgery was 17 days, thus many events occur after discharge.9 vte prophylaxis is recommended for high-risk cancer surgery patients for four weeks. patient are considered high risk for recurrence if they have had a previous vte, operation time greater than two hours, bed rest of four days or more, age > 60, or an intraabdominal malignancy. rather than treat all cancer outpatients with prophylaxis, attempts are being made to identify and institute prophylaxis in the highest risk patients. there are several risk assessment models being tested. One that has been incorporated into the ascO guidelines (exhibit 3).6,10 a risk score of three or greater on this assessment is high risk and suggests the need for prophylaxis. because of their very high risk for vte, certain patients with multiple myeloma without contraindications to anticoagulation should be anticoagulated continuously.5 those receiving thalidomide or lenalidomide plus high-dose dexamethasone, doxorubicin or multi-agent chemotherapy need anticoagulation.6 thalidomide and lenalidomide are potent thrombotic agents. When given alone, 2 to 3 percent of patients will develop clots. When combined with high-dose dexamethasone, doxorubicin, or multi-agent chemotherapy, there is a large increase

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 61

exhibit 2: Vte prophylaxis is Worth the risk4

event rate (% of subjects)

Placebo/control 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

dVT prophylaxis N=19,958

32%

63% 67%

sx dVT

sx Pe

62%

fatal Pe

Major Bleeding

exhibit 3: risk assesment of outpatient oncology patients 6,10

characteristic

risk score

Cancer site Very high risk (Pancreas, stomach)

2 points

high risk (lung, lymphoma, gynecologic, bladder, testicular)

1 point

Platelets > 350K

1 point

hemoglobin < 10 g/dl or esa use

1 point

BMi > 35 kg/m2

1 point

esa, erythropoietin stimulating agents ; BMi, body mass index

in the rate of patients who develop vte (15 to 25 percent). the ascO guidelines also recommend that patients with two or more myeloma thrombosis risk factors be continuously anticoagulated. the risk factors are previous vte, obesity, medical illness, surgery, trauma, immobility, esa use, hyperviscosity, and myeloma diagnosis. vte can present in cancer patients very subtlety â&#x20AC;&#x201C; increase in fatigue, more short of breath, or more swelling in one leg than the other. if there is any suspicion of vte, therapy should be initiated. treatment doses of the agents should be used according to the guidelines. patients should receive at least five

days of UFh or lMWh before moving to chronic therapy with lMWh or warfarin. in the cancer population, lMWh is a better choice for chronic therapy than warfarin because of better efficacy and lower rates of bleeding.11 Once a cancer patient has had vte, they are at very high risk for recurrence and will require continued therapy. the duration of therapy after an event should be at least three to six months or as long as cancer is active or under treatment. if the patient had a vte secondary to a central venous catheter, they should be treated for at least three months or duration of catheter placement. inferior vena cava

62 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

filters are indicated for treatment of acute vte with contraindications to anticoagulation or when a pulmonary embolism develops despite adequate longterm lMWh. health system compliance with vte prevention guidelines in cancer patients has been shown to be suboptimal.12 Only 26 to 33 percent of patients in various studies received appropriate prophylaxis. the Johns hopkins health system attempted to improve their rate of in hospital compliance by initially instituting provider education and paper order sets. the paper order sets were easy to develop but had several disadvantages. the paper orders made data collection labor intensive, were complex and disrupted work flow, and made compliance difficult to assess. these two interventions did improve performance from 26 percent to 66 percent.13 electronic alerts have been shown to improve compliance with guidelines and reduce rates of vte.14 based on that data and their transition to computer order entry, Johns hopkins instituted a mandatory system for vte prophylaxis assessment and added smart decision support which provides therapy recommendations. the hospital system can now easily track compliance with guidelines. rates have improved to greater than 90 percent, but some areas of the hospital do still present challenges. the plan for the future is to refine the data collected down to the provider level to determine which individuals may need additional interventions. in a health system, improving vte prophylaxis compliance requires engaging providers and leadership. the system has to collect baseline data, assess resources, and customize interventions to fit the local environment. the key to success is making vte risk assessment mandatory.

their compliance with vte prophylaxis guidelines by instituting mandatory risk assessment for all patients. JMCM Michael b. streiff, Md, facp is an associate Professor of Medicine and Medical director, Johns hopkins anticoagulation service at the sidney Kimmel Comprehensive Cancer Center at Johns hopkins Medical institutions.

references 1. stein pD, Matta F, Dalen Je. is the campaign to prevent vte in hospitalized patients Working? chest. 2011;139:1317-21.

2. stein pD, beemath a, Meyers Fa, et al. incidence of venous thromboembolism in patients hospitalized with cancer. am J Med. 2006;119:60-8.

3. bick rl. cancer-associated thrombosis. n engl J Med. 2003;349:109-11.

4. national comprehensive cancer network. nccn Guidelines. venous thromboembolic Disease. version 2.2011. available at www.nccn.org.

5. lyman Gh, Khorana aa, Falanga a, et al. american society of clinical Oncology Guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J clin Oncol. 2007;25:5490-505.

6. Dentali F, Douketis JD, Gianni M, et al. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. ann intern Med. 2007;146:278-88.

7. King cs, holley ab, Jackson Jl, et al. twice versus three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a metaanalysis. chest. 2007;131:507-16.

8. cornwell ee 3rd, chang D, velmahos G, et al. compliance with sequential compression device prophylaxis in at-risk trauma patients: a prospective analysis. am surg. 2002;68:470-3.

9. agnelli G, bolis G, capussotti l, et al. a clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @ristOs project. ann surg. 2006;243:89-95.

10. Khorana aa, Kuderer nM, culakova e, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. blood.

2008;111:4902-7.

11. lee aY, levine Mn, baker ri, et al. low-molecular-weight heparin versus

conclusion

a coumarin for the prevention of recurrent venous thromboembolism in pa-

Unless contraindicated, all hospitalized cancer patients should receive vte prophylaxis. pharmacologic prophylaxis is preferred. selected cancer outpatients should receive continued prophylaxis including high-risk cancer surgery patients and certain myeloma patients. health systems can improve

tients with cancer. n engl J Med. 2003;349:146-53.

12. spencer Fa, lessard D, emery c, et al. venous thromboembolism in the outpatient setting. arch intern Med. 2007;167:1471-5.

13. Data courtesy of Deb hobson, bsn.

14. Kucher n, Koo s, Quiroz r, et al. electronic alerts to prevent venous thromboembolism among hospitalized patients. n engl J Med. 2005;352:969-77.

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Update on Current and Novel Treatment Strategies in Non-Small Cell Lung Cancer ramaswamy govindan, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

summary There are many advances being made in the treatment of epithelial cancers like non-small cell lung cancer (NsClC). some of the new therapies are providing dramatic improvements in certain patients even with very advanced disease. it has been discovered that certain new therapies benefit patients with specific gene mutations. Over the next 10 to 15 years these advances will continue.

Key points • The epidemiology of lung cancer has changed with more women developing, fewer cases of small cell lung cancer occurring, and more cases of adenocarcinoma.

• genetic mutations that increase risk for certain kinds of NsClC have been discovered.

• Therapy is selected based on tumor histology.

• standard treatment for most patients with advanced disease is platinum-based chemotherapy.

• Targeted therapies are appropriate in certain patients to improve response to chemotherapy or in place of chemotherapy.

• Biomarker development to better select therapy will be the next wave of improvement in cancer treatment.

With all the evOlvinG KnOWleDGe in genomics, the one area that will benefit the most is cancer treatment. cancer, especially lung cancer, is an elegant model for applying this knowledge since it is the result of genetic mutations. lung cancer is not one disease – there are various types. in general, lung cancer is divided into small cell and non-small cell. non-small cell lung cancer (nsclc) is further divided into adenocarcinoma, squamous cell, and large cell. an understanding of the underlying histology of an individual’s tumor has lead to therapy being selected based on the tumor histology. Over the last 20 or 30 years, the epidemiology of lung cancer has changed.1 Fewer cases of small cell cancer now occur which is likely due to declines in the active smoking rate. Of all patients with small cell disease, the proportion of women increased from 28 percent in 1973 to 50 percent in 2002.1 small cell lung cancer accounts for 13 percent of total cases compared with 17 percent in the past.

For nsclc, adenocarcinomas are now most frequent compared with squamous cell in the past. this article focuses only on nsclc lung cancer is usually diagnosed in the later stages

where there is not a curative option (exhibit 1).2 Unfortunately, the five-year overall survival (Os) rate declines and the rate of relapse increases with each stage. patients with early stage nsclc are an important group. One-third of patients present with early stage disease. in the coming years, more patients will be diagnosed at earlier points in the disease process with improved screening methods. One reason is the increasing use of computed tomography (ct) scans for multiple indications, which incidentally finds early lung tumors. a sobering statistic is that even when lung cancer is diagnosed early, a third of these patients could die from recurrent disease within a year or two. the standard of care is surgical resection. in recent years, studies have shown an increase in overall survival with adjuvant chemotherapy after surgical resection. in stage ii patients, the cure rate can be 20 percent more with the use of adjuvant chemotherapy compared with surgical resection alone. the use of adjuvant chemotherapy with stage i disease is more controversial. therapy in locally advanced nsclc is moving

64 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

exhibit 1: nsclc surgical stage and prognosis2 surgical stage

survival 5-year (%)

local

relapse (%) distant

ia ib

t1n0M0 t 2n 0 M 0

67 57

10 10

15 30

iia iib

t1n1M0 t2n1M0 t 3n 0 M 0

55 39 38

12

40

iiia

t3n1M0 t1-3n2M0

25 23

15

60

exhibit 2: results with gefitinib

6 feb

11 feb

it from an incurable disease to a potentially curable disease. cancer in patients with positive mediastinal nodes is not generally considered operable because it has already spread beyond the lungs. these patients are treated with two cycles of chemotherapy and radiation. ten years ago with radiation alone, no one was cured. today, with chemotherapy and radiation, about 25 to 30 percent of patients are cured.

Docetaxel was used after chemotherapy and radiation as consolidation therapy for a while, but more recent studies have shown that docetaxel does not prolong survival. at this time, consolidation therapy after chemotherapy and radiation is not used in locally advanced nsclc. chemotherapy has a role in advanced metastatic disease. the only way to cure these patients is chemotherapy, which is accomplished in about onethird of patients with advanced disease.

Until a few years ago, the treatment of metastatic nsclc was two drug combination chemotherapy that included a platinum-based agent for four to six cycles. the second agent added was variable. targeted therapy alone was not considered a therapeutic option nor was targeted therapy combined with cytotoxic chemotherapy used very frequently. Maintenance therapy was not standard. therapy has changed and now patients are living longer and even living long enough to go on maintenance therapy. therapy today for metastatic nsclc is still a platinum-based two-drug combination for four to six cycles. studies have shown that pemetrexed should be included in regimens for non squamous cell to provide modest overall survival increases compared with other agents. patients with squamous cytology will not benefit from pemetrexed. some patients receive maintenance therapy. targeted ther-

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 65

apy is frequently used and molecularly or clinically selected. the use of targeted therapy plus cytotoxic chemotherapy is expanding, but there are currently limited indications. Within the next few years, we should be able to identify biomarkers, which will help with additional improvements in patient selection.

Genetic mutations can occur in critical locations in genes and lead to spontaneous cancers. exposure to smoke and other carcinogens increases the number of mutations and risk for cancer. patients who are lifelong non-smokers and develop nsclc tend to have one of two major genetic mutations – endothelial growth factor receptor (eGrF) or alK mutations. approximately 10 percent of cancer patients will have an eGFr mutation.3 in patients with this mutation, targeted therapy with eGFr inhibitors (gefitinib and erlotinib) works dramatically (exhibit 2). the response rates are three to four times the response that is obtained with chemotherapy alone. this is still not a cure, but the patients will live two to three times longer than those who get chemotherapy, even with advanced disease. eGFr antagonists result in massive cancer cell apoptosis. patients with certain cancers such as lymphoma who have a large disease burden must be hospitalized before getting one of these agents. Killing large numbers of cancer cells rapidly can result in patient death from high levels of potassium and other cell contents. in nsclc patients, tumor lysis does not occur; the cancer cells shrivel and die rather than lyse. patients with nsclc who were never smokers who don’t have eGFr mutation tend to be alKpositive which is a flipping of two genes on chromosome 2 which leads to the production of an abnormal protein. the abnormal protein leads to cellular changes and eventually cancer. crizotinib is one agent that is being studied for alK-positive patients. another area of targeted therapies is vascular endothelial growth factor (veGF). tumors need vasculature to continue to grow and veGF is one factor that turns on growth. at this time, there is not a biomarker for testing which determines patients who should receive anti-veGF antibodies (bevacizumab) or veGF inhibitors (sunitinib, sorafenib). the search is underway for such a biomarker. Once a biomarker is determined, testing will identify those 5 or 10 percent of patients who will most benefit from a veGF targeting agent. lung cancer is a complex disease and does not develop overnight. For example, it probably takes 10 to 15 years for the tumor to become large enough for detection. there are likely hundreds of mutations that can lead to lung cancer. some strategies for continuing advances in treating nsclc include systematic understanding of recurrent molecular events that lead to cancer, rational drug development, and non inva-

sive (or at least minimally invasive) continual molecular assessment of tumor cells. Genomic technology is going to allow a panoramic view of what is happening in cancer cells. rational drug development will lead to therapies targeted to the specific problematic genetic mutations. Gone are the days of giving one chemotherapy regimen to all patients. tumor cells constantly evolve spontaneously or in response to treatment. Over time, resistant clones of cells will develop. continual molecular assessment for monitoring would be able to identify changes in the cells that make them no longer susceptible to a particular therapy. it is difficult to keep doing lung biopsies but examining circulating tumor cells would make this much easier.

Dna sequencing is becoming faster and less expensive. currently, the process is still for discovery rather than routine use. by sequencing hundreds and thousands of common tumors, we will have enormous knowledge of the genetic mutations. eventually, imaging techniques will also be used to select patients for therapy and to identify potential responders. support of clinical trials is vital in developing new, effective therapies. there is considerable use of potentially ineffective agents because a patient’s insurance has denied them participation in a clinical trial so an approved but ineffective agent is used.

Managed care could potentially save money by allowing patients to participate in clinical trials. conclusion

lung cancer is molecularly a very diverse disease. the key to treating it is to identify the individual molecular pathways for a given patient’s cancer which are mutated and can be targeted with therapy. some of these mutations already have targeted therapy but more are needed. the research ongoing into genome sequencing is going to shed more light on pathways that can be targeted. biomarkers for efficacy need to be developed early in drug development to avoid exposing patients to ineffective agents. JMCM ramaswamy govindan, Md is a Professor of Medicine at the alvin J siteman Cancer Center, Washington university school of Medicine in st. louis, MO.

references 1. Govindan r, page n, Morgensztern D, et al. changing epidemiology of smallcell lung cancer in the United states over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24:4539-44.

2. pisters KM, le chevalier t. adjuvant chemotherapy in completely resected non-small-cell lung cancer. J clin Oncol. 2005;23:3270-8.

3. ciardiello F, tortora G. eGFr antagonists in cancer treatment. n engl J Med. 2008;358(11):1160-74.

66 Journal of Managed Care Medicine | Vol. 14, No. 4 | www.namcp.org

VIIBRYD:

Approved to treat Major Depressive Disorder (MDD) in adults

Important Safety Information WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of VIIBRYD or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. VIIBRYD is not approved for use in pediatric patients. mania, or suicidality that are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants should be alerted about the need patients who have taken MAOIs within the preceding 14 days due to the to monitor patients daily. Prescriptions for VIIBRYD should be written for risk of serious, sometimes fatal, drug interactions with serotonergic drugs. the smallest quantity of tablets consistent with good patient management, Allow at least 14 days after stopping VIIBRYD before starting an MAOI. in order to reduce the risk of overdose.

Warnings and Precautions • The development of potentially life-threatening serotonin syndrome or •All patients treated with antidepressants should be monitored Neuroleptic Malignant Syndrome (NMS)-like reactions has been reported appropriately and observed closely for clinical worsening, with antidepressants alone, but particularly with concomitant use of suicidality, and unusual changes in behavior, especially during the serotonergic drugs (including triptans) with drugs which impair first few months of treatment and when changing the dose. Consider metabolism of serotonin (including MAOIs), or with antipsychotics or changing the therapeutic regimen, including possibly discontinuing the other dopamine antagonists. Symptoms of serotonin syndrome were medication, in patients whose depression is persistently worse or noted in 0.1% of patients treated with VIIBRYD. Serotonin syndrome includes symptoms of anxiety, agitation, panic attacks, insomnia, symptoms may include mental status changes (eg, agitation, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood Please see brief summary of Prescribing Information on following pages.

Please also see full Prescribing Information at www.viibryd.com.

Contraindications

• VIIBRYD must not be used concomitantly in patients taking MAOIs or in

www.namcp.org | Vol. 14, No. 4 | Journal of Managed Care Medicine 67

The first and only SSRI and 5-HT1A receptor partial agonist1 • While the MOA is not fully understood, it is thought to be related to enhancement of serotonergic activity • The role of 5-HT1A partial agonist activity on serotonergic transmission and antidepressant effect is unknown

Proven efficacy in adults with MDD1–4

• Significant improvement vs placebo in Montgomery-Asberg Depression Rating Scale (MADRS) total score in two

8-week, randomized and controlled studies (P<0.01) – At week 8, least squares (LS) mean difference from placebo in change from baseline in MADRS total score was -2.5 in Khan et al and -3.2 in Rickels et al

MADRS mean total score reduction from baseline at week 82-4 Rickels et al

Placebo (n=232)

0 -2

42% change from baseline vs 34% for placebo2,4

-4 -6 -8 -10

-10.8

-12 -14

-13.3*

*P=0.009 vs placebo

-16

Baseline values: 31.9 for VIIBRYD and 32.0 for placebo

LS MEAN CHANGE FROM BASELINE

LS MEAN CHANGE FROM BASELINE

Khan et al VIIBRYD (n=231)

VIIBRYD (n=198)

Placebo (n=199)

0 -2

42% change from baseline vs 31% for placebo3,4

-4 -6 -8 -10

-9.6

-12 -14

-12.9†

†

P=0.001 vs placebo

-16

Baseline values: 30.8 for VIIBRYD and 30.7 for placebo

Randomized, double-blind, placebo-controlled, multicenter, 8-week clinical trials to determine the efficacy and safety of VIIBRYD in adults aged 18 to 70 years in Khan et al, and in adults aged 18 to 65 years in Rickels et al, who were diagnosed with MDD. Patients were randomized to receive VIIBRYD (n=231) or placebo (n=232) in Khan et al, and VIIBRYD (n=198) or placebo (n=199) in Rickels et al. Last observation carried forward analysis shown.1-3 The primary efficacy endpoint was the change from baseline in MADRS total score to week 8 (ITT population).

The LS mean difference (95% confidence interval) from placebo in change from baseline in MADRS total score was -2.5 (-4.4, -0.6) in Khan et al and -3.2 (-5.2, -1.3) in Rickels et al.

VIIBRYD treatment was initiated once daily at 10 mg for 7 days, followed by 20 mg for another 7 days, and 40 mg thereafter until the end of week 8. VIIBRYD was administered with food.1-3

pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms while treated with VIIBRYD. • Like other antidepressants, VIIBRYD should be prescribed with caution in patients with a seizure disorder.

• The use of drugs that interfere with serotonin reuptake, including VIIBRYD, may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of VIIBRYD and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation or bleeding.

• Symptoms of mania/hypomania were noted in 0.1% of patients treated with VIIBRYD in clinical studies. As with all antidepressants, VIIBRYD should be used cautiously in patients with a history or family history of bipolar disorder, mania or hypomania.

• 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. VIIBRYD is not approved for use in treating bipolar depression.

• Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as VIIBRYD. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible.

Monitor patients when discontinuing VIIBRYD. If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate.

VIIBRYD is a trademark of Forest Laboratories, Inc. © 2011 Forest Laboratories, Inc. 47-12000115-PR

8/11

•Advise patients that if they are treated with diuretics, or are otherwise

volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking VIIBRYD. Although no cases of hyponatremia resulting from VIIBRYD treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. Discontinuation of VIIBRYD in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Adverse Reactions • The most commonly observed adverse reactions in MDD patients treated with VIIBRYD in placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were: diarrhea (28% vs 9%), nausea (23% vs 5%), insomnia (6% vs 2%), and vomiting (5% vs 1%).

References: 1. Viibryd (vilazodone HCl) [package insert]. St Louis, MO: Forest Pharmaceuticals, Inc.; 2011. 2. Khan A, Cutler AJ, Kajdasz DK, et al. A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder.

J Clin Psychiatry. 2011;72:441-447. 3. Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR. Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry.

2009;70:326-333. 4. Data on file. Forest Laboratories, Inc.

VIIBRYD (vilazodone HCl) Tablets for oral administration Brief Summary of full Prescribing Information Initial U.S. Approval: 2011

Rx Only

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of VIIBRYD or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. VIIBRYD is not approved for use in pediatric patients [see Warnings and Precautions, Use in Specific Populations, and Patient Counseling Information] INDICATIONS AND USAGE: VIIBRYD is indicated for the treatment of major depressive disorder (MDD).

The efficacy of VIIBRYD was established in two 8-week, randomized, double-blind, placebo-controlled trials in adult patients with a diagnosis of MDD [see Clinical Studies]. Major depressive disorder consists of one or more major depressive episodes. A major depressive episode (DSM-IV-TR) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.

CONTRAINDICATIONS: Monoamine Oxidase Inhibitors - VIIBRYD must not be used concomitantly in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Allow at least 14 days after stopping VIIBRYD before starting an MAOI [see Drug Interactions].

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 18-24) 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 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 9 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 2 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. There were 14 additional cases reported in patients under the age of 18, while 5 additional cases were reported in patients between 18 and 24 years of age. Patients between 25 and 64 years of age reported 1 fewer case of suicidality, while patients 65 years of age and over reported 6 fewer cases. 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 placebo-controlled 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 major depressive disorder 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. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions and Dosage and Administration]. Families and caregivers of patients being treated with antidepressants for major depressive disorder 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. Prescriptions for VIIBRYD should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose [see also Patient Counseling Information]. 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 VIIBRYD is not approved for use in treating bipolar depression. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)like Reactions - The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions has been reported with antidepressants alone, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs that impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Symptoms of serotonin syndrome were noted in 0.1% of patients treated with VIIBRYD. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of VIIBRYD with MAOIs intended to treat depression is contraindicated [see Contraindications]. If concomitant treatment of VIIBRYD with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions]. The concomitant use of VIIBRYD with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions]. Treatment with VIIBRYD and any concomitant serotonergic (SSRI, serotonin–norepinephrine reuptake inhibitor [SNRI], triptan, buspirone, tramadol, etc.) or antidopaminergic drugs, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Seizures - VIIBRYD has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Like other antidepressants, VIIBRYD should be prescribed with caution in patients with a seizure disorder. Abnormal Bleeding - The use of drugs that interfere with serotonin reuptake inhibition, including VIIBRYD, 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 SSRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of VIIBRYD and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Activation of Mania/Hypomania - Symptoms of mania/hypomania were reported in 0.1% of patients treated with VIIBRYD in clinical studies.

Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use VIIBRYD cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. Discontinuation of Treatment with VIIBRYD - There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Monitor patients for these symptoms when discontinuing VIIBRYD. Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate [see Dosage and Administration]. Hyponatremia - Although no cases of hyponatremia resulting from VIIBRYD treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of VIIBRYD 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. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

ADVERSE REACTIONS: Clinical Studies Experience - The most commonly observed adverse reactions in VIIBRYD-treated MDD patients in placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were: diarrhea, nausea, vomiting, and insomnia. Patient Exposure - The safety of VIIBRYD was evaluated in 2,177 patients (18-70 years of age) diagnosed with MDD who participated in clinical studies, representing 552 patient-years of exposure. In an open-label 52 week study at 40 mg daily, 599 patients were exposed to VIIBRYD for a total of 348 patient-years. The information presented in these sections was derived from studies of VIIBRYD 40 mg daily in major depressive disorder including: 1) 2 placebo-controlled 8-week studies in 861 patients, including 436 receiving vilazodone; and 2) an open-label 52-week study of 599 patients. These studies included a titration period of 10 mg daily for 7 days followed by 20 mg daily for 7 days. In these clinical trials, VIIBRYD was administered with food. Because clinical trials are conducted under widely varying conditions and varying lengths of time, 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 rates observed in practice. Adverse reactions reported as reasons for discontinuation of treatment - In the placebo-controlled studies of MDD there was no single adverse reaction leading to discontinuation in > 1% of the patients. Overall, 7.1% of the patients who received VIIBRYD discontinued treatment due to an adverse reaction, compared with 3.2% of placebo-treated patients in these studies. Common adverse reactions in placebo-controlled MDD studies - Table 2 shows the incidence of common adverse reactions that occurred in ≥2% of VIIBRYDtreated MDD patients (and greater than in placebo-treated patients) in the placebo-controlled studies.

The first value displays the number of patients exhibiting the adverse reaction while receiving VIIBRYD 40 mg/day (N = 436) and the second value is the number of patients exhibiting the adverse reaction while receiving Placebo (N = 433). Gastrointestinal disorders: Diarrhea (28, 9); Nausea (23, 5); Dry mouth (8, 5); Vomiting (5, 1); Dyspepsia (3, 2); Flatulence (3, 2); Gastroenteritis (3, <1); Nervous system disorders: Dizziness (9, 5); Somnolence (3, 2); Paresthesia (3, 1); Tremor (2, 0); Psychiatric disorders: Insomnia (6, 2); Abnormal dreams (4, 1); Libido decreased (4, <1); Restlessness* (3, <1); Orgasm abnormal** (3, 0); General disorders: Fatigue (4, 3); Feeling jittery (2, <1); Cardiac disorders: Palpitations (2, <1); Musculoskeletal and connective tissue disorders: Arthralgia (3, 2); Reproductive system and breast disorders: Delayed ejaculation*** (2, 0); Erectile dysfunction*** (2, 1); Metabolism and nutrition disorders: Increased appetite (2, 1). *Includes restlessness, akathisia, and restless legs syndrome; **Includes orgasm abnormal and anorgasmia; ***Male patients only (Placebo n=182; VIIBRYD n=170). Table 3 shows the percentages of Sexual Adverse Reactions in the Placebo-Controlled Studies. The first grouping shows the percentages in Males with VIIBRYD (N=170) and Placebo (N=182).

The second grouping shows the percentages in Females with VIIBRYD (N=266) and Placebo (N = 251).

Decreased libido (5,0)/(3,<1); Abnormal orgasm* (4,0)/(2,0); Delayed ejaculation (2,0)/(−,−); Erectile dysfunction (2,1)/(−,−); Sexual dysfunction (2,0)/(<1,<1). − Not applicable; *Includes

anorgasmia. Laboratory Tests - VIIBRYD has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (including liver function tests), hematology and urinalysis, as measured in placebo-controlled studies. These studies include analysis of (1) mean change from baseline and (2) the proportion of patients meeting criteria for potentially clinically significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies. ECG - VIIBRYD has not been associated with any clinically significant effect on ECG parameters, including QT, QTc, PR and QRS intervals, or with any arrhythmogenic potential. ECGs were evaluated in a thorough QTc study at doses up to 80 mg daily with food and in the placebo-controlled studies [see Clinical Pharmacology]. Vital Signs - VIIBRYD has not been associated with any clinically significant effect on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies. These studies included analyses of (1) change from baseline, and (2) the proportion of patients meeting criteria for potentially clinically significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies. Weight - VIIBRYD had no effect on body weight as measured by the mean change from baseline in the 8-week, placebo-controlled studies. The mean changes in weight were +0.16 kg in the VIIBRYD group and +0.18 kg in the placebo group. The proportions of patients with a weight gain ≥7% were 0.9% in the VIIBRYD group and 1.2% in the placebo group.The proportions of patients with a weight decrease ≥7% were 1.4% in the VIIBRYD group and 1.4% in the placebo group. 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. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients; Cardiac disorders: infrequent: ventricular extrasystoles; Eye disorders: frequent: vision blurred, dry eye; infrequent: cataracts; General disorders: infrequent: feeling abnormal; Metabolism and nutrition disorders: frequent: decreased appetite; Nervous System: frequent: sedation, migraine; infrequent: dysgeusia; Psychiatric disorders: infrequent: panic attack, mania; Renal and Urinary disorder: infrequent: pollakiuria; Skin and subcutaneous tissue disorders: frequent: hyperhidrosis, night sweats DRUG INTERACTIONS: Central Nervous System (CNS)-Active Agents - The risk of using VIIBRYD in combination with other CNS-active drugs has not been systematically evaluated. Consequently, use caution when VIIBRYD is prescribed in combination with other CNS-active drugs. Monoamine Oxidase Inhibitors (MAOI) - 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 antidepressant(s) with pharmacological properties similar to VIIBRYD (e.g. SSRIs), or who have recently had SSRI therapy discontinued prior to initiation of an MAOI. Do not prescribe VIIBRYD concomitantly with an MAOI or within 14 days of discontinuing or starting an MAOI [see Contraindications]. Serotonergic Drugs - Based on the mechanism of action of VIIBRYD and the potential for serotonin toxicity, also known as serotonin syndrome, caution is advised when VIIBRYD is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., MAOI, SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.) [see Warnings and Precautions]. 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. Patients receiving warfarin therapy should be carefully monitored when VIIBRYD is initiated or discontinued [see Warnings and Precautions]. Potential for Other Drugs to Affect Vilazodone Figure 1. Impact of Other Drugs on Vilazodone PK

Inhibitors of CYP3A4 - Metabolism by CYP3A4 is a major elimination pathway for vilazodone. Concomitant use of VIIBRYD and strong inhibitors of CYP3A4 (e.g., ketoconazole) can increase vilazodone plasma concentrations by approximately 50% (see Figure 1). The VIIBRYD dose should be reduced to 20 mg if co-administered with a strong inhibitor of CYP3A4. During co-administration with moderate inhibitors of CYP3A4 (e.g., erythromycin), the VIIBRYD dose should be reduced to 20 mg for patients with intolerable adverse events. No dose adjustment is recommended when VIIBRYD is co-administered with mild inhibitors of CYP3A4 (e.g., cimetidine). Inducers of CYP3A4 - Concomitant use of VIIBRYD with inducers of CYP3A4 has the potential to reduce vilazodone systemic exposure. However, the effect of CYP3A4 inducers on vilazodone plasma concentrations has not been evaluated. Inhibitors of other CYP enzymes - Concomitant administration of VIIBRYD with inhibitors of CYP2C19 and CYP2D6 is not expected to alter plasma concentrations of vilazodone. These isoforms are minor elimination pathways in the metabolism of vilazodone. In vitro studies have shown that CYP1A2, CYP2A6, CYP2C9 and CYP2E1 have minimal contribution to the metabolism of vilazodone. Potential for Vilazodone to Affect Other Drugs - Drugs metabolized by CYP1A2, CYP2C9, CYP2D6, CYP3A4 or CYP2C19. Coadministration of VIIBRYD with substrates for CYP1A2, CYP2C9, CYP3A4, or CYP2D6 is unlikely to result in clinically significant changes in the concentrations of the CYP substrates. A study in healthy subjects found that VIIBRYD (20 mg/day for 8-10 days) had no effect on the pharmacokinetics of caffeine, flurbiprofen, nifedipine or debrisoquine, probes for CYP1A2, CYP2C9, CYP3A4, and CYP2D6, respectively. VIIBRYD coadministration with mephenytoin to healthy subjects resulted in a small (11%) increase in mephenytoin biotransformation, suggestive of a minor induction of CYP2C19. In vitro studies have shown that VIIBRYD is a moderate inhibitor of CYP2C19 and CYP2D6. Drugs metabolized by CYP2C8 - Coadministration of VIIBRYD with a CYP2C8 substrate may lead to an increase in concentration of the other drug. In vitro studies suggest that VIIBRYD may inhibit the biotransformation of substrates of CYP2C8. The effect of VIIBRYD on CYP2C8 activity has not been tested in vivo. Induction of CYP isoforms - VIIBRYD did not induce CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 or 3A5 in an in vitro study in cultured human hepatocytes. Chronic administration of vilazodone is unlikely to induce the metabolism of drugs metabolized by these major CYP isoforms. Drugs Highly Bound to Plasma Protein - The interaction between vilazodone and other highly protein-bound drugs has not been evaluated. Because vilazodone is highly bound to plasma protein, administration of VIIBRYD to a

patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug.

USE IN SPECIFIC POPULATIONS: Pregnancy, Teratogenic Effects - Pregnancy Category C - Vilazodone caused some developmental toxicity in rats, but was not teratogenic in rats or rabbits. There are no adequate and well-controlled studies of VIIBRYD in pregnant women. When treating pregnant women with VIIBRYD, carefully consider whether the potential benefits outweigh the potential risks of treatment.

No teratogenic effects were observed when vilazodone was given to pregnant rats or rabbits during the period of organogenesis at oral doses up to 200 and 36 mg/kg/day, respectively. These doses are 48 and 17 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 40 mg on a mg/m2 basis. Fetal body weight gain was reduced, and skeletal ossification was delayed in both rats and rabbits at these doses; these effects were not observed at doses up to 10 times the MRHD in rats or 4 times the MRHD in rabbits. When vilazodone was administered to pregnant rats at an oral dose of 30 times the MRHD during the period of organogenesis and throughout pregnancy and lactation, the number of live born pups was decreased. There was an increase in early postnatal pup mortality, and among surviving pups there was decreased body weight, delayed maturation, and decreased fertility in adulthood. There was some maternal toxicity at this dose. These effects were not seen at 6 times the MRHD. Nonteratogenic Effects - Neonates exposed to serotonergic antidepressants 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 serotonergic antidepressants 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]. Labor and Delivery - The effect of VIIBRYD on labor and delivery in humans is unknown. VIIBRYD should be used during labor and delivery only if the potential benefit outweighs the potential risk. Nursing Mothers - Vilazodone is excreted into the milk of lactating rats. The effect of VIIBRYD on lactation and nursing in humans is unknown. Breast feeding in women treated with VIIBRYD should be considered only if the potential benefit outweighs the potential risk to the child. Pediatric Use - Clinical studies on the use of VIIBRYD in pediatric patients have not been conducted; therefore, the safety and effectiveness of VIIBRYD in the pediatric population have not been established. VIIBRYD is not approved for use in pediatric patients [see Boxed Warning and Warnings and Precautions]. Geriatric Use - No dose adjustment is recommended on the basis of age (see Figure 2). Results from a single-dose (20 mg) pharmacokinetic study in elderly (> 65 years-old) vs. young (24-55 years-old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. Of the 2177 patients in clinical studies with VIIBRYD, 37 (1.7%) were 65 years of age or older, and 272 (12.5%) were 55 to 64 years of age. Greater sensitivity of some older individuals cannot be ruled out [see Dosage and Administration]. 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]. Hepatic Impairment - Vilazodone is eliminated primarily by hepatic metabolism. In mild and moderate hepatic impairment, no dose adjustment is necessary (see Figure 2). VIIBRYD has not been studied in patients with severe hepatic impairment [see Dosage and Administration]. Renal Impairment - In mild, moderate, and severe renal impairment, no dose adjustment is necessary (see Figure 2 below) [see Dosage and Administration]. Gender Effect - After adjustment for body weight, the systemic exposures between males and females are similar (see Figure 2) [see Dosage and Administration].

Figure 2. Impact of Intrinsic Factors on Vilazodone PK

OVERDOSAGE: Human Experience - There is limited clinical experience regarding human overdosage with VIIBRYD. Four patients and 1 patient’s child experienced an overdose of VIIBRYD; all recovered.

The adverse reactions associated with overdose of VIIBRYD at doses of 200-280 mg as observed in clinical trials included serotonin syndrome, lethargy, restlessness, hallucinations, and disorientation.

Management of Overdose - Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference® (PDR). No specific antidotes for vilazodone are known. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be considered. Removal of vilazodone by dialysis has not been studied; however, the high volume of distribution of vilazodone suggests that dialysis will not be effective in reducing vilazodone plasma concentrations.

Distributed by Licensed from Merck KGaA, Forest Pharmaceuticals, Inc. Darmstadt, Germany Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA VIIBRYD™ is a trademark of Forest Laboratories, Inc. © 2011 Forest Laboratories, Inc. Rev April 2011 47-1020722-BS-A-APR11 Please also see full Prescribing Information at www.viibryd.com.

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astellas pharma us Exhibit Booth 207 astellas Pharma us, inc., a u.s. affiliate of Tokyobased astellas Pharma inc., is a pharmaceutical company dedicated to changing tomorrow by improving the health of people around the world through innovative and reliable pharmaceutical products. in the us, astellas has an intense focus on seven key therapeutic areas – Cardiology, dermatology, infectious disease, Neuroscience, Oncology, Transplant, and urology. for more information about astellas Pharma us, inc., please visit our Web site at www.astellas.us.

astraZeneca Sponsor astraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. astraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. for more information about astraZeneca in the u.s. or our aZ&Me™ Prescription savings programs, please visit: www.astrazeneca-us.com or call 1-800-aZandMe (292-6363).

authentidate Exhibit Booth 331 authentidate is a provider of telehealth, hospital discharge, referral, and order management software and products. Our hospital discharge software automates and simplifies the discharge process while inscrybe healthcare enables healthcare providers, suppliers, and insurers to exchange, update and electronically sign healthcare orders faster and more accurately than ever before. Our telehealth solutions include vital signs monitoring devices and applications that help reduce hospital readmissions, increase care plan compliance and improve overall outcomes for chronically ill patients.

auxilium pharmaceuticals

brightsky

Exhibit Booth 307 auxilium Pharmaceuticals, inc. is a specialty biopharmaceutical company committed to providing innovative solutions for unmet medical needs which are often undiagnosed or under-treated.

Exhibit Booth 117 Brightsky offers a “total solutions” approach to diabetes management. We deliver more than diabetes testing supplies and prescription medications; we deliver support and proactive management, with tools, resources and education that will help your members, providers and case management staff manage diabetes more effectively. Brightsky offers the Brightsky advantage, a diabetes management program designed to increase test strip compliance and medication adherence, while also helping to improve your plan’s hedis and sTar ratings. Visit us in booth 117 for more information or call 1-800-774-0788.

bayer healthcare pharmaceuticals Exhibit Booth 316 Bayer healthCare Pharmaceuticals inc. is the u.s.-based pharmaceuticals unit of Bayer healthCare llC, a division of Bayer ag. The company markets products for diagnostic imaging, general Medicine, hematology, Neurology, Oncology and Women’s healthcare. its aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.

biorx Exhibit Booth 324 Biorx is a specialized provider of pharmacy and infusion services targeted at rare, chronic, costly diseases, including hemophilia, immune deficiencies, autoimmune disorders, nutrition and digestive disorders, alpha-1 antitrypsin deficiency, and hereditary angioedema. an aChC-accredited provider, Biorx delivers savings by providing increased patient monitoring and clinical assistance. learn more at www.biorx.com.

biogen idec Exhibit Booth 402 and Sponsor Biogen idec creates new standards of care in therapeutic areas with high unmet medical needs. founded in 1978, Biogen idec is a global leader in the discovery, development, manufacturing, and commercialization of innovative therapies. Patients in more than 90 countries benefit from Biogen idec’s significant products that address diseases such as multiple sclerosis.

boehringer ingelheim pharmaceuticals Exhibit Booth 303 and Sponsor Boehringer ingelheim Pharmaceuticals, inc., the us subsidiary of Boehringer ingelheim, headquartered in germany, operates globally in 50 countries with more than 41,500 employees. The company is committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine. for more information please visit http:// us.boehringer-ingelheim.com.

boston scientific Exhibit Booth 418 Boston scientific has developed a bronchoscopic procedure for the treatment of severe persistent asthma in adults not well controlled on iCs and laBa alone. The alair® Bronchial Thermoplasty system reduces the amount of excessive airway smooth muscle, decreasing the ability of the airway walls to contract and narrow during an asthma attack, providing long-lasting and improved asthma control for adult severe asthma patients. for more information, please visit www.BTforasthma.com.

ccs Medical Exhibit Booth 231 CCs Medical is an industry leader in the home delivery of chronic care medical products including wound care, urology, ostomy, diabetes, and pharmacy medications. CCs Medical is also the largest distributor of insulin pumps and pump supplies in the nation. We help quality-focused payors drive healthy outcomes through customized supply management. stop by our booth to learn how we can help you improve your disease management outcomes today.

caridianbct Exhibit Booth 223 following the april 2011 Terumo Corporation acquisition, CaridianBCT and Terumo Transfusion became the global leader in blood component technology, delivering unsurpassed value and quality with solutions to increase customer efficiency. Together we remain focused on touching patients’ lives with products and services designed to meet the demand for safer, high-quality blood components.

coram specialty infusion services Exhibit Booth 222 Coram is a leading national provider of specialty home infusion and specialty pharmacy services with more than 30 years of experience servicing the needs of complex patients. With more than 85 branches and over 65 infusion suites throughout the country, Coram offers both national presence and comprehensive local coverage. Coram’s nurses, pharmacists, dietitians and other clinical staff are known in the industry for providing an exceptional level of personalized care to thousands of home and infusion suite iV patients every day. for more information, please visit our website at www.coramhc.com.

cubist pharmaceuticals Exhibit Booth 415 Cubist Pharmaceuticals, inc. is a biopharmaceutical company focused on the research, development, and commercialization of pharmaceutical products that address significant unmet medical needs in the acute care environment. in the u.s., Cubist markets CuBiCiN(r) (daptomycin for injection), the first antibiotic in a class of anti-infectives called lipopeptides, and has an agreement with Optimer Pharmaceuticals, inc. to co-promote difiCid(TM)

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fall Managed Care forum: guide TO CONfereNCe suPPOrTers in the u.s. as a treatment of Cdad (Clostridium difficile-associated diarrhea) in adults.

dailyMedrx Exhibit Booth 318 dailyMed™ is the only comprehensive pharmacy solution for chronically ill, complex, high cost, noninstitutionalized patients. Our solution focuses on addressing the key issues driving medication non-compliance and adherence. dailyMed Pharmacy dispenses a monthly cycle of a patient’s prescriptions, OTC medications and vitamins, and organizes them into pre-sorted packets marked with the date and time the medications should be taken. dailyMed Benefits: Medication Consolidation & synchronization, Complete Prospective drug utilization review, Compliance Packaging, Medication Therapy Management

dexcom, inc.

Exhibit Booth 121 6340 sequence drive san diego, Ca 92121 Phone: 888-738-3646 www.dexcom.com dexCom™, inc., an innovation leader in continuous glucose sensing, produces the fda approved seVeN® Plus continuous glucose monitoring system, which also has Ce Mark approval for commercialization in the european union, latin america and asian countries. dexCom also has joint development agreements with animas® Corporation, insulet Corporation and edwards lifesciences llC. dexCom is located in san diego, Ca.

edgepark Medical supplies Exhibit Booth 230 edgepark is the nationwide leader in home-delivered medical supplies for diabetes, ostomy, wound care, urological, incontinence and much more. We are contracted with more than 1,000 health plans and accept Medicare assignment. Our products ship from one of our seven fully stocked, stateof-the-art distribution centers to ensure that you have what you need, when you need it. for more information, please call us at 1-800-321-0591 or visit us online at www.edgepark.com.

eisai Exhibit Booth 313 eisai inc. is the u.s. pharmaceutical operation of eisai Co., ltd., a research-based human health care (hhc) company that discovers, develops and markets products throughout the world. headquartered in Woodcliff lake, New Jersey, the company focuses its efforts in three commercial areas: neurology, gastrointestinal disorders and oncology/critical care. established in 1995 and ranked among the top-20 u.s. pharmaceutical companies (based on retail sales), the company began marketing its first product in the united states in 1997 and has rapidly grown to become a fully integrated pharmaceutical business. for more information about eisai, please visit www.eisai.com/us.

endo pharmaceuticals Exhibit Booth 309 endo Pharmaceuticals is a u.s.-based, specialty healthcare solutions company, focused on highvalue branded products and specialty generics. endo is redefining its position in the healthcare marketplace by anticipating and embracing the evolution of health decisions based on the need for high-quality and cost-effective care. We aim to be the premier partner to healthcare professionals and payment providers, delivering an innovative suite of complementary diagnostics, drugs, devices and clinical data to meet the needs of patients in areas such as pain, urology, oncology and endocrinology. for more information about endo Pharmaceuticals, and its wholly owned subsidiaries american Medical systems, inc., healthTronics, inc. and Qualitest Pharmaceuticals, please visit http:// www.endo.com/.

entellus Medical Exhibit Booth 412 about entellus Medical™: entellus Medical delivers innovative, high-quality, minimally-invasive therapeutic solutions to healthcare providers and their patients who suffer from sinusitis. Based in Maple grove, Minn., entellus Medical manufactures, markets, and distributes its products throughout the united states. for more information about entellus Medical, finess sinus Treatment, Xpress Multi-sinus dilation Tool, or the Pathassist light seeker visit www.entellusmedical. com or call 763/463-1595.

ethicon endo-surgery Exhibit Booth 212 and Sponsor ethicon endo-surgery, inc. resides in the medical device and diagnostics sector of the Johnson & Johnson family of companies. We develop and bring to market medical devices used in both open and laparoscopic (Minimally invasive Procedures MiP) surgeries around the world.

Our healthcare Policy & economics team goal is to increase the awareness of what quality surgical care can be with improved outcomes and a smarter healthcare spend. We value safe, efficient, patient-centered care; evident in our commitment to drive quality and cost-saving initiatives.

express scripts Exhibit Booth 317 express scripts specialty Benefit services provides the most comprehensive solution for managing specialty drugs in both the pharmacy and the medical benefit. By integrating our core services — specialty Pharmacy Benefit Management, Medical drug Management and specialty distribution and fulfillment — we deliver flexible solutions that enhance patient care and control costs.

fico Exhibit Booth 417 fiCO delivers superior predictive analytics solutions that drive smarter decisions. The company’s groundbreaking use of mathematics to predict consumer behavior has transformed entire industries and revolutionized the way risk is managed and products are marketed. fiCO’s

solutions include the fiCO® score, along with industry-leading solutions for managing credit accounts, fighting fraud, and customizing offers with pinpoint accuracy. fiCO’s health care solutions cut losses from fraud and drive engagement with members. learn more at www.fico.com/healthcare.

fifty50 Medical Exhibit Booth 411 fifty50 Medical is a full line diabetes product manufacturer/supplier offering all the national brands of diabetes supplies as well as our own brand of insulin pump supplies. We donate half our profits to fund diabetes research. We’re giving back to help find a cure.

first call pharmacy Exhibit Booth 422 first Call iV Pharmacy is a leading provider of home infusion and high-tech specialty pharmacy services throughout america. We are aChC accredited with a staff of professionals having combined homecare experience rivaling anyone in the business. Offering true national coverage and customer service second to none, we can provide services for your patients in any location – we specialize in those challenging cases in tough to reach rural areas. To top it off, we offer this comprehensive coverage and top-notch service at rates that are cheaper than most in-network rates. should your home infusion patient require additional nursing or therapy services, you can tap into the wealth of resources provided by our network of over 3,000 full service home health agencies across the country Make one call to our centralized intake center and speak to one of our customer service professionals today for help with your next home infusion case. No matter how challenging the case, we will make the process as easy and seamless as possible, getting your patient home quickly with all of their home infusion needs met. We are truly your “first Call” for the best in home infusion services. remember, regardless of location or time, first Call iV Pharmacy is always where you need us to be.

National Central intake - (800) 877-5705

first report®Managed care Sponsor first report®Managed Care (firstreportnow.com) is a managed markets print and online brand that circulates to more than 21,000 health plan CeOs, hospital formulary committee members, hMO pharmacists, health plan medical directors and pharmacy directors, large employer decisionmakers, and state prison facility managers. The editorial mission is focused on delivering the most comprehensive late-breaking information that affects managed market providers with topics that include clinical, legislative, and economic developments. first report Managed Care also reports on dozens of scientific and managed care conferences throughout the world, providing readers with pertinent news from scientific sessions, symposia, and late-breaking clinical trials.

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fall Managed Care forum: guide TO CONfereNCe suPPOrTers forest laboratories

healthpoint biotherapeutics

Exhibit Booth 216 and Sponsor forest Pharmaceuticals, inc. is a wholly-owned subsidiary of New york City-based forest laboratories, inc. forest’s longstanding global partnerships and track record developing and marketing pharmaceutical products in the united states have yielded its well-established central nervous system and cardiovascular franchises and an emerging portfolio in anti-infective and respiratory medicine. The Company’s pipeline, the most robust in its history, includes product candidates in all stages of development across a wide range of therapeutic areas.

Exhibit Booth 406 healthpoint Biotherapeutics is a commercialstage biopharmaceutical company focused on the development and commercialization of novel, cost-effective solutions for tissue repair and healing. The company’s diversified research and development strategy is presently centered around therapeutic enzymes, biologics and nextgeneration cell- and cell-matrix based therapies for the prevention and treatment of acute, chronic and burn-related wounds. healthpoint Biotherapeutics is a dfB Pharmaceuticals, inc., affiliate company, and is based in fort Worth, Texas. for more information, visit the company website at www.healthpointbio.com.

genentech Exhibit Booth 305 Considered the founder of the biotechnology industry, genentech has been delivering on the promise of biotechnology for more than 30 years, using human genetic information to discover, develop, manufacture and commercialize medicines to treat patients with serious or life threatening medical conditions. Today, genentech is among the world’s leading biotech companies, with multiple products on the market and a promising development pipeline.

genomic health Exhibit Booth 308 genomic health, inc., a life science company located in redwood City, California, conducts genomic research to develop clinically-validated oncology molecular diagnostics, which provide individualized information on the likelihood of disease recurrence and response to chemotherapy.

These diagnostic technologies generate information that payers, physicians and members can use in assessing treatment decisions.

healthways Exhibit Booth 304 and Sponsor healthways is a global provider of science-based solutions that improve well-being, enhance business and human performance and reduce overall healthcare costs. Our solutions are designed to help healthy individuals stay healthy, mitigate and slow the progression to disease associated with family or lifestyle risk factors and promote the best possible health for those already affected by disease. We provide highly specific and personalized interventions to millions of people domestically and internationally, surrounding them with tailored support when they are at home, at work, seeking medical care or pursuing health improvement.

hologic

Exhibit Booth 302 and Sponsor gilead sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. headquartered in foster City, California, gilead has operations in North america, europe and asia Pacific.

Exhibit Booth 326 hologic is a leading developer, manufacturer and supplier of premium diagnostic and medical imaging systems and surgical products dedicated to the healthcare needs of women.

We are committed to enhancing women’s lives through earlier detection, improved diagnosis and less invasive treatments. Our core business areas focus on mammography, breast Mri and breast biopsy, radiation treatment for early-stage breast cancer, cervical cancer screening, treatment for menorrhagia, osteoporosis assessment, and preterm birth screening. learn more at www.hologic.com.

glaxosmithKline

home instead senior care

Exhibit Booth 109 glaxosmithKline is a leading research-based pharmaceutical company with a powerful combination of skills to discover and deliver innovative medicines. We offer a number of programs to support effective health management strategies and improve patient care. Please visit our exhibit to learn more about our products. glaxosmithKline five Moore drive research Triangle Park, NC 27709 www.gsk.com

Exhibit Booth 123 home instead senior Care is the world’s largest provider of home care services for seniors. Our services are designed for practically any living arrangement where older adults simply need help to “age in place” with independence, security, and dignity. from basic home care needs to activities of daily living, alzheimer’s and dementia care, respite, and transitional care services, the home instead senior Care network of more than 900 offices are ready to serve.

Toll free Phone: (888) 825-5249 Phone: (919) 483-2565 fax: (919) 315-6049

Exhibit Booth 322 humana inc., headquartered in louisville, Kentucky, is one of the nation’s largest publicly traded health benefits companies. humana offers a

gilead sciences

humana

diversified portfolio of health insurance products and related services - through traditional and consumer-choice plans - to employer groups, government-sponsored plans, and individuals.

Today, humana is a leader in consumer engagement. Throughout its diversified customer portfolio, the company provides guidance that can both help lower costs and lead to a better health plan experience.

impediMed, inc.

Exhibit Booth 205 and Sponsor lymphedema: a devastating yet common side effect of breast cancer treatment. impediMed partners with health plans to promote prospective management of lymphedema. earlier detection allows earlier, more cost-effective intervention resulting in better outcomes. Nih data demonstrates successful intervention and return to pre-surgical baselines when identified at a subclinical stage. l-dex® devices are fda cleared and CPT coded. improve patient quality of life and survivorship while reducing costs for compression pumps and intensive long term treatment.

ipsen u.s.

Exhibit Booth 319 ipsen is an international specialty pharmaceutical group. Our expertise in steroid, peptide & protein engineering enables us to explore and develop new therapeutic approaches in the fields of Neuroscience, endocrinology, and Oncology. ipsen invests over 20% of sales in research & development and has a commercial presence in over 30 countries.

i-sens usa, inc.

Exhibit Booth 218 i-seNs, inc, founded by biosensor experts, is a strong r & d company with many innovative products in the world of blood glucose monitoring systems. With over 30 different patents worldwide, our products are on the cutting edge of technology. We also have many proprietary technologies including our own auto-coding system. after receiving approval from many worldwide ministries of health, including the fda and Ce, our products are being sold throughout the world.

Kindred healthcare Exhibit Booth 232 Kindred healthcare, inc. is a healthcare services company. Kindred through its subsidiaries provides healthcare services at long-term acute care hospitals, inpatient rehabilitation hospitals, nursing and rehabilitation centers, sub-acute units, hospice and home care locations, inpatient rehabilitation units (hospital-based) and a contract rehabilitation services business, rehabCare.

Kindred’s mission is to promote healing, provide hope, preserve dignity and produce value for each patient, resident, family member, customer, employee and shareholder we serve. for more information, go to www.kindredhealthcare.com.

labcorp/genzyme genetics Exhibit Booth 430 and Sponsor labCorp provides leading-edge diagnostic tests

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fall Managed Care forum: guide TO CONfereNCe suPPOrTers and services through a national network of primary clinical laboratories and specialized Centers of excellence, including genzyme genetics. labCorp’s comprehensive services for specialists in reproductive medicine include infectious disease donor screening, reproductive endocrinology, coagulation, genetic testing and counseling services, preimplantation genetics, drugs-of-abuse screening, and routine testing.

lilly usa, llc Sponsor lilly Corporate Center indianapolis, iN 46285 lilly, a leading innovation-driven corporation, is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. headquartered in indianapolis, iN, lilly provides answers - through medicines and information - for some of the world’s most urgent medical needs.

Medical review institute of america Exhibit Booth 323 review of medical/disability/work comp/behavioral health/pharmacy cases by board-certified, actively practicing physicians on a matched-specialty basis. uraC accredited in utilization Management and external review, and NCQa certified in utilization Management. Prospective, concurrent, or retrospective review. 24-72 hour written responses and phone consultations. 600+ physicians in 48 states reviewing medical necessity, appropriate treatment or hospitalization, experimental procedures/ drugs/medical devices/transplants.

Medtronic, inc.

Exhibit Booth 103-105 Medtronic, inc. (www.medtronic.com), headquartered in Minneapolis, is the global leader in medical technology – alleviating pain, restoring health and extending life for millions of people around the world. at Medtronic, we’re committed to innovating for life by pushing the boundaries of medical technology and changing the way the world treats chronic disease.

ment solutions, including the PhCs Network, MultiPlan Network, PhCs savility, healtheOs, Beech street and Texas True Choice. an estimated 57 million consumers access our products through our 1,400 clients, which include insurers/health plans, third-party administrators, self-funded employers, hMOs and other entities that pay medical bills in the commercial healthcare, government, workers compensation and auto markets. learn more at www.multiplan.com.

neurogesx inc.

Exhibit Booth 227 NeurogesX® is a san francisco Bay area-based biopharmaceutical company focused on developing and commercializing novel pain management therapies. NeurogesX was founded on the concept that the use of prescription strength capsaicin could help manage the pain associated with neuropathic pain conditions. Our lead product, Qutenza® (capsaicin) 8% patch, is a dermal delivery system containing a prescription strength of capsaicin that is currently approved in the united states and the european union.

nexus healthcare llc Exhibit Booth 311 Phone: 804-402-8088 email: dmara@nexushc.com www.nexushc.com Nexus healthcare is an executive search firm dedicated to placing medical directors, chief medical officers and exceptional healthcare executives in the heathcare industry nationwide. Our extraordinary client base consists of managed care organizations, health systems, hospitals and physician group practices. Our innovative approach to executive search allows us to identify key individuals for our clients’ organizational challenges that can best support their strategic objectives. We have access to the highest caliber of managed care talent. if you have an available position or have an interest in our placement service, please give us a call.

novartis pharmaceuticals

Exhibit Booth 224 Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as Msd outside the united states and Canada.

Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. for more information, visit www. merck.com

Exhibit Booth 206 www.us.novartis.com located in east hanover, N.J., Novartis Pharmaceuticals Corporation is an affiliate of Novartis ag, which provides healthcare solutions that address the evolving needs of patients and societies. focused solely on healthcare, the Novartis group offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. The Novartis group is the only company with leading positions in each of these areas. headquartered in Basel, switzerland, Novartis group companies employ approximately 99,000 full-time-equivalent associations and operate in more than 140 countries around the world.

Multiplan

novartis Vaccines

Exhibit Booth 330 founded in 1980, MultiPlan is the nation’s oldest and largest supplier of healthcare cost manage-

Exhibit Booth 208-210 and Sponsor “Caring Begins with Prevention” at Novartis Vaccines and diagnostics, we believe

Merck & co.

that caring for patients begins with protecting individuals and societies from infection in the first place.

The division has two businesses: Novartis Vaccines and Novartis diagnostics.

Novartis Vaccines is the world’s fifth-largest vaccines manufacturer and the second-largest supplier of influenza vaccines in the us. The division’s products also include meningococcal, pediatric and travel vaccines.

Novartis diagnostics is dedicated to providing innovative testing solutions to protect the world’s blood supply from transfusion-transmitted diseases. We are the world leader in nucleic acid testing for blood screening.

novo nordisk Exhibit Booth 306 and Sponsor Novo Nordisk is a focused healthcare company and a world leader in diabetes care.

novocure usa Exhibit Booth 402 Novocure limited is a private oncology company pioneering a novel anti-mitotic therapy for solid tumors. The company manufactures the NovoTTf100a system, a portable, non-invasive medical device that creates a low intensity, alternating electric field within the targeted tumor. The device has received an fda PMa approval and will be launched in 2011. Novocure is headquartered in the Jersey isle, its us operations are based in Portsmouth, Nh, and its r&d center is located in israel.

pamlab llc Exhibit Booth 226 Pamlab is a biomedical company that specializes in natural personalized medicine by offering health care providers high quality prescription medical foods to safely address the distinct nutritional requirements of patients suffering from a medical condition with a particular emphasis in clinical depression, diabetic peripheral neuropathy, mild cognitive impairment, and prenatal care.

perkinelmer Exhibit Booth 209 Perkinelmer Managed Markets offers the following service providers which leverage leading-edge technology and proprietary capabilities. signature genomics. The innovator in microarray as a diagnostic tool. We’ve processed over 50,000 cases, more than all other providers combined. NTd labs. a leader in prenatal screening is the exclusive provider of the free beta hCg first trimester down syndrome screen.

Perkinelmer genetics. The nation’s largest provider of newborn screening services. We‘ve screened over 4 million babies since 1994.

purdue pharma lp Exhibit Booth 410 Purdue Pharma l.P. is well known for its pioneering work on persistent pain, a principal cause of human suffering.

The company’s leadership and employees are dedicated to providing healthcare professionals, patients and caregivers with safe and effective therapies, and innovative educational resources

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Quidel corporation Exhibit Booth 213 and Sponsor Quidel® Corporation enhances people’s health and wellbeing through diagnostic solutions that can lead to improved patient outcomes and economic benefits for healthcare providers. With leading brands – QuickVue®, MicroVue™, d3 direct detection™ and Thyretain™, Quidel’s products aid in the detection and diagnosis of critical diseases and conditions, e.g., influenza, rsV, strep a, herpes, pregnancy, thyroid disease, Chlamydia, h. pylori and fecal occult blood.

rcM health care services Exhibit Booth 220 With over 30 years of experience, rCM healTh Care serViCes specializes in executive search and placement, as well as long-term and shortterm staffing of medical professionals within case management, quality assurance, utilization review, education, and performance improvement, just to name a few. rCM works with your staff to create a custom position profile, gather a pool of highly qualified candidates for targeted searches, and identify the best candidate for your organization.

registry of physician specialists Exhibit Booth 111 The registry of Physician specialists (rPs) is a staffing and recruiting company that has worked with various medical & mental health service providers Nationwide to provide stable employment and lucrative work opportunities. We look forward to becoming a flexible and reliable sTaffiNg aNd reCruiTiNg option for your business, or a source for nationwide tailored opportunities to diversify your practice and supplement your income. if you want more information stop by booth 111 Or call 800-882-0686.

resMed Exhibit Booth 119 resMed is a global leader in sleep and respiratory medicine which specializes in the diagnosis and management of sleep-disordered breathing (sdB), the most common type of which is sleep apnea. Our solutions include a suite of the finest treatment devices and data management solutions to help ensure therapy adherence for the over 50 million afflicted americans.

Our mission is to educate payors, physicians and the public about the health risks of untreated sdB and to deliver the best therapy on the market.

si-bone Exhibit Booth 125 si-BONe, inc. (san Jose, California) is the leading sacroiliac (si) joint medical device company dedicated to the development of tools and products for diagnosing and treating patients with low back issues related to si joint dysfunction. The company has developed, and is manufacturing and marketing, less invasive approaches using implants for the treatment of si joint pathology.

salix pharmaceuticals

sterling Medical services llc

Exhibit Booths 325-327 salix Pharmaceuticals is a specialty pharmaceutical company dedicated to acquiring, developing and commercializing brand name, prescription pharmaceutical products used in the treatment of a variety of gastrointestinal diseases. salix’s strategy is to identify and acquire late-stage proprietary pharmaceutical products having an existing base of safety and efficacy data in humans for the treatment of gastrointestinal disease, and to apply the Company’s regulatory, product development, and sales and marketing expertise to commercialize these products.

Exhibit Booth 113 founded in 1992, sterling Medical services, llC is a national provider and distributor of disposable medical supplies (wound care, urological, diabetic and ostomy) directly to the patient’s home. Our website, www.sterlingmedical.com, is interactive.

Phone in orders at 888-202-5700.

We carry thousands of supplies from leading manufacturers, including diabetic, ostomy, incontinence, urological and wound and skin care supplies. Patients can place an order by, phone, fax or online and we will bill insurance on their behalf. sterling Medical services is Medicare and Medicaid participating and has most managed care contracts nationwide. sterling is proud to be accredited by the Community health accreditation Program (ChaP), the leader in improving the quality of community based health care services in the usa.

seniorbridge Exhibit Booth 409 seniorBridge is a national health management company with a 10-year heritage of caring for people with complex chronic conditions in the comfort of their homes. seniorBridge’s integrated care management team of nurse practitioners, nurses and social workers coordinate and provide personalized care that improves health outcomes while reducing overall cost of care among our clients’ top 5% most costly patients. for more information, visit www.seniorBridge.com/MC3 or contact us at MC3@seniorBridge.com.

sequenom center for Molecular Medicine Exhibit Booth 107 sequenom CMM, a Clia-certified, CaP accredited genetic laboratory, is dedicated to the development and commercialization of laboratory-developed genetic testing services that can be used as tools by clinicians in managing patient care. Tests include sensigene® Cystic fibrosis Carrier screening, sensigene fetal rhd genotyping and retnagene™ aMd. in development: MaterniT21™. sequenom CMM is helping to advance patient care with the power of molecular diagnostics. Visit www.sequenomCMM. com for more information, or email us at info@ sequenomCMM.com.

shire Exhibit Booth 320 shire hgT, a business within the shire group of companies, is committed to developing, manufacturing, and commercializing therapies for rare genetic diseases. The company achieves this through collaboration with academic researchers, physicians and patient associations, with the goal of providing therapies for patients worldwide.

smith & nephew Exhibit Booth 211 Patients are our focus and healing the human body is our mission. We offer the world’s most prescribed joint fluid therapy and fracture healing devices and are a global provider of leading-edge joint replacement systems for the knee, hip and shoulders. Visit www.smith-nephew.com for more information on all of our products.

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tandem diabetes care Exhibit Booth 219 Tandem diabetes Care is experienced, not by age but through collaborative wisdom shared by our on-staff insulin pump users, more than 1,500 clinicians and people who live with diabetes. We are creating products that enable a flexible lifestyle, are engineered to the highest quality standards, and designed with uncompromising style. We understand “one size does not fit all” when it comes to pump therapy and want to offer product choices to meet individual needs. We strive to apply similar conveniences, useful data and tools, right at your fingertips.

teva pharmaceuticals Exhibit Booth 203 and Sponsor Teva Pharmaceuticals’ North america Brand Pharmaceuticals group is built on the knowledge and expertise of multiple innovative business units, including respiratory, neurology, women’s health and biologics/specialty products. This brand division leverages the skills and competencies of each therapeutic area, and coordinates and aligns efforts for a more efficient and effective delivery of healthcare solutions.

the assist group Exhibit Booth 416 The assist group is the leader in catastrophic facility claim review (Clinassist) and complex NiCu care management (Careassist).

Our Clinassist claim review, resolution and negotiation services combine hands-on clinical and financial expertise with advanced technology to minimize claim exposure by identifying improper billing and delivering payers, on average, a 21% reduction per claim.

Our Careassist care management program is designed to positively impact clinical and financial outcomes for complex newborns, with an average 15% reduction in length of stay.

united seating & Mobility Exhibit Booth 225 united seating and Mobility focuses on providing cost effective, appropriate mobility solutions to

fall Managed Care forum: guide TO CONfereNCe suPPOrTers persons with disabilities, using a care-centered approach and a passion to make lives better. Please call 800.500.9150 or visit unitedseating.com.

unitedhealth group Exhibit Booth 420 We are a fortune 21 global leader, and the most resourceful, prepared and visionary provider of health care benefits and health services in the world.

But that’s not really what sets us apart. Our greatest point of difference is our people – and the collective talent, energy, intelligence and drive our force of 80,000+ individuals bring every single day to the task of accomplishing our mission – helping people live healthier lives. for details on careers with us, visit careers. unitedhealthgroup.com unitedhealth group 9900 Bren road east Minnetonka, MN 55343 Phone: (860) 702-5889 fax: (860) 702-7220 email: andrea_eselunas@uhc.com

Valeritas Exhibit Booth 408 The V-go is the first simple, fully disposable device for the delivery of basal-bolus insulin therapy for adults with diabetes. The V-go provides a continuous preset basal rate of insulin and allows for ondemand bolus dosing around mealtimes thereby providing an alternative to taking multiple daily insulin injections. Patients apply a new V-go to the skin daily for one 24-hour period. The V-go is not electronic, making it easy to operate and use.

Verinata health Exhibit Booth 131 Verinata is driven by a sole, extraordinary purpose - maternal and fetal health. Our initial focus is to develop and offer non-invasive tests for early identification of fetal chromosomal abnormalities through our proprietary technologies. We aim to reduce the anxiety associated with today’s multi-step process, the unacceptable false positive rates, the non-specific and sometimes confusing results of current prenatal screening methods, and the risk of current invasive procedures. for more information please go to www.verinata.com.

ics and more than 370 worksite health centers.

Through more than 8,500 points of care, we are committed to comprehensive, community-based, patient-focused health services.

Wheelchair professionals Exhibit Booth 225 Wheelchair Professionals is the largest National Network of mobility providers and the preferred choice of many major health plans, with the resources to supply health plans with solutions for their members’ complete mobility needs.

Please call 800.729.0871 or visit Wheelchair Professionals.com.

xdx, inc.

Exhibit Booth 424 Xdx is a molecular diagnostics company focused on the discovery, development and commercialization of non-invasive gene expression testing in the areas of transplant medicine and autoimmunity.

The company has developed a proprietary method of utilizing gene expression in blood that provides a new tool for physicians to aid in the management of heart transplant patients.

Xdx has one marketed product, alloMap® Molecular expression Testing, and other products under development.

Yoh health care Exhibit Booth 333 yoh services llC is a national company that offers employers in various industries workforce solutions to meet business objectives. yoh health Care provides talent and outsourcing services with a focus on contract and per diem staffing and direct placement recruitment of skilled personnel with expertise in Managed Care and Case Management. With over 345 million usd in total sales and over 7 decades of experience, yoh operates from more than 75 locations across the country.

in addition to Our exhibitors and sponsors, the fall Managed Care forum is supported by educational grants from: amylin/lilly grant Office astellas Pharma us Boehringer ingelheim Bristol-Myers squibb dendreon Corporation eisai genentech genentech/Biogen idec gilead sciences lilly usa llC Millennium Pharmaceuticals Novo Nordisk Onyx Pharmaceuticals smith & Nephew Vertex Pharmaceuticals

Verisk health Exhibit Booth 426 Verisk health leverages healthcare data in order to help payors, providers and employers understand their medical and financial risk for the purpose of improving quality of care and reducing costs.

We approach healthcare risk with the focus and flexibility that leads to unique insights and opportunities for our clients. Please visit us at www. veriskhealth.com.

Walgreens Exhibit Booths 405-407 Walgreens is uniquely positioned as a singlesource national provider of pharmacy, health and wellness services. Take Care health systemssM a Walgreens health and wellness company, provides services nationwide at 350 convenient care clin-

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