Journal of Managed Care Medicine, Volume 18, Number 4 by Jeremy Williams

Vol.18, No.4, 2015

Journal of Managed Care Medicine

FEATURED ARTICLES INCLUDE: Improving Strategies for the Management and Treatment of Chronic Pain Therapeutic Challenges in the Diagnosis and Management of Psoriasis Metastatic Malignant Melanoma: Significant Treatment Advances

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Journal of Managed Care Medicine The Official Journal of the NAMCP MEDICAL DIRECTORS INSTITUTE A Peer-Reviewed Publication

Vol. 18, No. 4, 2015

TABLE OF CONTENTS

EDITOR-IN-CHIEF J. Ronald Hunt, MD

PUBLISHER Katie Eads

DIRECTOR OF COMMUNICATIONS Jeremy Williams

JOURNAL MANAGEMENT Douglas Murphy Communications Inc. P.O. Box 71895 Richmond, VA 23255-1895 (804) 387-7580 fax (703) 997-5842

Diagnostic and Treatment Challenges in Inflammatory Bowel Disease Joel Rosh, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Current and Emerging Therapies for LDL-C Reduction Michael Miller, MD, FACC, FAHA, FNLA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Current Treatments and Novel Strategies in the Management of Acute Coronary Syndromes Michael J. Lim, MD, FACC, FSCAI .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Exploring Current and Emerging Treatments for Chronic Hepatitis C: Cost and Effectiveness David H. Winston, MD, FACP, AGAF .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

B:11.25”

T:10.875”

MANAGING EDITOR

Improving Strategies for the Management and Treatment of Chronic Pain Eric S. Hsu, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

GRAPHIC DESIGN

Overcoming Challenges to Successful Asthma Adherence and Control Charles Vega, MD, FAAFP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Barry Barnum barry.barnum@douglasmurphy.com

Douglas Murphy Communications, Inc.

Custom Article Reprints

High quality 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. 1094-1525. The Thev Journal is published of Managed by Association Care Services Corporate and Circulation offices: Medicine Inc. is published by NAMCP Medical Directors 4435 Waterfront Drive, 101, Glen Allen,4435 VA Institute. Corporate andSuite Circulation offices: 23060; Tel (804) 527-1905; Fax (804) 747-5316. EditoWaterfront Drive, Suite 101, Glen Allen, VA 23060; rial and Production offices: 2613 N. Parham Rd., Tel (804) 527-1905; Fax 747-5316. Editorial and Suite B, Richmond, VA(804) 23294; Tel (804) 272-9100; Production offices: Advertising P.O. Box 71895, Richmond, VA Fax (804) 272-1694. offices: Jack Klose, 23255-1895; TelW. (804) 387-7580; (703) 997-5842. 804 Broadway, Long Branch, Fax NJ 07764; Tel (732) 229-8845; (856) Sloane 582-9596. Subscription Rates: AdvertisingFax offices: Reed, 4435 Waterfront one the United States; oneTel year $105 in Driveyear Ste$95 101,inGlen Allen, VA 23060 (804) 527Canada; one year $120 international. Back issues 1905, Fax (804) 747-5316. All rights reserved. Copyare available for $15 each. All rights reserved. right 2015. 2010. No part thisof publication may bemay reproCopyright Noofpart this publication be duced or transmitted in any in form by any reproduced or transmitted anyorform or means, by any means, electronic or mechanical, including photoelectronic or mechanical, including photocopy, recopy, recording, or any information storage orsysrecording, or any information storage or retrieval trieval system,written without writtenfrom consent from the tem, without consent the publisher. publisher. The publisher does not guarantee, eiThe publisher does not guarantee, either expressly ther expressly or by implication, the factual accuor by of implication, the and factual accuracy ofherein, the articles racy the articles descriptions nor and descriptions nor does the publisher does the publisherherein, guarantee the accuracy of any guarantee the accuracy ofby anythe views or opinions views or opinions offered authors of said ofarticles fered or by descriptions. the authors of said articles or descriptions. POSTMASTER: Send address changes to The POSTMASTER: Send address changes to The Journal of Managed Care Medicine, 4435 WaterJournal of Managed Waterfront Drive, Suite 101,Care GlenMedicine, Allen, VA4435 23060. front Drive, Suite 101, Glen Allen, VA 23060.

Patient Variability Calls for an Individualized Approach to the Management of OAB Pamela Ellsworth, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Recent Advances in the Treatment and Management of Multiple Sclerosis Patricia K. Coyle, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Therapeutic Challenges in the Diagnosis and Management of Psoriasis Robert E. Kalb, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Emerging Treatment Pathways in the Management of CINV Lee Schwartzberg MD, FACP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Metastatic Malignant Melanoma: Significant Treatment Advances Karl D. Lewis, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Individualized Treatment Options in the Management of Metastatic Breast Cancer George Somlo, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 3

Editorial Review Board Alan Adler, MD, MS Medical Director Independence Blue Cross

Sarath Gunatilake, MD, DrPH Professor, Health Science Department California State University, Long Beach

Gary Owens, MD Principal Gary Owens Associates

Devena Alston-Johnson, MD Medical Director CIGNA

John W. Heryer, MD, FACS Medical Director Blue Cross Blue Shield of Kansas City

Philip Painter, MD Chief Medical Officer Humana

E. Paul Amundson, MD Chief Medical Officer Dakotacare

Kathy Hudson, PhD Director, Genetics and Public Policy Center Johns Hopkins University

Linda Ash-Jackson, MD Medical Director Hometown Health

Larry L. Hsu, MD Medical Director Blue Cross Blue Shield of Hawaii (HMSA)

Paul Bluestein, MD Chief Medical Officer Connecticare

Stephen Keir, DrPH Co-Director, Center for Quality of Life Support Care Research Robert Preston Tisch Brain Tumor Center

Richard Bock, MD, MBA Chief Medical Officer Molina Health Care of California

John Knispel, MD, CPE, FACOG Regional Medical Officer Humana

Anthony Bonagura, MD Chief Medical Officer Aetna, Inc.

Karen Knowles, MD Internal Medicine Physician HCA/Emcare

Salil V. Deshpande, MD Market Medical Officer United Healthcare

Catherine Marino, MD Chief Medical Officer MagnaCare

Michael Fine, MD Medical Director Health Net John K. Fong, MD, MBA Vice President Blue Cross Blue Shield of North Carolina Stephen Friedhoff, MD Senior Vice President, National Medical Director Amerigroup/Wellpoint Ronald Y. Fujimoto, DO, FAAFP Chief Medical Officer United Healthcare Uwe G. Goehlert, MD, MSC, MPH, MBA Principal Goehlert & Associates Steven E. Goldberg, MD, MBA Vice President of Medical Affairs Coventry Health Care of Kentucky Humberto Guerra-Garcia, MD, MPH, FACP Chief Medical Officer MMM Healthcare, Inc./PMC Medicare Choice Puerto Rico

Jeff Martin, PharmD Clinical Account Director Innoviant, Inc. Monte Masten, MD, MBA, MPH Senior Consultant Health & Group Benefits, Tower Watson Wesley Mizutani, MD Director Clinical Research & Chairman Department of Rheumatology Healthcare Partners Thomas Morrow, MD Chief Medical Officer Next IT Barbara Nabrit-Stephens, MD, MBA Medical Director United Healthcare Tim Newman, MD Medical Director FirstEnergy Denis Oâ&#x20AC;&#x2122;Connell, MD Medical Director Blue Cross Blue Shield of North Carolina Arik Olson, MD, MBA Senior Medical Director CHOICE Health Plans

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Mary H. Pak, MD Medical Director Unity Health Plans Insurance Corporation Gary R. Proctor, MD Chief Medical Officer, Federal Division ValueOptions, Inc. Carlos Ramirez, MD Chief Medical Officer Valley Baptist Health Plans Paul Rein, DO Medical Director Port Warwick Ambulatory Surgery Center Kevin Roache, MD, MMM, CPE, FACPE President Medical Management Consulting, Inc. Joseph Schappert, MD Chief Medical Officer PAML Christine M. Seals, MD Medical Director Umpqua Health Alliance Jacque J. Sokolov, MD Chairman SSB Solutions Scott Spradlin, DO, FACPE, ACOI Vice President Medical Affairs/Chief Medical Officer Group Health Plan William D. Strampel, DO, FACOI Dean, College of Osteopathic Medicine Michigan State University Prentiss Taylor, MD Corporate Medical Director Advocate At Work at Advocate Health Care Pamella Thomas, MD,MPH, FACOEM Consulting Medical Director Wellness Health & Productivity Strategies Robert A. Ziff, MD, MBA, FACS, CPE Senior Corporate Medical Director, Medicare Humana

Diagnostic and Treatment Challenges in Inflammatory Bowel Disease Joel Rosh, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary The treatment paradigm for inflammatory bowel disease (IBD) is changing to a personalized risk stratification and early aggressive use of immunomodulators and biologics in those with higher risk disease. With this aggressive approach, it is possible to induce remission, heal the damaged intestinal mucosa, and maintain long-term remission to achieve optimal outcomes in this disease. Key Points • IBD is really a family of diseases currently simplified to two umbrella terms: Crohn’s disease and ulcerative colitis. • An accurate diagnosis and staging requires clinical suspicion and appropriate confirmatory testing. • A step-up therapy approach does not change the natural history of the disease or the disabling outcomes of surgery, hospitalization, and lowered quality of life. • A personalized approach of risk stratification and “treat-to-target” is emerging as the best practice. • Therapeutic drug monitoring and optimization of therapy are critically important goals in the biologic era.

INFLAMMATORY BOWEL DISEASE (IBD) IS a chronic intestinal inflammation from a dysregulated immune response to the enteric microbiome in a genetically predisposed host. Today IBD is labeled as Crohn’s disease (CD) and ulcerative colitis (UC), though a host of often overlapping phenotypes are recognized. The classification is evolving toward the use of IBD1 through IBD5 instead of Crohn’s and UC. Typical symptoms of IBD include abdominal pain, nausea, vomiting, diarrhea, and constipation. Presenting symptoms range from mild to severe and the clinical course is often unpredictable, ranging from easily controlled to fulminant disease. Clinical suspicion is the key to diagnosing IBD. Crohn’s disease, characterized by transmural small bowel disease, is diagnosed based on a composite of endoscopic, radiographic, and pathological findings which show documentation of focal, asymmetric, transmural, or granulomatous features. There are multiple new im-

aging techniques for small bowel imaging, including magnetic resonance (MR) enterography and computed topography (CT) enterography, which show transmural disease and video capsule endoscopy which can only identify mucosal involvement. MR enterography does not expose the patient to radiation but is time intensive. CT enterography is rapid but exposes the patient to radiation. Ultrasonography is used in Europe but not yet in the United States. Ulcerative colitis tends to be less subtle on presentation compared with Crohn’s disease and should be suspected in those presenting with persistent bloody diarrhea, rectal urgency, or tenesmus. Stool examination is done to exclude an infectious etiology of symptoms. Sigmoidoscopy or colonoscopy and biopsy are performed to confirm presence of colitis. The goals of IBD disease management – together with the corresponding clinical parameters and outcomes – have evolved with the development of

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Exhibit 1: Evolving Goals of Therapy for IBD: Sustained Deep Remission

Goal

Clinical Parameters

Outcomes

Response

Improved symptoms

Improved QOL

Remission

No symptoms

Decreased hospitalization

Deep remission

Normal endoscopy

Avoidance of surgery

SUSTAINED

QOL, quality of life

very effective medications (Exhibit 1). The goal is to achieve deep sustained remission with a normalization of the gastrointestinal mucosa. If a deep remission can be achieved, patients have a lower risk of needing surgery, strictures, fistulas, and other complications. In working to achieve these goals, it is important to treat the whole patient by addressing psychosocial issues, nutrition, and daily functioning (Exhibit 2). Patients need to understand that they can be made better and can achieve remission. In the past, therapy was started with induction therapies and stepped up according to severity at presentation or failure on prior therapy. Unfortunately, the step-up therapy approach does not change the natural history of the disease and the disabling outcomes of surgery, hospitalization, and lowered quality of life. A step-up approach to therapy can work with UC because the symptoms tend to be more dramatic, so it is easier to know when disease control has been achieved. In CD, what is seen on the outside (lack of overt symptoms) does not always indicate what is going on inside the gastrointestinal tract.1 Aggressive therapy is best with CD because symptoms are not as prevalent but underlying damage is occurring. A personalized approach of risk stratification for the prognosis for an individual is emerging as a best practice for choosing therapy. Three factors are independently predictive of a disabling CD course within five years, including initial requirement for steroids, age at diagnosis below 40, and perianal

disease at diagnosis.2 This describes most kids diagnosed with CD. It is well known that when CD presents in childhood, it is much more aggressive and impactful than when diagnosed in an adult. Other consensus predictors of poor outcome include deep colonic ulcerations on endoscopy, persistent severe disease despite adequate induction therapy, extensive (pan-enteric) disease, marked growth retardation, severe osteoporosis, stricturing or penetrating disease at onset, and severe perianal disease.3 Patients with these risk markers need more aggressive therapy. As we learn more about the different types of IBD, therapy selection will be better. Early aggressive therapy is better than step-up therapy because it has been shown that medications have the most impact early in the disease course when inflammation is predominant and before stricturing or other damage is done.4 Thus, the impact of therapy depends on the degree of structural damage and the velocity of progression. Additionally, a steroid-free remission is more likely with an aggressive combination of a tumor necrosis factor (TNF) inhibitor and an immunomodulator (infliximab plus azathioprine) compared with either alone.5 Numerous medications can be used to treat IBD. Cyclosporine and tacrolimus are immune suppressants, which are good induction therapies to get patients into remission but have too many adverse effects for long-term use. Steroids can also be used for induction of remission but also have too many adverse effects for long-term use. Topical anti-inflam-

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Exhibit 2: Management Goals Address psychosocial issues

Relieve symptoms

Identify dysplasia and detect cancer

Treat inflammation

Establish Diagnosis

Prevent & treat complications

Improve daily functioning

Minimize treatment toxicity

Replenish nutritional deficits

Maintain remission

Exhibit 3: Suggested Algorithm 6 Active Disease (including mucosal ulceration) risk stratification Treatment Optimize ongoing drug switch intra/ other class Add drugs

6 Months

Target – No symptoms – No positive surrogate marker (CRP, +/- fecal marker) – No mucosal ulceration

Yes Continue Treatment

matories (salicylate derivatives) are only effective in UC because they only treat the mucosa. They can be used as induction and maintenance agents. These can be very effective for less aggressive forms of UC. Immunomodulators (azathioprine, 6-mercaptopurine) are effective in “damping down” the immune system response in the GI tract and work for maintenance. Anti-TNF agents can be used to induce and maintain remission. Even today with nu-

1 - 2 Year(s)

merous effective medications, approximately 30 to 40 percent of adults and 20 percent of children with UC will eventually need colectomy. The newest agent for IBD is vedolizumab (Entyvio®), which blocks inflammatory cell migration into the bowel. This is a second-generation agent, which unlike natalizumab (Tysabri®), does not block immune cell migration into the brain. Its place in therapy is yet to be determined.

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Although the biologics in combination with immunomodulators are very effective in achieving deep remission, there are some issues with immunogenicity. To limit the problems with antibodies against biologics developing, patients need to continue on these agents for the long term (maintenance) and take concomitant immunomodulators. Once the disease is well controlled, the immunomodulators can be discontinued. Measurement of biologic levels needs to be done to ensure adequate amounts in the blood to keep from losing response, to prevent the development of antibodies, and to make sure the dosing interval is correct. Treat-to-target is a way of achieving the goal of deep remission. It means regular assessment of disease activity using objective clinical and biologic outcome measures (Exhibit 3).6 Treatment is adjusted if it is not accomplishing the goal. Long-term mucosal healing can be achieved. Conclusion

Inflammatory bowel disease is a family of diseases currently simplified to two umbrella terms: Crohn’s disease and ulcerative colitis. An accurate diagnosis requires clinical suspicion and appropriate confirmatory testing. The step-up therapy approach does not change the natural history and the disabling

outcomes of the disease. A personalized approach of risk stratification for therapy selection and “treat-totarget” are emerging as best practices. Therapeutic drug monitoring and optimization of therapy are critically important goals in the biologic era. Overall, treatment of the whole patient will result in the best overall outcomes. Joel Rosh, MD, is Director of Pediatric Gastroenterology at the Goryeb Children’s Hospital/Atlantic Health and Professor of Pediatrics at the Icahn School of Medicine at Mount Sinai.

References 1. Pariente B, Cosnes J, Danese S, et al. Development of the Crohn’s disease digestive damage score, the Lémann score. Inflamm Bowel Dis. 2011;17(6):1415-22. 2. Beaugerie L, Seksik P, Nion-Larmurier I, et al. Predictors of Crohn’s disease. Gastroenterology. 2006;130(3):650-6. 3. Ruemmele FM, Veres G, Kolho KL, et al. Consensus guidelines of ECCO/ ESPGHAN on the medical management of pediatric Crohn’s disease. J Crohn’s Colitis. 2014;8(10):1179-207. 4. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis. 2002;8(4):244-50. 5. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-95. 6. Bouguen G, Levesque BG, Feagan BG, et al. Treat-to-Target: A Proposed New Paradigm for the Management of Crohn’s Disease. Clin Gastroenterol Hepatol. 2015;13(6):1042-1050.e2

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Current and Emerging Therapies for LDL-C Reduction Michael Miller, MD, FACC, FAHA, FNLA For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Statins are still the primary proven therapy for lipid lowering and cardiovascular risk reduction. Updated treatment guidelines provide some general principles for selecting patients who will benefit the most from statin use. Two newly approved classes for lipid lowering are now available for difficult to treat homozygous familial hypercholesterolemia. Additional novel agents are under investigation. Key Points • Updated lipid-lowering guidelines still focus on LDL-C reduction. • Several groups of patients benefit significantly from statin treatment. • Statin-induced liver damage is rare. • Negative effects of statins on cognition are not proven. • There is no evidence that statins increase or reduce the risk of cancer. • Muscle effects and increased diabetes risk are the major proven adverse effects of statins. • Two new classes of agents have been FDA approved. • Additional classes of agents are likely to reach the market in the next few years.

UPDATED GUIDELINES ON THE TREATment of blood cholesterol to reduce atherosclerotic cardiovascular (CV) risk were published in 2013 and were somewhat controversial. The focus is still on using statins to lower low-density lipoprotein cholesterol (LDL-C) but achieving specific goal values is no longer recommended in favor of specific percentage reductions. The guidelines identified four groups of patients who benefit from the use of statins (Exhibit 1).1 In these groups, the benefits of medication exceed the risks. The one controversial group is those who don’t currently have disease but who are at high risk (group 4 in Exhibit 1). The basis for this recommendation is evidence for a 20 to 30 percent reduction of CV events with statin use from numerous primary prevention trials.2 Because the benefits of therapy do not outweigh the risks for all patients, those at highest risk for atherosclerotic cardiovascular disease (ASCVD) need to be identified. This can be done using the 2013 Pooled Cohort Equations ASCVD Risk Calculator,

which estimates 10-year risk. Therapy is recommended for 10-year risk greater than 7.5 percent.3 Estimated 10-year risk is only part of the treatment decision process; lifetime risk, which is also calculated by the equations, should also be considered. Beyond statin therapy for adults in groups demonstrated to benefit, the updated guidelines provide several other general principles for reduction of CV risk.3 All adults should adhere to a healthy lifestyle. There should be a clinician-patient discussion prior to initiating statin therapy, especially for primary prevention in patients with low ASCVD risk. Current evidence is inadequate to support treatment to specific LDL-C and/or non-HDL-C goals. An appropriate intensity of statin therapy should be initiated; high, medium, or low dose therapy will depend on the degree of lowering needed – 50 percent or greater, 30 to 50 percent, or less than 30 percent, respectively.3 An issue with widespread statin use in many patients’ minds, and in the lay press, is safety. Liver, muscle, and cognitive effects; cancer; and diabetes

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Exhibit 1: Four Statin Benefit Groups1

Individuals with clinical ASCVD – acute coronary syndromes, or a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin – without New York Heart Association (NYHA) class II-IV heart failure or receiving hemodialysis.

Individuals with primary elevations of low-density lipoprotein cholesterol (LDL-C) > 190 mg/dL

Individuals 40–75 years of age with diabetes, and LDL-C 70–189 mg/dL without clinical ASCVD.

Individuals without clinical ASCVD or diabetes, who are 40–75 years of age with LDL-C 70–189 mg/dL, and have an estimated 10-year ASCVD risk of 7.5% or higher.

ASCVD = atherosclerotic cardiovascular disease

risk are all issues to consider. In early clinical trials, a signal of possible liver damage tied to statin use was seen, so health care professionals were advised to regularly follow liver function tests (LFTs). However, the FDA has found that statin-induced liver damage is rare, and LFTs are not effective at predicting or preventing who will develop this rare side effect. The FDA is now recommending that LFTs be performed before statin treatment begins and then as needed if there are symptoms of liver damage. Important for patient education is that there has never been a death from statins related to liver toxicity in someone who had a normal liver before starting therapy. Statins can cause muscle pain (myalgia), muscle weakness (myopathy), and muscle damage and breakdown (rhabdomyolysis). In randomized clinical trials, myalgia was reported in 1 to 5 percent of patients in the statin groups and placebo groups alike, whereas clinical practice would suggest it is more common in those on statins. In “real-world” experience, the frequency of statin-induced myalgia is about 20 percent and myopathy is about 10 percent. Rhabdomyolysis is very rare.4 There are some well-known factors which increase the risk of myopathy (Exhibit 2).5 The FDA has been investigating reports of cognitive impairment from statin use for several years. Reports about memory loss, forgetfulness and confusion span all statin products and all age groups, and are often reported as feeling “fuzzy” or unfo-

cused. In general, the symptoms were not serious and were reversible within a few weeks after the patient stopped using the statin. Despite patient reports of cognitive impairment, no significant impairment in cognitive function was seen in seven observational cohort studies of statins.6 Overall, the impact of statins on cognition is not clear. If patients are having issues, it is worth discontinuing the statin to see if the problems improve. Importantly, the risk for dementia appears to be reduced by statins. It has been shown that the higher the statin dose, the lower the risk of dementia.7 A major concern that resurfaces frequently with statins is whether they cause cancer. There is no evidence that statins increase or reduce the risk of cancer.8 Diabetes is the one adverse effect that has been recently identified. Statin use leads to a 9 percent increased risk of developing type 2 diabetes.9 If a patient has no major risk factors for diabetes (elevated fasting glucose, metabolic syndrome, hemoglobin A1C > 6%, or obesity), they are not at increased risk from statin use. Those who develop diabetes secondary to use of a statin are those who were already on their way. Despite an increase in risk for diabetes, statins still benefit even those who develop diabetes. For patients with major risk factors for diabetes, the use of a statin led to 54 excess cases of diabetes but prevented 134 deaths or vascular events.10 Ezetimibe (Zetia®) has been an underused lipidlowering agent because, despite lipid- lowering ef-

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Exhibit 2: Factors that Increase the Risk of Statin-Induced Myopathy5 Patient Characteristics

Statin Properties

Increasing age

High systemic exposure

Female sex

Increased dose

Renal insufficiency

High bioavailability

Hepatic disfunction

Limited protein binding

Hypothyroidism

Potential for drug-drug interactions metabolized by CYP pathways (particularly CYP450 3A4)

Diet or Meds Polypharmacy

ficacy, there were no data showing its use lowered mortality risk. A long-term study in patients with recent acute coronary syndrome has provided data on mortality benefit. In the IMPROVE-IT trial, patients who had an acute coronary syndrome were targeted for lowering LDL well below 70 mg/dl using simvastatin with and without ezetimibe. Over a period of seven years, the addition of ezetimibe to simvastatin 40 mg reduced the primary end point— a composite of cardiovascular death, myocardial infarction (MI), unstable angina requiring re-hospitalization, coronary revascularization, or stroke—by 6.4 percent when compared with patients who received simvastatin alone. The absolute reduction in risk over seven years was 2.0 percent, with 32.7 percent in the ezetimibe/simvastatin arm experiencing a primary end point, compared with 34.7 percent in the simvastatin arm. The reduction was driven by a statistically significant reduction in the risk of MI and ischemic stroke. Overall, there was a significant 10 percent reduction in the risk of cardiovascular death, nonfatal MI, or nonfatal stroke.11 Two new classes of agents has been approved for lowering LDL-C - antisense oligonucleotides (ASO) and microsomal triglyceride transfer protein (MTP) inhibitors. The two new agents are approved for patients with homozygous familial hypercholesterolemia. These patients have markedly elevated cholesterol levels, respond poorly to current drug therapy, and have a very high risk of premature cardiovascular disease. The antisense oligonucleotides (ASO) reduce apolipoprotein B (ApoB) containing lipoproteins by inhibiting ApoB production. Inhibiting ApoB production ultimately reduces very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL production by the liver. Mipomersen (Kynamro®), an injectable, is the first ASO approved

by the FDA. It results in a 50 percent reduction of LDL-C.12 The most common adverse effects seen in the phase 3 trials of this agent were mild to moderate injection site reactions and flu-like symptoms. About 8 percent of mipomersen-treated patients had significantly increased liver function tests and reversible increases in hepatic fat with no effects on liver synthetic function (total bilirubin, prothrombin, albumin) also occur. MTP inhibitors prevent the assembly of ApoBcontaining lipoproteins, thus inhibiting the synthesis of chylomicrons and VLDL and leading to a decrease in plasma levels of LDL-C. Lomitapide ( Juxtapid®) is the first approved agent in this class. Unlike mipomersen, this agent is oral. Lomitapide results in a 40 to 50 percent reduction in LDL and a modest increase in high-density lipoprotein (HDL) levels.13 This agent is distributed under a REMS program through specialty pharmacies. Adverse events include diarrhea and hepatic steatosis. Other emerging therapies for lowering LDL-C include proprotein convertase subtilisin/kexin 9 (PCSK9) humanized monoclonal antibodies and cholesteryl ester transfer protein (CETP) inhibitors. PCSK9, a serine protease, binds to LDL receptors, leading to their accelerated degradation and to increased LDL cholesterol levels. The PCSK9 humanized monoclonal antibodies under development include alirocumab and evolocumab. Studies are showing substantial reductions in LDL (50% to 70%).14 These agents are given subcutaneously every two to four weeks. These will likely be used in statin-intolerant patients or in combination with statins. Injection site reactions are the most common adverse effects. Both of these agents are currently in long-term studies. CETP inhibitors inhibit the transfer of cholesterol from HDL to VLDL or LDL. Inhibition of this pro-

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cess results in higher HDL levels and reduces LDL levels. Investigation of two CETP inhibitors, torcetrapib and dalcetrapib, was discontinued because of excess deaths and lack of efficacy, respectively. Evacetrapib and anacetrapib are two of these inhibitors still under study; these agents lower LDL about 30 percent and raise HDL over 100 percent. Whether any of the CETP inhibitors will eventually reach the market is unknown. Conclusion

Statins are still the go to agents for reducing cardiovascular risk. Updated guidelines suggest four groups of patients who receive the most benefit from statin treatment. Newly approved drugs for homozygous familial hypercholesterolemia include mipomersen and lomitapide. Emerging lipid-lowering therapies include humanized monoclonal antibodies to PCSK9 and CETP inhibitors.

in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;00:000–000. 4. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8A):52C-60C. 5. Rosenson RS. Current overview of statin-induced myopathy. Am J Med. 2004;116(6):408-16. 6. Etminan M, Gill S, Samii A. The role of lipid-lowering drugs in cognitive function:

meta-analysis

observational

studies.

Pharmacotherapy.

2003;23(6):726-30. 7. Wong WB, Lin VW, Boudreau D, Devine EB. Statins in the prevention of dementia and Alzheimer’s disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol Drug Saf. 2013;22(4):345-58. 8. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-78. 9. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative

meta-analysis

randomised

statin

trials.

Lancet.

2010;375(9716):735-42. 10. Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JU-

Michael Miller, MD, FACC, FAHA, FNLA, is a Professor of Cardiovas-

PITER trial. Lancet. 2012;380(9841):565-71.

cular Medicine, Epidemiology and Public Health at the University of

11. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin

Maryland School of Medicine.

Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372:2387-97.

References

12. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cho-

1. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on

lesterol <50 mg/dl with rosuvastatin. The JUPITER trial ( Justification for the

the assessment of cardiovascular risk: a report of the American College of Car-

Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J

diology/American Heart Association Task Force on Practice Guidelines. Circu-

Am Coll Cardiol. 2011;57(16):1666-75.

lation. 2013;00:000–000.

13. Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyc-

2. Taylor FC, Huffman M, Ebrahim S. Statin therapy for primary prevention of

eride transfer protein in familial hypercholesterolemia. N Engl J Med.

cardiovascular disease. JAMA. 2013;310(22):2451-2.

2007;356(2):148-56.

3. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on

14. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody

the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk

to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12):1108-18.

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

Current Treatments and Novel Strategies in the Management of Acute Coronary Syndromes Michael J. Lim, MD, FACC, FSCAI For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Current treatment of acute coronary syndrome (ACS) includes invasive and conservative strategies depending on the type of ACS and patient risk factors. Most patients will be treated with multiple medications on hospital discharge to prevent another event. The mix of prescribed agents may change with the introduction of novel anticoagulants. There are opportunities to improve ACS management and continue to reduce the related morbidity and mortality. Key Points • Despite significant advances in care, ACS still results in significant morbidity and mortality. • Quality measures and appropriateness guidelines for ACS and coronary revascularization exist. • Clinicians need to better document their thought process in choosing ACS therapies, particularly for those cases that fall outside the appropriateness guidelines. • Other issues in ACS management include site of access for PCI procedures, use of antiplatelet therapy before and after procedures, choice of stents, and the role of novel anticoagulants.

ACUTE CORONARY SYNDROMES (ACSs) OCcur when blood flow to the heart is disrupted by atherosclerotic plaque rupture. When plaque ruptures, collagen and tissue factor exposure to blood in the vessel leads to thrombin activation and thrombus formation. As shown in Exhibit 1, ACS can be unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI). ACS results in 1.41 million hospital admissions annually in the United States. Fifty percent of cases are NSTEMI, 28 percent UA, and 22 percent STEMI.1 MI remains the number one killer of people. Death rates within 30 days of an ACS episode are highest with STEMI and lowest with UA, but those who have NSTEMI have higher rates during the one to six months post event.2 With innovations such as coronary angiography and bypass surgery, morbidity and mortality related to ACS have dramatically decreased since the 1950s.3 Improvements in in-hospital care have significantly

reduced the in-hospital mortality from 30 percent in the pre-critical care unit era to 5 percent in the era of reperfusion. Because STEMI is a complete occlusion, treatment is reperfusion with thrombolytics or percutaneous coronary intervention (PCI). Rapid restoration of blood flow to the heart preserves muscle tissue. PCI results in lower rates of death, reinfarction, hemorrhagic stroke, and other types of stroke compared with thrombolytics.4 The relative risk of one-year mortality increases by 7.5 percent for each 30-minute delay between onset of symptoms and treatment.5 The thrombolytics should be started within 30 minutes of arrival at a hospital or PCI should be done within 90 minutes. Because symptoms may have been going on long before the person arrives at the hospital, the focus of care is shifting to time since the onset of symptoms. There is an abundance of data showing that second ACS events can be prevented. The focus after the initial ACS therapy is to prevent another event using

www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 13

Exhibit 1: Acute Coronary Syndromes

Plaque Rupture

Unstable Angina

Incomplete/ Transient occlusion

NSTEMI Non-ST-segment elevation Myocardial infarction

STEMI ST-segment elevation Myocardial infarction

Partial occlusion or occlusion followed by spontaneous recanalization

Complete occlusion

a cocktail of medications. Patients with STEMI are typically discharged on aspirin, beta-blocker, angiotensin covering enzyme inhibitor or angiotensin receptor blocker and lipid-lowering therapy. Aspirin is very efficacious in decreasing the rate of subsequent heart attacks within the first year after ACS. The other agents also decrease risk. Patients who receive a coronary stent during PCI require dual antiplatelet therapy with aspirin and another antiplatelet agent to prevent events. As noted previously, NSTEMI is the most frequent presentation of ACS. An early invasive management strategy with PCI can significantly improve outcomes, however, treatment has to be individualized based on risk of subsequent events.6 Those at high risk for subsequent events benefit the most from PCI.7 UA may also be treated with an invasive procedure or a conservative approach with medications. Risk for a recurrent event is important in choosing treatment. Risk with UA can be determined with the Thrombolysis in Myocardial Infarction (TIMI) risk scoring system. As the risk score increases, the risk of an event increases (Exhibit 2).8 This score should be documented in the patient record as justification for an early invasive intervention. There are also other factors not accounted for in the TIMI risk score which can also favor an invasive intervention. Some of these include hemodynamic instability, ventricular tachycardia, and reduced left ventricular ejection fraction. A low-risk score and patient preference are in favor of conservative intervention. Much of this cannot be documented in electronic medical records â&#x20AC;&#x201C; there needs to be free text fields to do this documentation. There are several current issues in ACS management. These include quality measures, appropriate-

ness of procedures, site of access for PCI procedures, use of antiplatelet therapy before and after procedures, choice of stents, and the role of novel anticoagulants. CMS has quality measures in place for ACS, but these are rudimentary (Exhibit 3).9 None of these identify why the doctor or the hospital team in place chose the particular therapy. There needs to be improved documentation of the thought process behind therapeutic decisions that on the surface appear to be outside the guidelines but which may be appropriate if all the facts are known. The American College of Cardiology Foundation (ACCF), Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, and the American Association for Thoracic Surgery, along with key specialty and subspecialty societies, regularly update their appropriate use criteria (AUC) for coronary revascularization.10 Using these criteria, facilities may be rated based on percentage of appropriate and inappropriate procedures. The idea is not to stop inappropriate use but to encourage documentation of why a procedure was done when on the surface it does not appear that the criteria were met. Another issue is a case of changing how clinicians do a particular procedure. For many years, heart catheterizations were only done through the femoral artery and many clinicians only know how to use this route. It has been shown that radial artery access is better than femoral. Radial access is favored for reduced risk of death, major bleeding, stroke, and MI, but femoral access results in fewer PCI procedure failures.11 Access site bleeding makes a huge difference in care. Almost all bleeding that occurs in patients with ACS is from access site bleeding. Patients also like the radial artery access better because

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

1. Age > 65 years 2. >3 CAD risk factors (high cholesterol, family history, hypertension, diabetes, Smoking) 3. Prior coronary stenosis > 50% 4. Aspirin in last 7 days 5. > 2 anginal events < 24 hours 6. ST - segment deviation 7. Elevated cardiac markers (CK-MB or troponin)

% Death / MI / Urgent Revasc at 14 d

Exhibit 2: Risk Stratification with TIMI Risk Score for UA/NSTEMI8 45 40 35 30 25 20 15 10 5 0

0/1 2 3 4 5 6/7

Number of Predictors

Exhibit 3: CMS Measures9 Acute Care Quality Indicators

Reperfusion Quality Indicators

Discharge Quality Indicators

Median time to ECG

Fibrinolytic therapy within 30 minutes of arrival

Aspirin on discharge

Median time to transfer to another facility for PCI

PCI within 90 mins of arrival

Statin on discharge

ASA on arrival

they are able to get up and move sooner. Choice of the antiplatelet or anticoagulant agents to prevent subsequent ACS is undergoing change. Long-term (> 1 year) use of aspirin is going to come into question. Aspirin does decrease the risk of stroke and subsequent ACS events, but all the data on aspirin are from before newer agents were available. The newer antiplatelet agents are more potent than aspirin and may have advantages over aspirin. Currently, aspirin plus one of the newer agents (clopidogrel, ticagrelor, or prasugrel) are used for up to one year after an event. Prescribing rates for antiplatelet therapy have significantly improved over the years, in part because of CMS quality measures. Unfortunately, by 90 days after hospital admission for ACS, many patients are no longer taking their antiplatelet therapy. Interventions to improve patient adherence are needed. Another issue with antiplatelet therapy is preloading before procedures. Data favor reloading with

antiplatelet therapy but most clinicians donâ&#x20AC;&#x2122;t do this because they are afraid the patient will need bypass.12 With these agents on board, the patient has to wait several days before bypass but only 7 percent of patients will eventually require bypass. Hospitals should be doing this upfront to cover the 93 percent who will not require bypass. Preloading is not in the quality indicators but makes a difference in outcomes. Another area of debate is the extent of revascularization. Currently, patients with STEMI are taken to the catheterization lab for opening of their problem blockage. About 15 percent have blockages in other places. Most clinicians do not touch blockages that are not currently causing problems. Data suggest that all the issues should be fixed in one procedure and this approach results in improved outcomes.13 One-time complete revascularization could allow a decrease in the overall number of procedures by fixing everything upfront.

www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 15

The use of drug-eluting stents to reopen coronary vessels for the majority of patients needs to be re-evaluated. Currently, 80 percent of patients get drug-eluting stents and 20 percent receive bare metal stents.14 The drug-eluting stents are embedded with a chemotherapy agent that gives everyone the same dose, which may not be appropriate, and can be hyper-inflammatory. Dual antiplatelet therapy for 12 months is required after drug-eluting stent placement. With a bare metal stent placement, a single antiplatelet agent is needed for four months to prevent clots. Dual antiplatelet therapy has a higher bleeding rate than antiplatelet monotherapy. Therefore, bare metal stents may be a better choice for many patients. There are now four novel anticoagulants (NOACs) – dabigatran (Pradaxa®), rivaroxaban (Xarelto®), apixaban (Eliquis®), and edoxaban (Lixiana®). These NOACs are going to be used more frequently because use requires less laboratory monitoring and may result in less bleeding. They are being studied in the ACS setting in combination with aspirin and clopidogrel but their roles has yet to be determined. Conclusion

There are many challenges in the management of ACS. Treatment must be individualized. Patients need to understand why they need to take multiple medications after an event and why a stent in their coronary artery did not cure them. There is an opportunity to start using bare metal stents more and using the novel anticoagulants to decrease bleeding rates. There are definitely opportunities to improve ACS management and continue to reduce the related morbidity and mortality.

2. Fox KA, Dabbous OH, Goldberg RJ, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ. 2006;333(7578):1091. 3. Nabel EG, Braunwald E. A tale of coronary artery disease and myocardial infarction. N Engl J Med. 2012;366(1):54-63. 4. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003; 361(9351):13-20 5. De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation. 2004;109:1223-5. 6. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA. 2005; 293:2908-17. 7. Fox KA, Clayton TC, Damman P, et al. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. J Am Coll Cardiol. 2010; 55:2435-45. 8. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000;284:835–42. 9. Centers for Medicare & Medicaid Services. Available at https://www.cms. gov/Regulations-and-Guidance/Regulations-and-Guidance.html. 10. Patel MR, Dehmer GJ, Hirshfeld JW, et al. Appropriate use criteria for coronary revascularization focused update: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, American Society of Nuclear Cardiology, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2012;59(9):857-81. 11. Jolly SS, Amlani S, Hamon M, et al. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: a systematic review and meta-analysis of randomized trials. Am Heart J. 2009;157:132-40.

Michael J. Lim, MD, FACC, FSCAI, is the Jack Ford Shelby Endowed

12. Sabatine MS, Hamdalla HN, Mehta SR, et al. Efficacy and safety of clopi-

Professor and Co-Director of the Center for Comprehensive Cardio-

dogrel pretreatment before percutaneous coronary intervention with and with-

vascular Care at Saint Louis University.

out glycoprotein IIb/IIIa inhibitor use. Am Heart J. 2008;155(5):910-7.

References

13. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;369:1115-23.

1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statis-

14. Sarno G, Lagerqvist B, Nilsson J, et al. Stent thrombosis in new-generation

tics--2014 update: a report from the American Heart Association. Circulation.

drug-eluting stents in patients with STEMI undergoing primary PCI: a report

2014;129:e28-e292.

from SCAAR. J Am Coll Cardiol. 2014;64:16-24.

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

Exploring Current and Emerging Treatments for Chronic Hepatitis C: Cost and Effectiveness David H. Winston, MD, FACP, AGAF For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary This is an exciting time for those who care for people with hepatitis C. A dramatic paradigm shift in hepatitis C virus (HCV) treatment has occurred with all oral regimens that produce very high cure rates. In addition to high cure rates, new directacting antiviral combinations are leading to shorter duration of treatment and fewer adverse effects. Treatment guidelines have dramatically changed to reflect these newer agents. Key Points • HCV is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. • HCV should be suspected based on risk factors, not symptoms or lab tests. Primary care physicians should screen all patients with risk factors and all baby boomers for HCV. • New all oral combinations produce higher cure rates, shorter duration of treatment, and fewer side effects than older regimens. • All oral regimens are the recommended treatment of naïve patients. • The cost of oral therapy is offset by future savings through the prevention of liver related complications.

HCV INFECTION IS WORLDWIDE AND MOST prevalent in Asia and Africa. Although the prevalence is lower in the United States, three and a half million Americans are known to be infected with HCV), but the true prevalence is probably over five million.1,2 Of those known to be infected, 2.7 million have chronic disease.1 Chronic HCV cases not included in this estimate include those who are homeless, incarcerated, veterans, active military, health care workers, nursing home residents, chronic hemodialysis, or hemophiliacs; thus the true prevalence of chronic disease is probably closer to four million. Of those who get diagnosed, only 41 percent get treated. In the U.S., males and African Americans have the highest rates of HCV infection.1 Baby boomers are the most common age group to be affected. Of the six different HCV genotypes, the most commonly seen in the U.S. are 1, 2, and 3.3,4 The majority of

those infected in the U.S. have genotype 1 and have high viral loads (Exhibit 1). 3,4 Unlike the DNA viruses human immunodeficiency virus (HIV) and hepatitis B virus (HBV), HCV infection can be cured. This is possible because the virus resides in the cytoplasma of the cell rather the nucleus or incorporated into DNA like HBV and HIV respectively. To be cured though requires that the infection has to be identified. The major reason to diagnose and treat HCV infection is to prevent the consequences of long-term infection.5 The majority of people who get infected with HCV acutely will develop chronic HCV. Twenty to 30 percent of those will develop cirrhosis. Some will develop hepatocellular carcinoma and decompensated cirrhosis. HCV infection is the reason for 60 percent of all cases of hepatocellular carcinoma in the U.S. Chronic HCV is a progressive disease in the ma-

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Exhibit 1: Genotype and Viral Load in U.S. Patients3,4

Genotype 2,3, LVL 7.3%

Genotype 4,5,6 HVL 2.7%

Genotype 4,5,6 LVL 1.3%

Genotype 2,3 HVL 14.7%

Genotype 1 HVL 49.5%

Genotype 1 LVL 24.5%

HIGH VIRAL LOAD: >800,000 IU/ML LOW VIRAL LOAD: <800,000 IU/ML

jority of patients. There are several factors associated with progression from chronic HCV infection to cirrhosis, including alcohol consumption (>30 g/day in males, >20 g/day in females), disease acquired at greater than 40 years, male gender, HIV or HBV co-infection, concomitant hepatic steatosis, and daily cannabis use. Patients who are infected when they are older than 40 years of age generally have a higher degree of fibrosis regardless of how long they have had the disease, compared with those infected at a younger age. Because of high obesity rates in the U.S., hepatic steatosis is relatively common and is an independent risk factor for cirrhosis. Transaminase level (ALT), viral load, mode of transmission, and genotype do not affect progression. Primary care providers (PCPs) have an opportunity to make a diagnosis of HCV and refer for treatment before the development of cirrhosis and its complications. Early diagnosis and treatment can improve survival, improve quality of life, and will reduce the economic burden of HCV and result in cost savings. Although HCV screening is the first step to a cure, there are both patient and provider barriers to screening. Persons infected with HCV are usually asymptomatic, unaware of their infection, and are unaware of the risk factors for HCV.6 Fifty-six percent of infected people are asymptomatic. For those that are symptomatic, the most common symptom is nonspecific fatigue. In general, PCPs do not include routine HCV risk factor assessment in their practice. Elevated LFTs, not risk factors, are the typical rea-

son for PCPs to screen patients for HCV. There is so much fatty liver disease in America that the curve of â&#x20AC;&#x153;normalâ&#x20AC;? LFTs has shifted (40 to 70), even though normal in males is really 30; thus many PCPs are not recognizing elevated LFTs. The common risk factors for HCV infection are contaminated needles, intranasal cocaine use with shared implements, body piercing with contaminated needles, tattooing with contaminated needles or ink, and incarceration. Intravenous drug use now accounts for two- thirds of the HCV cases in the U.S. Other risk factors include receiving blood or blood products or solid organ transplant before 1992 and hemodialysis before 1992. Less common are sharing of household items that could carry infected blood, traumatic contact with blood, perinatal transmission, and high-risk sexual behavior (i.e., multiple sex partners, prostitutes, man to man sex). PCPs should be looking for these risk factors in everyone. Since 75 percent of HCV cases are found in baby boomers, the CDC and the U.S. Preventive Services Task Force (USPSTF) recommend a one-time screening for all persons born between 1945 and 1965.6,7 Thus, PCPs should screen all baby boomers, all patients with risk factors regardless of age, and all patients with elevated liver function tests. Acute infections peaked between 1970 and 1990 when intravenous drug use peaked and have fallen off partially as a result of needle exchange programs. The peak of chronic HCV prevalence was 2001. The highest prevalence of cirrhosis is projected to be

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Total cost per successfully treated patient

Exhibit 2: Genotype 1 Cost Per SVR: Treatment-Naïve Without Cirrhosis19

300,000 250,000 200,000 150,000 100,000 50,000

$162,658 $111,794

$117,976

$118,972 $81,948

SOF + PR SMV + PR SOF + SMV BOC + PR

LDV/SOF 8 weeks or 12 weeks

Treatment-Naïve Without Cirrhosis

between 2010 and 2030. 8 Without HCV treatment, by 2030, over a million people are going to develop cirrhosis, 254,664 will develop HCC, and 537,928 will die.8 The health care system is currently in a tsunami of HCV-induced cirrhosis and its complications (hepatic decompensation, portal hypertension, ascites, variceal bleed, and encephalopathy) which are expensive to treat. The primary goal of HCV treatment is permanent eradication of virus from serum. This is defined as a sustained viral response (SVR), which is an undetectable HCV RNA three months after completion of treatment. An SVR is synonymous with “cure”. Cure rates have significantly improved since the early 1990s from 5 percent of patients to greater than 90 percent with improved regimens utilizing directacting antivirals (DAA). SVR leads to improved outcomes of reduced morbidity and mortality including decreased rates of HCC, decompensated cirrhosis, and improved liver histology.9-11 Since successful HCV treatment results in a virologic cure, it is expected to benefit nearly all chronically infected persons. Evidence clearly supports treatment in all HCV-infected persons, except those with limited life expectancy (less than 12 months) due to non-liver-related comorbid conditions.12 Highest priority for treatment owing to highest risk for severe complications are those with advanced fibrosis or compensated cirrhosis, already on the organ transplant list, type 2 or 3 essential mixed cryoglobulinemia and those with vasculitis, proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis.12 Those who are high priority for treatment owing to high risk for complications are patients with Stage 2 fibrosis, HIV or HBV coinfection, other coexistent liver disease (e.g., nonalcoholic steatohepatitis), debilitating fatigue, diabetes mel-

litus (insulin resistant), or porphyria cutanea tarda.12 Interferon and ribavirin were the first two therapies approved for HCV management. Because of the multiple issues with interferon and newer more effective therapies, guidelines for treatment naïve patients no longer recommend interferon as first-line therapy. The unsatisfactory response rate in genotype 1 (54% to 56%) to interferon and ribavirin led to the development of the DAAs that directly inhibit viral replication. The first approved DAAs were the protease inhibitors, telaprevir and boceprevir. Because of significant adverse effects, drug interactions, multiple daily dosing, and lower efficacy, the first-generation DAAs are no longer recommended for use.12 Two second-generation protease inhibitors [Simeprevir (Olysio®) and sofosbuvir (Sovaldi®)] were approved in late 2013. These agents are improvements over the first-generation agents in terms of pill burden, drug interactions, and adverse effects. Sofosbuvir raised the SVR rate to 90 percent. A third second-generation agent, ledipasvir, was approved in a combination product with sofosbuvir (Harvoni®) in October 2014. It is the first approved regimen that does not require administration with interferon or ribavirin and results in a 95 percent or higher SVR. In December of 2014, another evolution in therapy was approved with a prepackaged four-medication regimen. This product (Viekira Pak®) contains ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets to treat chronic HCV genotype 1 infection, including those with cirrhosis, and requires twice-daily dosing. The standard of care for treating HCV infection in treatment naïve patients with genotype 1 as of July 2015 is the use of sofosbuvir in combination with ledipasvir or simeprevir or the quadruple combination

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product.12 Ribavirin is recommended to be added in some instances. The current duration of therapy is eight to 24 weeks, again depending on which therapy is selected and presence of cirrhosis. An eightweek duration of treatment can be considered when sofosbuvir/ledipasvir is used in treatment-naïve patients without cirrhosis with genotype 1 who have pre-treatment HCV RNA less than six million IU/ mL. Regimens for the other genotypes are specified in the treatment guidelines.12 Because therapy for HCV is changing rapidly, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in collaboration with the International Antiviral Society–USA (IAS–USA) has developed a web-based process for the rapid formulation and dissemination of evidence-based, expert-developed recommendations for HCV management. These up-to-date guidelines can be found at hcvguidelines.org. Because the recommendations change rapidly, a table of recommended regimens is not published here. When considering the costs of HCV treatment, the cost of not treating the infection is important to consider. The estimated cost of untreated HCV for 2010 to 2019 is $86 billion in direct and indirect costs.13 That total includes $10.7 billion in direct medical costs and $75.3 billion in societal costs from premature disability and mortality. In that 10-year period, there would be an estimated 208,500 HCVrelated deaths. Although the oral only regimens are expensive in terms of acquisition costs, they are cost effective. Curing HCV markedly reduces the national cost of treating cirrhosis and hepatocellular carcinoma ($30,000 to $70,000 annual cost x 5 to 10 years/patient) and markedly reduces need for liver transplantation ($350,000 to $577,000/transplant + $145,000 year maintenance).14 On an individual health plan basis, the per member per month health care costs are 24 to 35 percent lower in those who receive treatment compared to an untreated population.15 The higher SVR rates with the oral regimens provide significant benefits. An SVR in noncirrhotic HCV patients prevents the development of cirrhosis and its complications. An SVR in compensated cirrhosis lowers the rate of complications, liver cancer, and transplant. SVR improves all-cause mortality, quality of life, and increases life expectancy.16-18 Exhibit 2 illustrates the differences among different regimens as a cost per SVR in patients without cirrhosis.19 The once a day pill combination of sofosbuvir and ledipasvir has the lowest acquisition cost per SVR. The most costly medication is the one that does not lead to treatment success despite the initial invest-

ment due to lack of efficacy or premature discontinuation (i.e., adverse effects, adherence). Therefore, it is important for patients to have support to take their regimen as directed for the complete duration of treatment to achieve the high SVR rates seen in clinical trials. The one pill per day regimens will go a long way toward improving adherence and persistence with treatment. There are more medications under study that will hopefully continue to raise the SVR rates closer to 100 percent, further reduce adverse effect rates, and allow treatment regimens as short as four weeks. It is hoped the future will bring one medication which covers all six genotypes of HCV. Conclusion

HCV is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. Clinicians should screen all patients with risk factors and all baby boomers for HCV. A dramatic paradigm shift in HCV treatment is here, with new DAA combinations that promise higher cure rates, shorter treatment duration and fewer side effects. The cost of all oral therapy should be offset by future savings through the prevention of liver-related complications. Because recommended regimens are constantly being updated, clinicians are urged to consult online updated guidelines. David H. Winston, MD, FACP, AGAF, is Section Head of Gastroenterology and Hepatology at CIGNA HealthCare of Arizona in Sun City, AZ.

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15. Gordon SC, Hamzeh FM, Pockros PJ, et al. Hepatitis C virus therapy is as-

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patients with end-stage liver disease. Aliment Pharmacol Ther. 2013;38(7):784-93

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12. AASLD/IDSA/IASâ&#x20AC;&#x201C;USA. Recommendations for testing, managing, and

18. McAdam-Marx C, McGarry LJ, Hane CA, et al. All-cause and incremental

treating hepatitis C. Available at /www.hcvguidelines.org.

per patient per year cost associated with chronic hepatitis C virus and associated

13. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future

liver complications in the United States: a managed care perspective. J Manag

hepatitis C morbidity, mortality, and costs in the United States. Am J Public

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19. Younossi ZM, Singer ME, Mir HM, et al. Impact of interferon free regi-

14. Reau NS, Jensen DM. Sticker shock and the price of new therapies for

mens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients.

hepatitis C: is it worth it? Hepatology. 2014;59(4):1246-9.

J Hepatol. 2014;60(3):530-7.

www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 21

COMING

SOON KOVALTRY

Antihemophilic factor (recombinant)

Register for updates at www.KOVALTRY.com Bayer and the Bayer Cross are registered trademarks of Bayer. KOVALTRY is a trademark of Bayer. ÂŠ 2015 Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Printed in USA 08/15 PP-675-US-0043

Improving Strategies for the Management and Treatment of Chronic Pain Eric S. Hsu, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Because of the complexity, successful management of chronic pain requires a multimodality and interdisciplinary approach and should focus on improving the patient’s daily activity and function. Although pharmacologic therapy tends to be the first treatment chosen, various nonpharmacologic options should be considered and used in combination with pharmacologic agents.

B:11.125”

T:10.875”

S:10.375”

• • • •

Key Points The chronic pain management plan and chosen therapies should aim to improve daily activity and function. Comorbid conditions, including depression, anxiety, and sleep disturbance, have to be managed. Nonpharmacologic therapies, including interventional approaches and complementary and alternative treatments, are options to add to the pain management plan. The overall goal with chronic pain management is improve a patient’s quality of life.

PAIN IS A SUBJECTIVE EXPERIENCE. BY definition, pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Patients with chronic pain have an abnormal or exaggerated response to pain including allodynia and hyperalgesia. Allodynia is a painful response to a nonpainful stimulus, whereas hyperalgesia is a heightened response to a painful stimulus. Chronic pain has a major impact on the patient, families, coworkers, and more. Although most pain disorders begin with injury or disease, their course and outcome are affected by emotional, behavioral and social factors. An individual’s emotional reaction to, and capacity to cope with, the fluctuating course of pain disorders and their complications such as physical impairment, disability, and loss of role functioning will also affect clinical outcome. Chronic pain significantly interferes with sleep, with

most studies showing a positive correlation between pain intensity and the degree of sleep disturbance. Many chronic pain patients have signs and symptoms of depression and anxiety; sleep deprivation can lead to anxiety, and depression can be both the cause and result of sleep deprivation. Chronic pain, sleep disturbances, and depression/anxiety must be addressed if patients are to be restored to optimal functionality. Clinicians must evaluate all aspects of pain, sleep and mood in patients with chronic pain. Management and treatment should address both the pain and the comorbidities in order to improve a patient’s daily functioning, and enhance their quality of life.1 Nociceptive, or inflammatory, pain (Exhibit 1) is pain resulting from activity in neural pathways caused by tissue-damaging stimuli. Examples include postoperative pain, arthritis, mechanical low back pain, sickle cell crisis, and sports or exercise injuries. Neuropathic pain is pain caused by a pri-

www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 23

Exhibit 1: Common Pain Syndromes

Nociceptive Pain

Visceral Abdominal Obstetrical Musculoskeletal Osteoarthritis Rheumatoid Arthritis Low Back Pain

Neuropathic Pain

Mixed Type

CRPS

Head Headache Orofacial

Postherpetic Neuralgia

Postoperative Cancer Pain Trauma Chronic back pain Sciatica

Trigeminal Neuralgia

Postoperative Cancer Pain

Central Poststroke Pain

Distal Polyneuropathy (eg, diabetic, HIV)

CRPS = complex regional pain syndrome

mary lesion or dysfunction in the peripheral and/ or central nervous systems. Examples of peripheral neuropathic pain syndromes include postherpetic neuralgia and diabetic neuropathy. Examples of central neuropathic pain include central poststroke pain, spinal cord injury pain, trigeminal neuralgia, and multiple sclerosis pain. Chronic pain can also be of mixed etiology with both nociceptive and neuropathic characteristics. Chronic pain management has several principles including: • Assess pain systemically and identify comorbidities • Measure improvement in pain and functional capacity • Institute universal precautions in prescribing pain medicine • Reinforce patient participation and family involvement • Update any progress and modify pain management plan • Develop a comprehensive and multidisciplinary treatment plan Because the underlying cause of a patient’s pain and response to treatment can change over time, it is very important that the treatment plan be updated periodically. Because of the complexity, successful management of chronic pain requires a multimodality and interdisciplinary approach. Following these principles, chronic pain management includes nonpharmacologic and pharmacologic therapy. With medications including nonopioids, adjuvants and coanalgesics, and opioids, the risk to

benefit ratio must be addressed for each individual patient. Nonpharmacologic therapy can help address pain relief and physical function. It can include physical and occupational therapy, interventional procedures such as nerve block, epidural steroid injection, and facet block, and psychological management. Physical therapists can provide an exercise program, especially for musculoskeletal pain, and may include the topical application of electrical stimulation, heat or cold, and massage in their treatment plan. Interventional procedures can be used for both pain relief and diagnostic purposes for identifying the source of pain. Psychological management includes cognitive-behavioral therapy, hypnosis, relaxation, biofeedback and neurofeedback training. Psychological management is very important in managing chronic pain. Complementary and alternative medicine (CAM) interventions such as acupuncture are also options for treatment. Nonsteroidal anti-inflammatories (NSAIDs) are typically the first medication step for chronic pain. Clinical data have shown cyclooxygenase-2 (COX2) selective inhibitors offer similar pain relief as nonspecific NSAIDs but have a better gastrointestinal safety profile compared with nonspecific NSAIDs for up to six months of therapy. Overall, long-term safety is similar among all NSAIDs. All NSAIDs including COX-2 inhibitors possess potential risk for cardiovascular or cerebrovascular thromboembolic events. These agents need to be avoided in patients with cardiovascular risk and in those requiring aspirin therapy. To minimize risk, the lowest dose and

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

shortest duration of therapy should be used. Three intravenous, nonopioid agents are available for acute pain management and may be good choices for patients with opioid abuse potential. Ketorolac (Toradol®) is an injectable NSAID which is only recommended for use for four days. It is a potent analgesic but only a moderately effective anti-inflammatory drug which does not lead to tolerance, withdrawal, or respiratory depression, unlike the opioids. Intravenous ibuprofen (Caldolor ®) is indicated in adults for the management of mild to moderate pain alone or as an adjunct to opioid analgesics for moderate to severe pain. It is given every six hours, as necessary, and results in significant reduction in pain intensity scores above and beyond patient controlled anesthesia delivered opioids and has a significant opioid-sparing effect. Intravenous acetaminophen (Ofirmev ®) can be used for the same indications as ibuprofen. Importantly, intravenous acetaminophen actually reaches the cerebral spinal fluid faster and at three times the level of oral therapy at the same dose. It is important that the maximum recommended daily dose not be exceeded. These intravenous agents can be used to reduce opioid use and the related adverse effects of those agents in the acute pain and postsurgical setting. Opioids should be reserved for moderate or severe pain, but their use in chronic pain can cause dependence issues. Additionally, they have significant adverse effects which have to be managed. Constipation is a major issue with chronic opioid use. Several agents have been FDA approved for managing opioid-related constipation. Naloxegol (Movantik®) is a once-daily oral peripherally-acting mu-opioid receptor antagonist for use in adult patients with chronic, noncancer pain. Lubiprostone (Amitiza®), a chloride channel activator, is approved to treat constipation caused by opioids in adults with chronic, noncancer pain. Methylnaltrexone (Relistor ®) is a selective peripherally-acting mu–opioid receptor antagonist displacing opioid binding in the gastrointestinal tract. Methylnaltrexone is indicated for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Beyond simple analgesics and opioids, choice of pain medications can depend on the reason for the pain. Agents that impact norepinephrine and serotonin in the brain are beneficial in several neuropathic chronic pain conditions. Agents with consistent efficacy demonstrated in multiple, randomized, controlled trials and having an FDA approved indication for postherpetic neuralgia (PHN) include lidocaine patch, gabapentin (Neurontin®), and pre-

gabalin (Lyrica®). Other agents such as tricyclic antidepressants, other anti-epileptics, and opioids can be used for PHN, but clinicians have to consider safety and tolerability when initiating treatment with these off-label agents. Agents with consistent efficacy demonstrated in painful diabetic polyneuropathy and which are also FDA indicated include duloxetine (Cymbalta®), pregabalin (Lyrica®), and tapentadol (Nucynta®). Tapentadol has a dual central mechanism in analgesia (mu-opioid agonist activity and inhibition of norepinephrine reuptake), which is similar to tramadol. Cancer pain management is somewhat different from other chronic pain management because of the patient’s life expectancy. Clinicians need to have a patient’s and their family’s feedback regarding ongoing treatment efficacy. The first step in the World Health Organization cancer pain management ladder is nonopioid analgesics and adjuvant medication. If pain is not controlled, weak opioid analgesics are added to the first step agents. Strong opioid analgesics are then added onto step one and two agents. Transdermal delivery, subcutaneous or intravenous patient-controlled analgesia, neuraxial drug delivery system, neuromodulation, nerve blocks, and chemical or radiofrequency ablation of nerves are options for managing end-of-life pain. Cancer breakthrough pain is important to manage. Immediate-release fentanyl products given via the oral or nasal mucosa are one option for breakthrough pain management. These transmucosal immediate-release fentanyl (TIRF) products include oral transmucosal lozenges, buccal tablets, soluble film, sublingual tablets, sublingual spray, and nasal spray. TIRF medicines are indicated only for the management of breakthrough pain in adult cancer patients 18 years of age and older who are already receiving and tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. The TIRF Risk Evaluation and Mitigation Strategy (REMS) program is an FDA-required program that is designed to ensure informed risk-benefit decisions before initiating treatment, and while patients are treated to ensure appropriate use of TIRF medicines. Low back pain (LBP) is a major issue in the United States and is a common chronic pain syndrome. A joint clinical guideline from the American College of Physicians and the American Pain Society provides evidence-based information on managing LBP.2 First-line medications for this condition are acetaminophen and NSAIDs. The guidelines note that nonpharmacological therapy has proven benefits for LBP. Acute LBP can be managed with spinal manipulation. Sub-acute or chronic LBP can be treated with intensive interdisciplinary rehabilitation, exercise therapy, acupuncture, massage thera-

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py, spinal manipulation, yoga, cognitive-behavioral therapy, relaxation training and biofeedback. Universal precautions in pain medicine refers to a standardized approach to the assessment and ongoing management of all chronic pain patients. Approaching patient assessment and management within chronic pain treatment in a thorough and respectful manner can help to lessen the stigma, optimize patient care, and contain overall risk from pain medications. In applying this approach, clinicians need to periodically assess the 4Aâ&#x20AC;&#x2122;s: analgesia, activities of daily living, adverse effects, and aberrant drug-related behavior. In trying to prevent aberrant drug-related behaviors, patients treated with opioids should have a pain medication treatment agreement which covers several issues. A typical agreement will require the patient to agree that pain medication is the responsibility of the patient, no illicit substances are allowed, only one health care provider will prescribe pain medications, and unannounced drug screens can be enforced in follow-up visits. Conclusion

To adequately manage chronic pain, comorbid

conditions, including depression, anxiety, and sleep disturbance, have to also be managed. The chronic pain management plan and chosen therapies should aim to improve daily activity and function. Universal precautions should be instituted when analgesics are used. In addition to medications, nonpharmacologic therapies, including interventional approach and complementary and alternative treatments, are options to add to the pain management plan. The overall goal with chronic pain management is to improve the patientâ&#x20AC;&#x2122;s quality of life. Eric S. Hsu, MD, is a Clinical Professor in the Department of Anesthesiology at the Pain Management Center at the David Geffen School of Medicine at UCLA.

References 1. Nicholson B, Verma S. Comorbidities in chronic neuropathic pain. Pain Med. 2004;5(suppl 1):S9-S27. 2. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147(7): 478-91.

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Overcoming Challenges to Successful Asthma Adherence and Control Charles Vega, MD, FAAFP For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Asthma control continues to be a major issue in the United States. Numerous quality improvement strategies have been shown to improve outcomes. Managed care can consider implementing several of these strategies to improve treatment adherence and disease control. Key Points • Prevalence of asthma has been increasing. • Uncontrolled asthma results in exacerbations and increases in asthma care costs. • Clinicians need to do a better job in preventing exacerbations and controlling asthma. • Following guideline-based best practices in asthma management and instituting evidence- based quality improvement strategies will improve control, reduce symptoms, and reduce yearly exacerbation rates. • Evidence-based quality improvement strategies include caregiver education for children with asthma; adult educational programs based on theoretical frame works, of relatively long durations, and utilizing combinations of educational modalities; education in the emergency room; asthma action plans; and decision support for clinicians. • Decision support, especially through technology at the point of care, is the best way to improve clinician adherence with best practices.

ASTHMA CONTINUES TO BE A MAJOR HEALTH issue in America. The prevalence of this disease increased from 3.1 percent in 1980 to 8.4 percent in 2010.1 There are multifactorial reasons for the increases, including pollution, environmental exposures, and more effective diagnosis. Children, women, and African Americans have higher rates of asthma compared with adults, men, and other races (Exhibit 1).1 Asthma results in significant morbidity, mortality, and economic costs. The rate of mortality strictly due to asthma is very low (1.1 deaths per 100,000). However, this disease, when uncontrolled, still causes significant morbidity. There were 1.3 million emergency room visits in 2012 for asthma exacerbations and 440,000 hospitalizations.

From 2001 to 2010, both children and adults had fewer asthma exacerbations. In 2001, 61.7 percent of children and 53.8 percent of adults with asthma had at least one asthma attack in the previous 12 months compared with 58.3 and 49.1 percent in 2010, respectively.1 It is good news that there are fewer exacerbations occurring, but the bad news is that still 50 percent of those affected by asthma have at least one exacerbation yearly and the higher prevalence of asthma means more exacerbations to manage. Asthma exacerbations occurred more often in females (52.7%) than males (49.2%) and, among those with a family income less than 100 percent of the federal poverty threshold (55.1%) than persons with income between 250 percent and less than 450 percent of the poverty threshold (47.9%), and among

www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 27

Exhibit 1: Asthma Prevalence in U.S.1 Current Asthma Prevalence Percents by Age, Sex, and Race/Ethnicity. United States 2012 14 12 10

Age

Sex

Hispanic 7.0%

Black 11.9%

White 8.1%

Male 7%

Adult 8.0%

Child 9.3%

Female 9.5%

Race/Ethnicity

Exhibit 2: Step 1- Get the Initial Classification Right9 • Intermittent -Symptoms less than 2 days/week • Mild Persistent -Symptoms not daily -< 4 nighttime awakenings/month -FEV1/FVC > 80% • Moderate Persistent -Daily symptoms -Awakening at least weekly -FEV1 60% - 80% • Severe Persistent -Symptoms throughout day -Extremely limited function -FEV1 < 60% FEV1 = forced expiratory volume in 1 second FVC = forced vital capacity

those living in South and West, than those living in Northeast.1 Asthma exacerbation prevalence did not differ by race or ethnicity. Uncontrolled asthma, resulting in exacerbations in 50 percent of patients yearly, is a significant gap in care. In an analysis of quality improvement strategies to close this gap, the Agency for Healthcare Research and Quality Review analyzed 200 articles from 171 studies.2 Among all studies of pediatric asthma evaluating self-monitoring, self-management, or patient education interventions, those directed at parents or caregivers, as opposed to at the children themselves and not their parents, were more likely to be associated with a statistically significant improvement in clinical outcomes (e.g.,

improvements in asthma symptoms or spirometric measures). General populations with asthma, especially adults, can have clinically significant improvements in spirometric measures after participating in self-monitoring, self-management, or patient education interventions—especially interventions that are based on theoretical frameworks, are of relatively long durations, and utilize combinations of educational modalities. Overall, the improvements reported in the included studies were often statistically significant but possibly only of borderline clinical significance. Many patients, particularly those who live below the poverty level, depend on emergency rooms (ER) for asthma care. Educational interventions for

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Exhibit 3: Step 2- Initiate Hazard Reduction9 • Spirometry for Patients Over Five Years of Age -Ensure reversibility with SABA • Treatment Goals -Reduce impairment -Reduce exacerbations • Find and Avoid Triggers/Allergens -Consider skin or in vitro testing if persistent asthma -Multifaceted approaches to trigger avoidance most effective • Mask or Scarf Can Improve EIB in Cold Weather -EIB shouldn’t limit play -EIB may be a sign to initiate inhaled corticosteroid SABA = short acting beta agonist EIB = exercise-induced bronchoconstriction

adults who attend the ER for acute asthma have been shown to reduce subsequent hospital admissions by 50 percent and modestly reduce additional emergency room visits.3 Thus, health care systems and managed care could utilize educational programs in ERs to target those with asthma. Self-management using an action plan has been studied in asthma and is effective in reducing health care utilization. Optimal self-management allowing for optimization of asthma control by adjustment of medications may be conducted by either selfadjustment with the aid of a written action plan or by a regular medical review. Action plans can be based on peak expiratory flow values or symptoms; each approach is equally effective in adults.4 In children, symptom-based plans are better than peak flow-based plans; in this group, written action plans can reduce acute care visits compared to populations without a written plan. Children using action plans have better school attendance, fewer nocturnal symptoms, and improved symptom scores.5 Minorities are disproportionately affected by asthma. Education delivered by health care professionals is effective in improving outcomes for minority patients with asthma. In 24 studies of mostly non-white adults (14 of which were African Americans), the most common intervention was patient education, but less than half of the education was culturally-focused. Language-appropriate and culturally-focused education is the most successful.6 Team-based specialty clinics and long-term followup for asthma are also effective in minority populations. Health disparities community collaboratives are less effective. Community evidence-based asthma care programs have been studied. Development and implementation of a community-based primary care

asthma care program led to risk reductions in exacerbations, symptoms, urgent health service use and productivity loss related to asthma.7 Exercise training is another possible intervention. In 21 studies, physical training led to significant improvement in maximum oxygen uptake, though no effects were observed in other measures of pulmonary function.8 Physical training was well tolerated among people with asthma in the included studies and, as such, people with stable asthma should be encouraged to participate in regular exercise training, without fear of symptom exacerbations. Four of five studies evaluating health-related quality of life showed clinically significant benefit for exercise. A last quality improvement strategy is to improve clinician performance in controlling asthma and preventing exacerbations. Instituting guidelinebased best practices in asthma may help clinicians improve the gaps in care. The first best practice is to classify each individual correctly because classification drives treatment selection (Exhibit 2).9 Many patients may be treated for intermittent asthma when they truly have persistent disease. The next best practice is hazard reduction, which frequently gets neglected by clinicians (Exhibit 3).9 The third best practice is to make sure everyone prescribed an inhaler knows how to properly use the device. Studies have shown that 40 percent or more of patients incorrectly use their inhaler.10 Improper asthma inhaler device use is associated with poor asthma control and more frequent ER visits.11 A great nonprofit website for inhaler instructional videos is www.use-inhalers.com. This is an excellent resource for patients with low literacy values and those who learn best visually. The fourth best practice is to medicate appropriately (Exhibit 4).9 Therapy in many patients needs

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Exhibit 4: Step 4 - Medicate9 • Intermittent -SABA only -SABA 1st line for exercise-induced asthma • Mild Persistent -Low-dose ICS • Moderate Persistent -Medium-dose ICS, possibly with LABA or montelukast • Severe Persistent -High-dose ICS w LABA or montelukast. May need oral steroids (and referral)

SABA = short acting beta agonist ICS = inhaled corticosteroid LABA = long acting beta agonist

to be adjusted frequently. Clinicians can be reluctant to prescribe a sufficient level of medications, but the recommended combinations have very low rates of adverse effects. Allergic asthma, which results from overexpression of immunoglobulin E (IgE) in response to environmental allergens, can be very difficult to control and may require multiple medications. Omalizumab (Xolair ®) is a relatively new injectable recombinant DNA-derived humanized monoclonal antibody indicated as an add-on therapy in patients aged 6 years and older with severe persistent allergic asthma uncontrolled on a combination of high-dose inhaled corticosteroid and a long-acting beta agonist or montelukast. Omalizumab is effective in reducing asthma exacerbations and hospitalizations as an adjunctive therapy to inhaled steroids.12 Omalizumab is significantly more effective than placebo in increasing the numbers of participants who were able to reduce or withdraw their inhaled steroids. When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma.13 It is generally well tolerated, although injection site reactions do occur. Although this agent is very effective in reducing exacerbations, it is expensive in terms of acquisition costs. A cost-effectiveness evaluation from the United Kingdom found that omalizumab was more economical in cases of recent hospitalizations, when factoring in inhaled corticosteroid use. The evaluation concluded that the cost per QALY for this agent was above other National Health Service interventions.14 Given the high cost of the drug, identifica-

tion of biomarkers predictive of response is of major importance for future research. Once medication is initiated, active follow-up is the fifth best practice. Follow-up should be every two to six weeks until adequate control is achieved. At each visit, asthma triggers and inhaler technique should be reviewed. Education on the disease and treatments has to be ongoing. Medications should be adjusted as necessary at each visit. Every patient should have an asthma action plan. Training health care providers can be done to improve adherence with best practices in asthma. There is moderate evidence for decision support, feedback and audit, and pharmacy support as a means to improve prescriptions for controller medications.15 Decision support is also important in improving patient education rates, prescribing self-management plans, and reducing emergency room visits. Clinical pharmacy interventions are effective for improving patient education and self-management plan use. Pay-for-performance has not been shown to be effective in improving ER visit rates. Decision support, especially through technology at the point of care, is the best way to improve clinician adherence with best practices. Conclusion

Clinicians need to do a better job in controlling asthma and preventing exacerbations. Chronic disease management requires a motivated patient. Clinicians can empower and motivate patients with education and asthma action plans so they know how and why to manage their treatment. Best practices in asthma management include a good diagnosis, education on the risks of asthma, lifestyle measures to reduce disease, appropriate use of medications, and follow-up. Following these principles will AL-

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WAYS be more efficacious than usual care.

care program improve clinical outcomes? A longitudinal study. Med Care. 2008;46(12):1257-66.

Charles Vega, MD, FAAFP, is a Clinical Professor of Family Medicine at

8. Carson KV, Chandratilleke MG, Picot J, et al. Physical training for asthma.

the University of California in Irvine, CA.

Cochrane Database Syst Rev 2013;9:CD001116. 9. National Heart, Lung, and Blood Institute. National Asthma Education and

References

Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and

1. Centers for Disease Control. Summary Health Statistics for U.S. Adults: Na-

Management of Asthma . 2007. Available at http://www.nhlbi.nih.gov/health-

tional Health Interview Survey, 2012. Available at www.cdc.gov/nchs/data/

pro/guidelines/current/asthma-guidelines/full-report.

series/sr_10/sr10_260.pdf

10. Scarfone RJ, Capraro GA, Zorc JJ, Zhao H. Demonstrated use of metered-

2. Bravata DM, Sundaram V, Lewis R, et al (eds). Closing the Quality Gap: A

dose inhalers and peak flow meters by children and adolescents with acute asth-

Critical Analysis of Quality Improvement Strategies (Vol. 5: Asthma Care).

ma exacerbations. Arch Pediatr Adolesc Med. 2002;156(4):378-83.

Rockville (MD): Agency for Healthcare Research and Quality (US); 2007 Jan.

11. Al-Jahdali H, Ahmed A, Al-Harbi A, et al. Improper inhaler technique is

Report No.: 04(07)-0051-5.

associated with poor asthma control and frequent emergency department visits.

AHRQ Technical Reviews.3. Cochrane Database Syst Rev. 2007 Jul

Allergy Asthma Clin Immunol. 2013;9(1):8.

18;(3):CD003000.

12. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults

4. Powell H, Gibson PG. Options for self-management education for adults with

and children. Cochrane Database Syst Rev. 2014;1:CD003559.

asthma. Cochrane Database Syst Rev. 2003;(1):CD004107.

13. Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab

5. Zemek RL, Bhogal SK, Ducharme FM. Systematic review of randomized

(anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364(11):1005-15.

controlled trials examining written action plans in children: what is the plan?

14. Norman G, Faria R, Paton F, et al. Omalizumab for the treatment of severe

Arch Pediatr Adolesc Med. 2008;162(2):157-63.

persistent allergic asthma: a systematic review and economic evaluation. Health

6. Press VG, Pappalardo AA, Conwell WD, et al. Interventions to improve

Technol Assess. 2013;17(52):1-342.

outcomes for minority adults with asthma: a systematic review. J Gen Intern

15. Okelo SO, Butz AM, Sharma R, et al. Interventions to modify health care

Med. 2012;27(8):1001-15.

provider adherence to asthma guidelines: a systematic review. Pediatrics.

7. To T, Cicutto L, Degani N, et al. Can a community evidence-based asthma

2013;132(3):517-34.

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Patient Variability Calls for an Individualized Approach to the Management of OAB Pamela Ellsworth, 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 major impact on those affected. Once diagnosed, there are effective treatments which can improve symptoms and quality of life. Selection of these treatments needs to be individualized. Successful management requires setting goals and treatment expectations while also managing treatmentrelated adverse effects. Key Points • OAB is more than just the symptoms. • There should be an individual approach to choosing treatment. • Therapy includes behavioral intervention, pharmacotherapy, neurostimulation and bladder injections. • Setting appropriate goals and treatment expectations and managing adverse effects are critical to a successful outcome.

OVERACTIVE BLADDER (OAB) IS NOT A disease but is a common symptom complex which has enormous impact on those affected. It is associated with urgency (a strong, sudden desire to void), frequency (more than 8 times per 24 hours), and a large amount of urinary leakage in patients who have episodes of incontinence. Patients with OAB are often unable to reach the toilet in time after an urge to void and usually wake up to pass urine during the night. One in three adults in the United States over 40 years of age reported symptoms of OAB at least “sometimes.”1 OAB is more than urinary frequency, urgency and urgency urinary incontinence (UUI). Urinary tract infections, vulvovaginitis, skin infections, depression, falls, and fractures are common comorbidities. Additionally, OAB has a significant impact on quality of life (QOL, Exhibit 1).2,3 QOL scores among people with OAB are worse than those of people with diabetes in several domains, including physical functioning, role–physical, vitality, social function-

ing, role–emotional, and mental health.4,5 When urinary incontinence is present, the impact of OAB is even greater. Urinary incontinence is one of the most bothersome chronic disorders affecting physical function.6,7 It and OAB are associated with significant morbidity and correlated with an increased risk of hospitalization and admission to a nursing home.8 In addition to health impact, OAB has significant economic impact. In 2007, the annual per capita costs of OAB were estimated to be $1,925 of which 75 percent was direct medical costs, 22 percent lost productivity, and 4 percent direct nonmedical costs.9 By 2020, the projected per capita cost of OAB is $1,970. Overall, OAB is estimated to cost $76.2 billion in 2015 and $82.6 billion in 2020. The most common risk factor for OAB is increasing age. Other common risk factors include obesity, Caucasian race, depression, and hormone replacement therapy. Neurogenic OAB may be secondary to multiple sclerosis, Parkinson’s disease, dementia,

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

Exhibit 1: Impact of Overactive Bladder on Quality of Life2,3

Physical • Limitations or cessation of physical activities Sexual • Avoidance of sexual contact and intimacy

Quality of Life

Psychological • Guilt/depression • Loss of self-esteem • Fear of -Being a burden -Lack of bladder control -Urine odor

Social • Reduction in social interaction • Limit and plan travel around toilet accessibility

Occupational • Absence from work • Decreased productivity

Domestic • Require specialized underwear, bedding • Special precautions with clothing

spinal cord injury, stroke, or diabetes.10 Clinical practice guidelines for screening, diagnosis, and management of OAB recommend that the goal of the initial evaluation is to rule out other conditions which may cause or mimic OAB.11 A simplified approach to diagnosis and evaluation includes a focused history, a focused physical examination (abdominal, pelvic, and neurologic), an urinalysis, and a patient assessment of the degree of bother. A bladder diary and post-void residual can supplement the evaluation. Urodynamics, cystoscopy, and ultrasound are not indicated in the initial evaluation of an uncomplicated patient. Post-void residual is not necessary for uncomplicated patients if the patient is being treated with first-line behavioral interventions. It is necessary for obstructive symptoms, history of incontinence or prostatic surgery, neurologic disease, and in men with symptoms before antimuscarinic therapy can be started. Certain patients should be referred to an urologist for further evaluation, including those with hematuria, significant pelvic organ prolapse, recurrent urinary tract infections, increased post-void residual, failure to improve with medical therapy, and prior pelvic surgery. Management of OAB is multifaceted (Exhibit 2). Patients have to be educated regarding normal bladder function. They may have a goal of only voiding two times per day, but this may not be realistic. Getting to a normal voiding pattern (less than eight

times daily) is the ultimate goal of treatment. Patients need to understand that OAB is not cured, it is managed. Several factors can help determine if therapy is needed. Factors governing treatment include bother, patient expectations and goals of therapy, underlying comorbidities, patient tolerability of side effects, and contraindications to therapies. Exhibit 3 illustrates how two different patients can have very different goals. Patient goals are often task oriented instead of number oriented (i.e., be able to go out to dinner). Behavioral modification is the first-line treatment. Useful strategies for behavioral modification include patient education, timed or delayed voiding, and positive reinforcement of any changes made. Pelvic floor exercises are useful for women, primarily those with concomitant stress urinary incontinence. Additionally, learning to tighten the correct muscles can suppress an involuntary bladder contraction, which can be used to reduce the incidence of urge incontinence. A 25 percent reduction in fluid intake has been shown to reduce frequency and urgency. Similarly, reducing caffeine intake decreases voiding frequency. Dietary changes, such as avoiding spicy foods, citrus fruits and juices, tomato-based foods, and alcohol, may also help in the management of OAB. There are not strong data to support dietary changes, but sequential elimination of these problem foods may help some patients. An

www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 33

Exhibit 2: Treatment of OAB

Management Strategies

Education

OAB Treatment Behavioral Modification

Medications

Surgical Procedures

Exhibit 3: Evaluating Goals/Expectations Patient 1 • Doesn’t want surgery • Concerned about side effects • Wants something that won’t make her more of a burden • Focus on urgency and UUI

often forgotten behavioral intervention for OAB is weight loss. Generally, behavioral therapy is equivalent to medications in reducing incontinence episodes, improving voiding parameters, and enhancing quality of life. Pharmacologic therapy is second-line therapy in managing OAB. Antimuscarinic and beta agonists are the two classes of therapy. Antimuscarinic agents block the muscarinic (M3) receptor, which stabilizes the detrusor muscle. This increases bladder capacity, diminishes frequency of involuntary bladder contractions, and delays the initial urge to void. Darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium chloride are all antimuscarinic agents. All are effective for treating OAB symptoms, but there are differences in adverse effect profiles and thus tolerability. There are now multiple different dosage forms, including extended-release oral, liquids, topical patches, topical gels, and bladder instillation. Finding an effective and tolerable antimuscarinic can

Patient 2 • Wants to be able to hold her urine for longer than 30 minutes • Wants to be able to watch a child’s soccer game without going to bathroom • Focus is on frequency and urgency

require trying several different agents. Dry mouth and constipation are two most bothersome adverse effects of antimuscarinic therapy. The OAB guidelines suggest that clinicians should manage these before abandoning effective antimuscarinic therapy. To treat constipation, patients can increase fluid intake, increase dietary fiber, and take an osmotic laxative. Many patients with OAB will fluid restrict without realizing the impact on their bowel habits and the bladder irritant effect of concentrated urine. If there is no improvement with these simple measures, clinicians should consider a gastrointestinal evaluation. Tips for treating dry mouth include sipping cool water throughout the day, drinking milk to lubricate the oral mucosa, restricting caffeine and alcohol intake, chewing sugar-free gum to stimulate saliva flow, and utilizing saliva replacements. Because of the anticholinergic effects, there are concerns regarding antimuscarinic use in elderly patients. Many commonly prescribed drugs have an-

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

ticholinergic properties. Clinical manifestations of anticholinergic toxicity are likely to be nonspecific and reflect the effects of cumulative anticholinergic burden. Clinicians need to minimize the number of medications with anticholinergic effects in their elderly patients. Oxybutynin is often recommended in insurance guidelines as the first-line medication for OAB, but this agent may not be the best choice for elderly patients. Oxybutynin, especially immediate-release formulations, is associated with a higher incidence of adverse effects compared with other antimuscarinics. Its chemical structure predisposes it to cross the blood- brain barrier to a greater degree than other antimuscarinics. Oxybutynin has been shown to adversely affect cognition in elderly patients and they may not be aware of the resulting functional decline.12,13 Adherence and persistence with antimuscarinics is important to controlling costs of OAB treatment. All-cause and OAB-related health care costs of patients with OAB who persist on antimuscarinics are significantly lower compared with those who switch agents.14 Extended- release formulations of antimuscarinics are associated with significantly better adherence than immediate-release formulations and thus should be the first choice for therapy.15 In one study, those with greater than 80 percent adherence with OAB antimuscarinic therapy had lower medical , sick leave and short-term disability costs and higher overall drug costs than those with lower levels of adherence.16 In that same study, increased medication copays were associated with lower adherence.16 Beta agonists are the other class of medications for OAB treatment. Mirabegron [MyrbetriqÂŽ] is a selective beta-3 adrenoceptor agonist. It activates beta-3 adrenoceptors on the detrusor muscle of the bladder to facilitate filling of the bladder and improved storage. Essentially, this is a bladder relaxant that does not affect detrusor muscle contractility. This agent is only available as a once day extended-release tablet that cannot be crushed, which is a consideration if patients have difficulty swallowing. Unlike with the antimuscarinics, dry mouth and constipation are not major concerns with this agent, so it would be a good choice for the person who already has these issues. It does have several drug interactions and can increase blood pressure which must be monitored. With medications, patients should see a response within one to two weeks of starting therapy. A significant reduction in symptoms should be seen by the end of a month. Therefore, patients should be given a medication for at least one month to assess

efficacy. Response can continue to increase out to three months. Comparisons of OAB medication efficacy and safety have been published.17 Mirabegron has similar efficacy against frequency and UUI compared with antimuscarinics. Only solifenacin showed a significantly superior efficacy in improvement of micturition and UUI episode frequency versus mirabegron. Solifenacin and fesoterodine were among the medications with the highest incidence of adverse effects, especially dry mouth. In this review, mirabegron had the most favorable tolerability profile. For effective control of symptoms, most patients will need both behavioral and pharmacologic therapy, which is more effective than either alone.18 If combination therapy fails, patients will need to move to third-line therapies. Third-line therapies include neuromodulation and onabotulinum toxin A injections. Neuromodulation can be with either sacral nerve stimulation or percutaneous tibial nerve stimulation. Sacral nerve stimulation (SNS) is a minimally invasive surgical procedure that requires a two-step process with an initial test stimulation and, if good response occurs with the test, permanent stimulator implantation. Small doses of electric current are sent from the stimulator to the sacral nerve. A systematic review of four randomized, controlled trials found that 80 percent of patients achieved continence or greater than 50 percent improvement in main incontinence symptoms after SNS versus 3 percent of control subjects.19 The benefits persisted for three to five years after implantation. Patients may require reoperation for relocation of the generator due to pain or infection. The reoperation rate in implanted cases is 33 percent.20 A long-term study of Medicare recipients who underwent sacral stimulation found that 74 percent still had the device at the end of five years.21 Overall adverse effects were low over the five-year period. Percutaneous tibial nerve stimulation (PTNS) is an external device treatment that is given in the office for 30 minutes once a week for 12 weeks. Patients who respond may require occasional medication to sustain response. In a trial of PTNS compared with antimuscarinic therapy, 79.5 percent of those in the PTNS arm reported significant improvement compared to 54.8 percent of subjects on tolterodine.22 It is an alternative to sacral nerve stimulation if the patient has failed other options and doesnâ&#x20AC;&#x2122;t want the implanted device. Onabotulinum toxin A [Botox ÂŽ] works at the parasympathetic nerve terminal to prevent the release of acetylcholine. In OAB, this agent reduces contractions of the detrusor muscle. The key issue

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with this toxin is the limited effective range of an injection. Thus, 20 to 30 injection sites one centimeter apart are required to treat the entire bladder. It takes about two weeks for efficacy onset. Although the most common adverse effect of the injections is urinary tract infection, 5.4 percent of patients will develop urinary retention. Due to the risk of urinary retention, only people who are willing and able to initiate catheterization posttreatment, if required, can be considered for treatment. The need for self-catheterization can last for the duration of the drug efficacy, which is 12 weeks or more. The people who are at most risk for this adverse effect are the frail elderly. In a Phase III, randomized, placebo controlled trial, onabotulinum toxin A injections significantly decreased the frequency of UUI episodes per day versus placebo (-2.65 vs -0.87, p<0.001).23 In other trials, it was better than placebo at improving symptoms of OAB for up to 12 months.24,25 Onabotulinum toxin A is also superior to solifenacin in curing severe forms of UUI.24,25 Onabotulinum toxin A doses greater than 100U do not appear to confer additional improvement in efficacy and quality of life, but increase risk of increased PVR.26 Onabotulinum toxin A injections are not a cure for OAB; repeat injections will be required. The median time between injections appears to stay about the same over time within an individual but will vary from person to person. Efficacy is maintained over repeat injections. The key to successful OAB management is not always in the number of times a day urination occurs. Meeting the patient’s goals and expectations are key to achieving patient satisfaction. Objective clinical improvement, treatment-related side effects, accessibility and convenience of treatment, education regarding the condition, and comorbidities all play a role in successful OAB management. Importantly, patient satisfaction with OAB therapy is associated with compliance with therapy. Conclusion

OAB is a common condition that causes a major impact on quality of life. It can be identified by a simplified evaluation and effectively managed with therapy. There are three tiers of therapy, with behavioral interventions first line. Second line is pharmacologic therapy with anticholinergic agents and beta agonists. Third line are onabotulinum toxin A intra detrusor injections and neuromodulation. Setting appropriate goals and treatment expectations and managing adverse effects are critical to a successful outcome. No single therapy is ideal for all patients. Special considerations regarding treatment

selection and side effects are necessary in the elderly. Pamela Ellsworth, MD, is a Professor of Urology at the UMassMemorial Medical Center at the University of Massachusetts Medical School.

References 1. Coyne KS, Sexton CC, Vats V, et al. National community prevalence of overactive bladder in the United States stratified by sex and age. Urology. 2011;77(5):1081-7. 2. Tubaro A. Defining overactive bladder: epidemiology and burden of disease. Urology. 2004;64(suppl 6A):2-6. 3. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:327-36. 4. Kobelt G, Kirchberger I, Malone-Lee J. Quality-of-life aspects of the overactive bladder and the effect of treatment with tolterodine. BJU Int. 1999;83:583–90. 5. Komaroff A, Fagioli L, Doolittle T, et al. Health status in patients with chronic fatigue syndrome and in general population and disease comparisons groups. Am J Med. 1996;101:281–90. 6. Schlenk EA, Erlen JA, Dunbar-Jacob J, et al. Health-related quality of life in chronic disorders: a comparison across studies using the MOS SF-36. Qual Life Res. 1998;7(1):57-65. 7. Mittmann N, Trakas K, Risebrough N, Liu BA. Utility scores for chronic conditions

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1999;15(4):369-76. 8. Coyne KS, Zhou Z, Thompson C, Versi E. The impact on health-related quality of life of stress, urge and mixed urinary incontinence. BJU Int. 2003;92(7):731-5. 9. Ganz ML, Smalarz AM, Krupski TL, et al. Economic costs of overactive bladder in the United States. Urology. 2010;75(3):526-32, 532.e1-18. 10. DuBeau CE. Interpreting the effect of common medical conditions on voiding dysfunction in the elderly. Urol Clin North Am. 1996;23(1):11-8. 11. Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU Guideline. 2012. Available at www.auanet.org. 12. Gibson W, Athanasopoulos A, Goldman H, et al. Are we shortchanging frail older people when it comes to the pharmacological treatment of urgency urinary incontinence? Int J Clin Pract. 2014;68(9):1165-73. 13. Sink KM, Thomas J 3rd, Xu H, et al. Dual use of bladder anticholinergics and cholinesterase inhibitors: long-term functional and cognitive outcomes. J Am Geriatr Soc. 2008;56(5):847-53. 14. Ivanova JI, Hayes-Larson E, Sorg RA, et al. Healthcare resource use and costs of privately insured patients who switch, discontinue, or persist on antimuscarinic therapy for overactive bladder. J Med Econ. 2014;17(10):741-50. 15. D’Souza AO, Smith MJ, Miller LA, et al. Persistence, adherence, and switch rates among extended-release and immediate-release overactive bladder medications in a regional managed care plan. J Manag Care Pharm. 2008;14(3):291-301. 16. Kleinman NL, Odell K, Chen CI, et al. Persistence and adherence with urinary antispasmodic medications among employees and the impact of adherence on costs and absenteeism. J Manag Care Spec Pharm. 2014;20(10):1047-56. 17. Maman K, Aballea S, Nazir J, et al. Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur Urol. 2014;65(4):755-65. 18. Burgio KL, Locher JL, Goode P, et al Combined behavioral and drug therapy for urge incontinence in older women. J Am Geriatr Soc. 2000;48:370-4. 19. Janknegt RA, Hassouna MM, Siegel SW, et al. Long-term effectiveness of

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sacral nerve stimulation for refractory urge incontinence. Eur Urol.

the treatment of patients with overactive bladder and urinary incontinence: re-

2001;39(1):101-6

sults of a phase 3, randomized, placebo controlled trial. J Urol. 2013;189(6):2186-

20. Brazzelli M, Murray A, Fraser C, et al. Efficacy and safety of sacral nerve

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stimulation for urinary urge incontinence: a systematic review. J Urol.

24. Nambiar A, Lucas M. Chapter 4: Guidelines for the diagnosis and treatment

2006;175(3 pt 1):835-41.

of overactive bladder (OAB) and neurogenic detrusor overactivity (NDO).

21. Chughtai B, Sedrakyan A, Isaacs A, et al. Long term safety of sacral nerve

Neurourol Urodyn. 2014;33 Suppl 3:S21-5.

modulation in medicare beneficiaries. Neurourol Urodyn. 2014 Jul 25.

25. Visco AG, Brubaker L, Richter HE, et al. Anticholinergic therapy vs. ona-

22. Peters KM, Macdiarmid SA, Wooldridge LS, et al. Randomized trial of

botulinumtoxin a for urgency urinary incontinence. N Engl J Med.

percutaneous tibial nerve stimulation versus extended-release tolterodine: re-

2012;367(19):1803-13.

sults from the overactive bladder innovative therapy trial. J Urol.

26. Dmochowski R, Chapple C, Nitti VW, et al. Efficacy and safety of ona-

2009;182(3):1055-61.

botulinumtoxin A for idiopathic overactive bladder: a double-blind, placebo

23. Nitti VW, Dmochowski R, Herschorn S, et al. Onabotulinum toxin A for

controlled, randomized, dose ranging trial. J Urol. 2010;184(6):2416-22.

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LATUDA helps your patients with bipolar depression experience more of lifeâ&#x20AC;&#x2122;s everyday moments

INDICATIONS AND USAGE LATUDA is indicated for treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate. The efficacy of LATUDA was established in a 6-week monotherapy study and a 6-week adjunctive therapy study with lithium or valproate in adult patients with bipolar depression. The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established.

IMPORTANT SAFETY INFORMATION FOR LATUDA Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. LATUDA is not approved for use in patients under the age of 18 years. Please see additional Important Safety Information, including Boxed Warning, and Brief Summary of Prescribing Information on adjacent pages.

Bipolar depression is different than other types of depression. LATUDA treats bipolar depression so patients can take part in life’s everyday moments. • Efficacy established in both a monotherapy study and an adjunctive therapy study with lithium or valproate1 –In these studies LATUDA was superior to placebo in reduction of Montgomery-Åsberg Depression Rating Scale (MADRS) scores at Week 61 • Safety and tolerability evaluated in multiple bipolar depression studies for 6 weeks and 24 weeks1 • Once-daily dosing, taken with food (at least 350 calories)1

Learn more at www.LATUDAhcp.com

CONTRAINDICATIONS LATUDA is contraindicated in the following: • Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone. • Strong CYP3A4 inhibitors (e.g., ketoconazole) • Strong CYP3A4 inducers (e.g., rifampin)

WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions, Including Stroke: In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including LATUDA. NMS can cause hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.

IMPORTANT SAFETY INFORMATION FOR Latuda® (lurasidone HCI) (Continued) Tardive Dyskinesia (TD): TD is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients with antipsychotic drugs. There is no known treatment for established cases of TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of TD. If signs and symptoms appear in a patient on LATUDA, drug discontinuation should be considered. Metabolic Changes

Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy, and LATUDA should be discontinued at the first sign of a decline in WBC in the absence of other causative factors. Orthostatic Hypotension and Syncope: LATUDA may cause orthostatic hypotension. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension, in patients with known cardiovascular disease or history of cerebrovascular disease and in patients who are antipsychotic-naïve. Seizures: LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold (e.g., Alzheimer’s dementia). Potential for Cognitive and Motor Impairment: Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely. Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration. Suicide: The possibility of suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for LATUDA should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. LATUDA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

ADVERSE REACTIONS

Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, LATUDA elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Commonly observed adverse reactions (≥5% incidence and at least twice the rate of placebo) for LATUDA were akathisia, extrapyramidal symptoms, and somnolence.

In the short-term, placebo-controlled monotherapy study, the median change from baseline to endpoint in prolactin levels for LATUDAtreated females was 3.1 ng/mL and was 1.5 ng/mL for males. The proportion of female patients with prolactin elevations ≥5x ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated male patients.

LATUDA is indicated for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate in adults.

INDICATIONS

Please see Brief Summary of Prescribing Information, including Boxed Warning, on adjacent pages. Reference: 1. LATUDA prescribing information. Sunovion Pharmaceuticals Inc. July 2013.

In the short-term, placebo-controlled adjunctive therapy with lithium or valproate study, the median change from baseline to endpoint in prolactin levels for LATUDA-treated females was 3.2 ng/mL and was 2.4 ng/mL for males. The proportion of female patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated male patients. Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/ neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Patients with a preexisting low white blood cell count (WBC) or a history of drug-induced

LATUDA, SUNOVION, and are registered trademarks of Sumitomo Dainippon Pharma Co., Ltd. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Sumitomo Dainippon Pharma Co., Ltd. ©2015 Sunovion Pharmaceuticals Inc. All rights reserved. LAT666-15 10/15

BRIEF SUMMARY OF LATUDA FULL PRESCRIBING INFORMATION WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL THOUGHTS AND BEHAVIORS • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death [see Warnings and Precautions (5.1)]. • LATUDA is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.1)]. • Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.2)]. • In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 1.1 Schizophrenia LATUDA is indicated for the treatment of patients with schizophrenia. The efficacy of LATUDA in schizophrenia was established in five 6-week controlled studies of adult patients with schizophrenia [see Clinical Studies (14.1)]. The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2)]. 1.2 Depressive Episodes Associated with Bipolar I Disorder Monotherapy: LATUDA is indicated as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA was established in a 6-week monotherapy study in adult patients with bipolar depression [see Clinical Studies (14.2)]. Adjunctive Therapy with Lithium or Valproate: LATUDA is indicated as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA as adjunctive therapy was established in a 6-week study in adult patients with bipolar depression who were treated with lithium or valproate [see Clinical Studies (14.2)]. The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.2)]. The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established. 4 CONTRAINDICATIONS • Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone [see Adverse Reactions (6.1)]. • Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Drug Interactions (7.1)]. • Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine, etc.) [see Drug Interactions (7.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning]. 5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults 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 trials of antidepressant drugs (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 major depressive disorder (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 trials in children and adolescents with MDD, obsessive

compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (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 of 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. Table 1 Age Range <18 18-24 25-64 ≥65

Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo 14 additional cases 5 additional cases Decreases Compared to Placebo 1 fewer case 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, 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 trials 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. 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 suicidal thoughts and behaviors, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for LATUDA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. 5.3 Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)]. 5.4 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported. 5.5 Tardive Dyskinesia Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which

patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on LATUDA, drug discontinuation should be considered. However, some patients may require treatment with LATUDA despite the presence of the syndrome. 5.6 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatmentemergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because LATUDA was not marketed at the time these studies were performed, it is not known if LATUDA is associated with this increased risk. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Schizophrenia Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 2. Table 2: Change in Fasting Glucose in Schizophrenia Studies

Serum Glucose Serum Glucose (≥ 126 mg/dL)

LATUDA Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day Mean Change from Baseline (mg/dL) n=680 n=71 n=478 n=508 n=283 n=113 -0.0 -0.6 +2.6 -0.4 +2.5 +2.5 Proportion of Patients with Shifts to ≥ 126 mg/dL 8.3% 11.7% 12.7% 6.8% 10.0% 5.6% (52/628) (7/60) (57/449) (32/472) (26/260) (6/108)

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in glucose of +1.8 mg/dL at week 24 (n=355), +0.8 mg/dL at week 36 (n=299) and +2.3 mg/dL at week 52 (n=307). Bipolar Depression Monotherapy Data from the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 3. Table 3: Change in Fasting Glucose in the Monotherapy Bipolar Depression Study LATUDA Placebo 20 to 60 mg/day 80 to 120 mg/day n=148 n=140 n=143 Mean Change from Baseline (mg/dL) Serum Glucose +1.8 -0.8 +1.8 Proportion of Patients with Shifts to ≥ 126 mg/dL Serum Glucose 4.3% 2.2% 6.4% (≥ 126 mg/dL) (6/141) (3/138) (9/141) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129).

Adjunctive Therapy with Lithium or Valproate Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 4. Table 4: Change in Fasting Glucose in the Adjunctive Therapy Bipolar Depression Studies LATUDA Placebo 20 to 120 mg/day Mean Change from Baseline (mg/dL) n=302 n=319 Serum Glucose -0.9 +1.2 Proportion of Patients with Shifts to ≥ 126 mg/dL Serum Glucose 1.0% 1.3% (≥ 126 mg/dL) (3/290) (4/316) Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88). Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Schizophrenia Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 5. Table 5: Change in Fasting Lipids in Schizophrenia Studies Placebo

20 mg/day

40 mg/day

LATUDA 80 mg/day

120 mg/day 160 mg/day

Mean Change from Baseline (mg/dL) Total Cholesterol Triglycerides

n=660 -5.8 -13.4

Total Cholesterol (≥ 240 mg/dL) Triglycerides (≥ 200 mg/dL)

5.3% (30/571) 10.1% (53/526)

n=71 -12.3 -29.1

n=466 -5.7 -5.1

n=499 -6.2 -13.0

n=268 -3.8 -3.1

n=115 -6.9 -10.6

3.8% (9/238) 10.5% (22/209)

4.0% (4/101) 7.0% (7/100)

Proportion of Patients with Shifts 13.8% (8/58) 14.3% (7/49)

6.2% (25/402) 10.8% (41/379)

5.3% (23/434) 6.3% (25/400)

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356) and -15.1 (n=357) mg/dL at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dL at week 36 and -2.5 (n=307) and -6.9 (n=307) mg/dL at week 52, respectively. Bipolar Depression Monotherapy Data from the short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 6. Table 6: Change in Fasting Lipids in the Monotherapy Bipolar Depression Study LATUDA Placebo 20 to 60 mg/day 80 to 120 mg/day Mean Change from Baseline (mg/dL) n=147 n=140 n=144 Total cholesterol -3.2 +1.2 -4.6 Triglycerides +6.0 +5.6 +0.4 Proportion of Patients with Shifts Total cholesterol 4.2% 4.4% 4.4% (≥ 240 mg/dL) (5/118) (5/113) (5/114) Triglycerides 4.8% 10.1% 9.8% (≥ 200 mg/dL) (6/126) (12/119) (12/122) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 (n=130) and -1.0 (n=130) mg/dL at week 24, respectively. Adjunctive Therapy with Lithium or Valproate Data from the short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 7. Table 7: Change in Fasting Lipids in the Adjunctive Therapy Bipolar Depression Studies LATUDA Placebo 20 to 120 mg/day Mean Change from Baseline (mg/dL) n=303 n=321 Total cholesterol -2.9 -3.1 Triglycerides -4.6 +4.6 Proportion of Patients with Shifts Total cholesterol 5.7% 5.4% (≥ 240 mg/dL) (15/263) (15/276) Triglycerides 8.6% 10.8% (≥ 200 mg/dL) (21/243) (28/260) Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and 5.3 (n=88) mg/dL at week 24, respectively. Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Schizophrenia Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 8. The mean weight gain was +0.43 kg for LATUDA-treated patients compared to -0.02 kg for placebotreated patients. Change in weight from baseline for olanzapine was +4.15 kg and for quetiapine extended-release was +2.09 kg in Studies 3 and 5 [see Clinical Studies (14.1)], respectively. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 4.8% for LATUDAtreated patients versus 3.3% for placebo-treated patients. Table 8: Mean Change in Weight (kg) from Baseline in Schizophrenia Studies

All Patients

Placebo (n=696) -0.02

LATUDA 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day (n=71) (n=484) (n=526) (n=291) (n=114) -0.15 +0.22 +0.54 +0.68 +0.60

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in weight of -0.69 kg at week 24 (n=755), -0.59 kg at week 36 (n=443) and -0.73 kg at week 52 (n=377). Bipolar Depression Monotherapy Data from the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 9. The mean weight gain was +0.29 kg for LATUDA-treated patients compared to -0.04 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 2.4% for LATUDA-treated patients versus 0.7% for placebo-treated patients. Table 9: Mean Change in Weight (kg) from Baseline in the Monotherapy Bipolar Depression Study LATUDA Placebo 20 to 60 mg/day 80 to 120 mg/day (n=151) (n=143) (n=147) All Patients -0.04 +0.56 +0.02 Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130). Adjunctive Therapy with Lithium or Valproate Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 10. The mean weight gain was +0.11 kg for LATUDA-treated patients compared to +0.16 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 3.1% for LATUDA-treated patients versus 0.3% for placebo-treated patients. Table 10: Mean Change in Weight (kg) from Baseline in the Adjunctive Therapy Bipolar Depression Studies LATUDA 20 to 120 mg/day Placebo (n=327) (n=307) All Patients +0.16 +0.11 Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86). 5.7 Hyperprolactinemia As with other drugs that antagonize dopamine D2 receptors, LATUDA elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients [see Adverse Reactions (6)]. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a LATUDA carcinogenicity study conducted in rats and mice [see Nonclinical Toxicology (13)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive. Schizophrenia In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +0.4 ng/mL and was -1.9 ng/mL in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/mL and for females was -0.2 ng/mL. Median changes for prolactin by dose are shown in Table 11.

Table 11: Median Change in Prolactin (ng/mL) from Baseline in Schizophrenia Studies

All Patients Females Males

Placebo -1.9 (n=672) -5.1 (n=200) -1.3 (n=472)

20 mg/day -1.1 (n=70) -0.7 (n=19) -1.2 (n=51)

40 mg/day -1.4 (n=476) -4.0 (n=149) -0.7 (n=327)

LATUDA 80 mg/day -0.2 (n=495) -0.2 (n=150) -0.2 (n=345)

120 mg/day 160 mg/day +3.3 +3.3 (n=284) (n=115) +6.7 +7.1 (n=70) (n=36) +3.1 +2.4 (n=214) (n=79)

The proportion of patients with prolactin elevations ≥ 5× upper limit of normal (ULN) was 2.8% for LATUDA-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 5.7% for LATUDA-treated patients versus 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 1.6% versus 0.6% for placebo-treated male patients. In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a median change in prolactin of -0.9 ng/mL at week 24 (n=357), -5.3ng/mL at week 36 (n=190) and -2.2 ng/mL at week 52 (n=307). Bipolar Depression Monotherapy The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with LATUDA 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 12. Table 12: Median Change in Prolactin (ng/mL) from Baseline in the Monotherapy Bipolar Depression Study LATUDA Placebo 20 to 60 mg/day 80 to 120 mg/day All Patients +0.3 +1.7 +3.5 (n=147) (n=140) (n=144) Females 0.0 +1.8 +5.3 (n=82) (n=78) (n=88) Males +0.4 +1.2 +1.9 (n=65) (n=62) (n=56) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.4% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% versus 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of -1.15 ng/mL at week 24 (n=130). Adjunctive Therapy with Lithium or Valproate The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with LATUDA 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes for prolactin across the dose range are shown in Table 13. Table 13: Median Change in Prolactin (ng/mL) from Baseline in the Adjunctive Therapy Bipolar Depression Studies LATUDA Placebo 20 to 120 mg/day All Patients 0.0 +2.8 (n=301) (n=321) Females +0.4 +3.2 (n=156) (n=162) Males -0.1 +2.4 (n=145) (n=159) Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.0% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% versus 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88). 5.8 Leukopenia, Neutropenia and Agranulocytosis Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and LATUDA should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue LATUDA and have their WBC followed until recovery. 5.9 Orthostatic Hypotension and Syncope LATUDA may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs. Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥ 20 mm Hg decrease in systolic blood pressure and ≥ 10 bpm increase in pulse from sitting to standing or supine to standing position. Schizophrenia The incidence of orthostatic hypotension and syncope reported as adverse events from short-term, placebo-controlled schizophrenia studies was (LATUDA incidence, placebo incidence): orthostatic hypotension [0.3% (5/1508), 0.1% (1/708)] and syncope [0.1% (2/1508), 0% (0/708)]. In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.8% with LATUDA 40 mg, 2.1% with LATUDA 80 mg, 1.7% with LATUDA 120 mg and 0.8% with LATUDA 160 mg compared to 0.7% with placebo. Bipolar Depression Monotherapy In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with LATUDA 20 to 60 mg and 0.6% with LATUDA 80 to 120 mg compared to 0% with placebo. Adjunctive Therapy with Lithium or Valproate In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 120 mg compared to 0.9% with placebo. 5.10 Seizures As with other antipsychotic drugs, LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older. Schizophrenia In short-term, placebo-controlled schizophrenia studies, seizures/convulsions occurred in 0.1% (2/1508) of patients treated with LATUDA compared to 0.1% (1/708) placebo-treated patients. Bipolar Depression Monotherapy In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, no patient experienced seizures/convulsions. Adjunctive Therapy with Lithium or Valproate In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions. 5.11 Potential for Cognitive and Motor Impairment LATUDA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely. In clinical studies with LATUDA, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence. Schizophrenia In short-term, placebo-controlled schizophrenia studies, somnolence was reported by 17.0% (256/1508) of patients treated with LATUDA (15.5% LATUDA 20 mg, 15.6% LATUDA 40 mg, 15.2% LATUDA 80 mg, 26.5% LATUDA 120 mg and 8.3% LATUDA 160 mg/day) compared to 7.1% (50/708) of placebo patients. Bipolar Depression Monotherapy In the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with LATUDA 20 to 60 mg and 80 to120 mg, respectively compared to 6.5% (11/168) of placebo patients. Adjunctive Therapy with Lithium or Valproate In the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies, somnolence was reported by 11.4% (41/360) of patients treated with LATUDA 20-120 mg compared to 5.1% (17/334) of placebo patients. 5.12 Body Temperature Dysregulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see Patient Counseling Information (17.9)]. 5.13 Suicide The possibility of a suicide attempt is inherent in psychotic illness and close supervision of highrisk patients should accompany drug therapy. Prescriptions for LATUDA should be written for the

smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. Schizophrenia In short-term, placebo-controlled schizophrenia studies, the incidence of treatment-emergent suicidal ideation was 0.4% (6/1508) for LATUDA-treated patients compared to 0.8% (6/708) on placebo. No suicide attempts or completed suicides were reported in these studies. Bipolar Depression Monotherapy In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the incidence of treatment-emergent suicidal ideation was 0.0% (0/331) with LATUDA-treated patients compared to 0.0% (0/168) with placebo-treated patients. No suicide attempts or completed suicides were reported in this study. Adjunctive Therapy with Lithium or Valproate In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, the incidence of treatment-emergent suicidal ideation was 1.1% (4/360) for LATUDA-treated patients compared to 0.3% (1/334) on placebo. No suicide attempts or completed suicides were reported in these studies. 5.14 Activation of Mania/Hypomania Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes. In the bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the LATUDA and placebo groups developed manic or hypomanic episodes. 5.15 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. LATUDA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. 5.16 Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy Bodies Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome. 6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)] • Suicidal Thoughts and Behaviors [see Boxed Warning and Warnings and Precautions (5.2)] • Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis [see Warnings and Precautions (5.23)] • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.4)] • Tardive Dyskinesia [see Warnings and Precautions (5.5)] • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.6)] • Hyperprolactinemia [see Warnings and Precautions (5.7)] • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)] • Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.9)] • Seizures [see Warnings and Precautions (5.10)] • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.11)] • Body Temperature Dysregulation [see Warnings and Precautions (5.12)] • Suicide [see Warnings and Precautions (5.13)] • Activation of Mania/Hypomania [see Warnings and Precautions (5.14)] • Dysphagia [see Warnings and Precautions (5.15)] • Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy Bodies [see Warnings and Precautions (5.16)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The information below is derived from an integrated clinical study database for LATUDA consisting of 3799 patients exposed to one or more doses of LATUDA for the treatment of schizophrenia and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250.9 patient-years. A total of 1106 LATUDA-treated patients had at least 24 weeks and 371 LATUDA-treated patients had at least 52 weeks of exposure. Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. Schizophrenia The following findings are based on the short-term, placebo-controlled premarketing studies for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 160 mg (n=1508). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia, extrapyramidal symptoms, and nausea. Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1508) LATUDA-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to

adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 14. Table 14: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Short-term Schizophrenia Studies

Body System or Organ Class

Placebo (N=708) (%)

Percentage of Patients Reporting Reaction LATUDA 160 120 80 40 20 mg/day mg/day mg/day mg/day mg/day (N=487) (N=538) (N=291) (N=121) (N=71) (%) (%) (%) (%) (%)

All LATUDA (N=1508) (%)

5 6 5

11 7 11

10 6 6

9 9 5

13 9 8

7 7 6

10 8 6

Musculoskeletal and Connective Tissue Disorders Back Pain

7 3

15 6

16 11

15 12

26 22

8 7

17 13

Nervous System Disorders Somnolence* Akathisia Extrapyramidal Disorder** Dizziness Psychiatric Disorders Insomnia 8 8 10 11 9 7 10 Agitation 4 10 7 3 6 5 5 Anxiety 4 3 6 4 7 3 5 Restlessness 1 1 3 1 3 2 2 Note: Figures rounded to the nearest integer *Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence **Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus

Dose-Related Adverse Reactions in the Schizophrenia Studies Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 10.7% for LATUDA 40 mg, 12.3% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 11.5% for LATUDA 40 mg, 11.9% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Bipolar Depression (Monotherapy) The following findings are based on the short-term, placebo-controlled premarketing study for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg (n=331). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence â&#x2030;Ľ 5%, in either dose group, and at least twice the rate of placebo) in patients treated with LATUDA were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety. Adverse Reactions Associated with Discontinuation of Treatment: A total of 6.0% (20/331) LATUDAtreated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 15. Table 15: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in a Short-term Monotherapy Bipolar Depression Study Body System or Organ Class Dictionary-derived Term

Percentage of Patients Reporting Reaction All LATUDA LATUDA Placebo LATUDA 20-60 mg/day 80-120 mg/day (N=168) (N=331) (N=167) (N=164) (%) (%) (%) (%)

Gastrointestinal Disorders Nausea Dry Mouth Vomiting Diarrhea

8 4 2 2

10 6 2 5

17 4 6 3

Infections and Infestations Nasopharyngitis Influenza Urinary Tract Infection

1 1 <1

4 <1 2

4 2 1

4 2 2

2 2 7

5 8 7

9 11 14

7 9 11

Musculoskeletal and Connective Tissue Disorders

Gastrointestinal Disorders Nausea Vomiting Dyspepsia Salivary Hypersecretion

Body System or Organ Class Dictionary-derived Term

Percentage of Patients Reporting Reaction All LATUDA LATUDA LATUDA 20-60 mg/day 80-120 mg/day (N=331) (N=167) (N=164) (%) (%) (%)

Placebo (N=168) (%)

14 5 4 4

Back Pain Nervous System Disorders Extrapyramidal Symptoms* Akathisia Somnolence** Psychiatric Disorders

Anxiety 1 4 5 4 Note: Figures rounded to the nearest integer *Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus **Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

Dose-Related Adverse Reactions in the Monotherapy Study: In the short-term, placebo-controlled study (involving lower and higher LATUDA dose ranges) [see Clinical Studies (14.2)] the adverse reactions that occurred with a greater than 5% incidence in the patients treated with LATUDA in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively. Bipolar Depression Adjunctive Therapy with Lithium or Valproate The following findings are based on two short-term, placebo-controlled premarketing studies for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg as adjunctive therapy with lithium or valproate (n=360). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence â&#x2030;Ľ 5% and at least twice the rate of placebo) in subjects treated with LATUDA were akathisia and somnolence. Adverse Reactions Associated with Discontinuation of Treatment: A total of 5.8% (21/360) LATUDAtreated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 16. Table 16: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Short-term Adjunctive Therapy Bipolar Depression Studies Body System or Organ Class Dictionary-derived Term

Percentage of Patients Reporting Reaction LATUDA 20 to 120 mg/day (N=360) (%)

Placebo (N=334) (%)

Gastrointestinal Disorders Nausea Vomiting General Disorders Fatigue Infections and Infestations Nasopharyngitis Investigations Weight Increased

10 1

14 4

9 5 5

14 11 11

Metabolism and Nutrition Disorders Increased Appetite Nervous System Disorders Extrapyramidal Symptoms* Somnolence** Akathisia Psychiatric Disorders Restlessness <1 4 Note: Figures rounded to the nearest integer *Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus **Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

Extrapyramidal Symptoms Schizophrenia In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% versus 5.8% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 12.9% versus 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 17. Table 17: Incidence of EPS Compared to Placebo in Schizophrenia Studies Placebo (N=708) (%) 9 6

20 mg/day (N=71) (%) 10 6

40 mg/day (N=487) (%) 21 11

LATUDA 80 mg/day 120 mg/day 160 mg/day (N=121) (N=291) (N=538) (%) (%) (%) 23 39 20 12 22 13

Adverse Event Term All EPS events All EPS events, excluding Akathisia/ Restlessness Akathisia 3 6 11 12 22 7 Dystonia* <1 0 4 5 7 2 Parkinsonism** 5 6 9 8 17 11 Restlessness 1 1 3 1 3 2 Note: Figures rounded to the nearest integer *Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus **Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

Bipolar Depression Monotherapy In the short-term, placebo-controlled monotherapy bipolar depression study, for LATUDA-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6.9% versus 2.4% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 9.4% versus 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 18. Table 18: Incidence of EPS Compared to Placebo in the Monotherapy Bipolar Depression Study Placebo (N=168) (%) 5 2

LATUDA 80 to 120 mg/day 20 to 60 mg/day (N=167) (N=164) (%) (%) 12 20 5 9

Adverse Event Term All EPS events All EPS events, excluding Akathisia/ Restlessness Akathisia 2 8 11 Dystonia* 0 0 2 Parkinsonism** 2 5 8 Restlessness <1 0 3 Note: Figures rounded to the nearest integer *Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus **Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

Adjunctive Therapy with Lithium or Valproate In the short-term, placebo-controlled adjunctive therapy bipolar depression studies, for LATUDAtreated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% versus 8.7% for placebo. The incidence of akathisia for LATUDA-treated patients was 10.8% versus 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 19. Table 19: Incidence of EPS Compared to Placebo in the Adjunctive Therapy Bipolar Depression Studies Placebo (N=334) (%)

LATUDA 20 to 120 mg/day (N=360) (%) 24 14

Adverse Event Term All EPS events 13 All EPS events, excluding Akathisia/ 9 Restlessness Akathisia 5 11 Dystonia* <1 1 Parkinsonism** 8 13 Restlessness <1 4 Note: Figures rounded to the nearest integer *Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus **Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias.

Schizophrenia The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (LATUDA, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 14.4%; placebo, 7.1%), the SAS (LATUDA, 5.0%; placebo, 2.3%) and the AIMS (LATUDA, 7.4%; placebo, 5.8%). Bipolar Depression Monotherapy The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 8.4%; placebo, 5.6%), the SAS (LATUDA, 3.7%; placebo, 1.9%) and the AIMS (LATUDA, 3.4%; placebo, 1.2%). Adjunctive Therapy with Lithium or Valproate The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 8.7%; placebo, 2.1%), the SAS (LATUDA, 2.8%; placebo, 2.1%) and the AIMS (LATUDA, 2.8%; placebo, 0.6%). Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Schizophrenia In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2% of LATUDA-treated subjects (0.0% LATUDA 20 mg, 3.5% LATUDA 40 mg, 4.5% LATUDA 80 mg, 6.5% LATUDA 120 mg and 2.5% LATUDA 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events â&#x20AC;&#x201C; four were receiving LATUDA 80 mg/day and three were receiving LATUDA 120 mg/day. Bipolar Depression Monotherapy In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, dystonia occurred in 0.9% of LATUDA-treated subjects (0.0% and 1.8% for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively) compared to 0.0% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events. Adjunctive Therapy with Lithium or Valproate In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1.1% of LATUDA-treated subjects (20 to 120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events. Other Adverse Reactions Observed During the Premarketing Evaluation of LATUDA Following is a list of adverse reactions reported by patients treated with LATUDA at multiple doses of â&#x2030;Ľ 20 mg once daily within the premarketing database of 2905 patients with schizophrenia. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions listed in Table 14 or those that appear elsewhere in the LATUDA label are not included. Although the reactions reported occurred during treatment with LATUDA, they were not necessarily caused by it. Reactions are further categorized by organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare). Blood and Lymphatic System Disorders: Infrequent: anemia Cardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris, bradycardia Ear and Labyrinth Disorders: Infrequent: vertigo Eye Disorders: Frequent: blurred vision Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis General Disorders and Administrative Site Conditions: Rare: sudden death Investigations: Frequent: CPK increased Metabolism and Nutritional System Disorders: Frequent: decreased appetite Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema Vascular Disorders: Frequent: hypertension Clinical Laboratory Changes Schizophrenia Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for LATUDA-treated patients compared to +0.02 mg/dL for placebotreated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of LATUDA-

treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 20). Table 20: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in Schizophrenia Studies Laboratory Parameter Serum Creatinine Elevated

Placebo (N=708)

LATUDA 20 mg/day (N=71) 1%

LATUDA 40 mg/day (N=487) 2%

LATUDA 80 mg/day (N=538) 2%

LATUDA 120 mg/day (N=291) 5%

LATUDA 160 mg/day (N=121) 7%

Bipolar Depression Monotherapy Serum Creatinine: In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for LATUDA-treated patients compared to -0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 2.8% (9/322) of LATUDA-treated patients and 0.6% (1/162) on placebo (Table 21). Table 21: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in a Monotherapy Bipolar Depression Study Placebo (N=168)

Laboratory Parameter Serum Creatinine Elevated

LATUDA 80 to 120 mg/day (N=167) 4%

LATUDA 20 to 60 mg/day (N=164) 2%

<1%

Adjunctive Therapy with Lithium or Valproate Serum Creatinine: In short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for LATUDAtreated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/360) of LATUDA-treated patients and 1.6% (5/334) on placebo (Table 22). Table 22: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adjunctive Therapy Bipolar Depression Studies Placebo (N=334)

Laboratory Parameter Serum Creatinine Elevated

LATUDA 20 to 120 mg/day (N=360) 4%

7 DRUG INTERACTIONS 7.1 Potential for Other Drugs to Affect LATUDA LATUDA is predominantly metabolized by CYP3A4. LATUDA should not be used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) or strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. Johnâ&#x20AC;&#x2122;s wort, phenytoin, carbamazepine, etc.) [see Contraindications (4)]. The LATUDA dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 (e.g., diltiazem, atazanavir, erythromycin, fluconazole, verapamil, etc.). If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose [see Dosage and Administration (2.5)]. Lithium: It is not necessary to adjust the LATUDA dose when used concomitantly with lithium (Figure 1). Valproate: It is not necessary to adjust the LATUDA dose when used concomitantly with valproate. A dedicated drug-drug interaction study has not been conducted with valproate and LATUDA. Based on pharmacokinetic data from the bipolar depression studies valproate levels were not affected by lurasidone, and lurasidone concentrations were not affected by valproate. Grapefruit: Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations [see Dosage and Administration (2.5)]. Figure 1: Impact of Other Drugs on LATUDA Pharmacokinetics Fold Change and 90% CI

Interacting drug PK

Recommendation

Strong CYP3A4 Inhibitor Ketoconazole 400 mg/day

Should not be coadministered

Cmax AUC

Moderate CYP3A4 Inhibitor Diltiazem 240 mg/day

Starting dose = 20 mg

Cmax AUC

Maximum dose = 80 mg

Strong CYP3A4 Inducer Rifampin 600 mg/day

Should not be coadministered

Cmax AUC

Lithium 600 mg BID

Adjustment not required

Cmax AUC

4 6 8 Change relative to lurasidone alone

7.2 Potential for LATUDA to Affect Other Drugs No adjustment is needed for lithium, substrates of P-gp, CYP3A4 (Figure 2) or valproate when coadministered with LATUDA. Figure 2: Impact of LATUDA on Other Drugs Interacting drug PK

Fold Change and 90% CI

Recommendation

P-gp Substrates Digoxin 0.25 mg SD

Adjustment not required

Cmax AUC

CYP3A4 Substrates Midazolam 5 mg SD

Adjustment not required

Cmax AUC

Oral Contraceptive Ethinyl Estradiol

Adjustment not required

Cmax AUC

Adjustment not required

Norelgestromin Cmax AUC Lithium 600mg BID*

Ctrough 0.0

Adjustment not required 0.5

1.0 1.5 2.0 2.5 Change Relative to Interactive Drug Alone

3.0

*Steady state lithium Ctrough on Day 4 vs Day 8 when lithium was coadministered with lurasidone at steady state

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well controlled studies of LATUDA use in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. LATUDA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data Safe use of LATUDA during pregnancy or lactation has not been established; therefore, use of LATUDA in pregnancy, in nursing mothers, or in women of childbearing potential requires that the benefits of treatment be weighed against the possible risks to mother and child. Animal Data No adverse developmental effects were observed in a study in which pregnant rats were given lurasidone during the period of organogenesis and continuing through weaning at doses up to 10 mg/kg/day, which is approximately half of the maximum recommended human dose (MRHD) of 160 mg/day, based on mg/m2 body surface area. No teratogenic effects were seen in studies in which pregnant rats and rabbits were given lurasidone during the period of organogenesis at doses up to 25 and 50 mg/kg/day, respectively. These doses are 1.5- and 6-times, in rats and rabbits, respectively, the MRHD of 160 mg/day based on mg/m2 body surface area. 8.3 Nursing Mothers LATUDA was excreted in milk of rats during lactation. It is not known whether LATUDA or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the risk of drug discontinuation to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies with LATUDA did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In elderly patients with psychosis (65 to 85), LATUDA concentrations (20 mg/day) were similar to those in young subjects. It is unknown whether dose adjustment is necessary on the basis of age alone. Elderly patients with dementia-related psychosis treated with LATUDA are at an increased risk of death compared to placebo. LATUDA is not approved for the treatment of patients with dementiarelated psychosis [see Boxed Warning].

8.6 Other Patient Factors The effect of intrinsic patient factors on the pharmacokinetics of LATUDA is presented in Figure 3. Figure 3: Impact of Other Patient Factors on LATUDA Pharmacokinetics Fold Change and 90% CI

PK Renal impairment Mild Moderate Severe

Recommendation Adjustment not required

Cmax AUC Cmax AUC Cmax AUC

Starting dose = 20 mg Maximum dose = 80 mg Starting dose = 20 mg Maximum dose = 80 mg

Hepatic impairment Cmax Mild AUC Cmax Moderate AUC Severe Cmax AUC Population description Gender Females Race Asian*

Adjustment not required Starting dose = 20 mg Maximum dose = 80 mg Starting dose = 20 mg Maximum dose = 40 mg

Adjustment not required

Cmax AUC

Adjustment not required

Cmax AUC 0

2 3 4 Change relative to reference

*Compare to Caucasian

10 OVERDOSAGE 10.1 Human Experience In premarketing clinical studies, accidental or intentional overdosage of LATUDA was identified in one patient who ingested an estimated 560 mg of LATUDA. This patient recovered without sequelae. This patient resumed LATUDA treatment for an additional two months. 10.2 Management of Overdosage Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific antidote to LATUDA, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consider the possibility of multiple-drug overdose. Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of LATUDA. Similarly, the alphablocking properties of bretylium might be additive to those of LATUDA, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of LATUDA-induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Manufactured for: Sunovion Pharmaceuticals Inc. Marlborough, MA 01752 USA For Customer Service, call 1-888-394-7377. For Medical Information, call 1-800-739-0565. To report suspected adverse reactions, call 1-877-737-7226. Revised: July 2013 901456R10 LATUDA and are registered trademarks of Sumitomo Dainippon Pharma Co., Ltd. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Sumitomo Dainippon Pharma Co., Ltd. ÂŠ 2014 Sunovion Pharmaceuticals Inc.

Recent Advances in the Treatment and Management of Multiple Sclerosis Patricia K. Coyle, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Therapy for multiple sclerosis continues to evolve. Effective treatment with various disease-modifying therapies is available for the relapsing subtype. Clinicians have a wide range of oral and injectable medications to select from, each of which has advantages and disadvantages. There are several areas of unmet need in this disease, particularly treatment of progressive disease. Key Points • There are effective medications to reduce relapses in relapsing disease. • There are no currently approved disease management therapies for progressive disease. • DMT use is cost effective in preventing disability. • A wellness program to maintain brain function is especially important in those with MS. • There are still unmet needs in MS management.

MULTIPLE SCLEROSIS (MS) IS A CHRONIC inflammatory condition of the central nervous system (CNS) induced by an environmental trigger in a genetically susceptible person with CNS lesions disseminated in time and space without an alternative explanation. It is the most common, nontraumatic cause of disability in young adults. At least 400,000 people are diagnosed in the United States and more than 2.3 million worldwide. Characteristic features of this disease are young age of onset, female predominance, Caucasian predominance, and variable course (i.e., no two patients are alike). Ninety percent of cases are identified between the ages of 15 to 50; less than 1 percent are identified in those under age 10 or over age 60. Women affected by MS outnumber men three to one; the incidence is actually increasing in women. Over 90 percent of those affected are Caucasians.

There are four phenotypes of MS: clinically isolated syndrome (CIS), relapsing MS, primary-progressive MS, and secondary-progressive MS. CIS is the first MS attack experienced by a patient. CIS can be optic neuritis, transverse myelitis, or isolated brain stem cerebellar syndrome. Patients can be classified as low/high risk for developing the other phenotypes based on brain MRI findings of silent lesions. High-risk CIS is treated. Eighty-five to 90 percent of MS cases are relapsing MS at onset and are characterized by episodes of relapse. The remaining 10 to 15 percent will have primary-progressive MS. These patients have a slow worsening (typically in gait) from onset. Primary-progressive has about equal gender onset and a decade later age of onset. These patients may have superimposed relapses. Secondary-progressive MS is when an initial relapsing patient transitions to slow worsening disease.

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Exhibit 1: Treatment Principles 3 • Initiate DMT – relapsing MS; CIS and MRI c/w MS, with other possible causes excluded; SPMS with relapses or inflammatory MRI changes. • There should be full access to range of treatment options. • Treatment access should not be limited by relapse frequency, disability level, personal characteristics (age, gender, ethnicity). • Lack of relapses on DMT is not justification to discontinue. • DMT should not be stopped while payer coverage is being evaluated. • DMT therapy is indefinite (unless sub-optimal response, intolerable adverse effects, non-adherence.)

The natural history of MS is to start out as relapsing, then transition to secondary-progressive subtype. MS increases mortality risk by greater than 2.5fold and decreases life expectancy by seven to 14 years. With better treatment, lifespan is improved from a generation ago. Death can occur from secondary MS issues (>50%, i.e., aspiration pneumonia), suicide, or MS relapse in the medulla.1,2 Clinically apparent untreated MS results in disability (motor, cognitive, vocational). This is typically in the setting of progressive MS. All progressive MS patients will become disabled; none of the diseasemodifying therapies (DMTs) currently available are effective in altering disability once progression occurs. Hopefully, the early use of DMT will prevent progression from occurring; it appears DMT is delaying the development of secondary- progressive. MS has a negative impact on activities of daily living and quality of life. Exhibit 1 outlines the treatment principles from the MS Coalition Consensus Paper.3 The treatment principles of MS are to initiate DMT as soon as possible following a relapsing MS diagnosis, for CIS and an MRI consistent with MS, and for secondary-progressive MS with relapses or inflammatory MRI changes. Factors affecting the DMT choice are complex; these are most appropriately addressed collaboratively by the patient and the treating clinician. DMT use is indefinite, unless there is suboptimal treatment response (determined by patient and treating clinician), intolerable side effects, inadequate adherence to the DMT regimen, or more appropriate DMT available. Moving between DMTs should occur only for medically appropriate reasons and not cost reasons alone. When evidence of breakthrough clinical/MRI activity suggests a suboptimal response, clinicians should consider switching to a different mechanism of action DMT. The ra-

tionale for having multiple DMT options available to all patients is to have different mechanism of actions to allow suboptimal response switch, potential DMT contraindications, variable risk tolerance, adherence and quality of life issues (route of delivery, side effects), and individual differences in tolerability/adherence issues. It is increasingly accepted to treat high-risk CIS and all relapsing forms of MS with early institution of therapy. Early treatment is within three to six months of presentation of symptoms and is best for preventing or minimizing damage from the disease process. Monitoring of brain MRIs for silent disease lesions is typically done annually, at least for the first years of therapy. The first six to 24 months of therapy are particularly crucial to judge poor response. The overall expectation of DMT therapy is that patients should be well controlled with minimal relapses, disability, and new MRI lesions. The current DMTs shown in Exhibit 2 are approved for relapsing MS. Several injectable and oral agents are considered first-line therapy. Until the availability of the oral agents, interferon and glatiramer acetate were the mainstays of therapy. Natalizumab and alemtuzumab are reserved for later lines of therapy because of the potential for serious adverse effects and the newness of the agents, respectively. Glatiramer was originally approved as 20 mg qd and then double dose three times weekly was improved, which increases adherence. Advantages of glatiramer include the fact that long-term safety and efficacy data are available. Patients may do very well on this agent and it is well tolerated, and it is also the only DMT that does not require laboratory testing, and it has the safest rating for use during pregnancy. The major disadvantage is the requirement for injection.

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Exhibit 2: Current MS DMTs • First-line parenterals – SC IFNβ-1b 250 mcg every other day (Betaseron; Extavia) – SC IFNβ-1a 44, 22 mcg 3x weekly (Rebif) – IM IFNβ-1a 30 mcg weekly (Avonex) – SC peg IFNβ-1a 125 mcg every 14 days (Plegridy) – SC glatiramer acetate 40 mg 3x weekly, or 20 mg daily (Copaxone) • First-line orals – Fingolimod 0.5 mg (Gilenya) – Teriflunomide 7, 14 mg (Aubagio) – Dimethyl fumarate 240 mg twice a day (Tecfidera) • Second-line parenterals – IV natalizumab (Tysabri) 300 mg monthly IV – Alemtuzumab (Lemtrada)

Fingolimod is an oral sphingosine 1-phosphate receptor modulator (binds to receptors 1, 3, 4, 5). It blocks the ability of naïve and central memory T cells to exit lymph nodes; effector memory T cells that are needed for immune surveillance are not affected. It also enters the CNS to potentially have direct effects. Teriflunomide is an oral dihydroorotate dehydrogenase inhibitor that is cytostatic for rapidly dividing B cells and T cells. It is the active form of leflunomide, an FDA approved treatment for RA and psoriatic arthritis. Dimethyl fumarate is a twice daily oral fumaric acid ester that affects the Nrf2 oxidative stress pathway and has direct effects on lymphocytes and dendritic cells. Activation of the Nrf2 pathway protects cells from oxidative stress-induced cell death. Increased oxidative stress is associated with neuronal cell death in MS. The oral agents have the advantages of oral convenience, very good efficacy, and good tolerability. On the negative side, there is limited experience with using the oral agents and no long-term safety or efficacy data.4 Each oral agent has its own unique adverse events and tolerability issues. The first case of progressive multifocal leukoencephalopathy (PML) with an oral agent, dimethyl fumarate, has been reported in Europe.5 PML is a brain infection with the John Cunningham ( JC) virus which can be fatal. Dimethyl fumarate can cause lymphocytopenia, a risk factor for PML. Natalizumab has excellent efficacy, assured adherence because it is given as a monthly infusion, and is well tolerated. In the past it was used as first-line therapy until cases of PML were reported. There have been approximately 500 PML cases related to natalizumab, with a 25 percent mortality rate. Accurate counseling on PML risk is critical before a patient is started on the therapy. Risk factors for PML include JC virus antibody titer and index, du-

ration of natalizumab therapy, and prior immunosuppression therapy. Patients who are negative for JC virus antibodies or have low antibody titers have approximately a one in 10,000 risk of PML over two years. If a patient has a high antibody titer, their risk is one in 1,000 over two years. Alemtuzumab, the newest agent approved, is a humanized IgG1-kappa anti-CD52 monoclonal antibody which depletes T cells, and to a lesser extent B cells, natural killer (NK) cells, monocytes, and dendritic cells. It was initially approved for B cellchronic lymphocytic leukemia and was approved for relapsing MS in late 2014. It is given as intravenous infusions for five consecutive days initially and for three consecutive days one year later. This is an induction strategy which lasts five or more years. Over a seven-year follow-up, 48 percent of patients required additional treatment cycles.6 Because of its safety profile, the prescribing information suggests reserving alemtuzumab for people who have had an inadequate response to two or more MS therapies. A risk mitigation program is required which involves mandatory monitoring for several years for thyroid dysfunction (17% to 33%), idiopathic thrombocytopenic purpura (1% to 3%), and kidney dysfunction (<1%). Upcoming generic DMTs raise issues of what is acceptable for the approval of biosimilar products. Generic interferon beta is already available in other countries. Several generic glatiramer acetates are under investigation. For many years in Britain, MS was not treated because of the cost of the DMT agents. Then the country entered into a risk-sharing agreement to study a large cohort of patients to see if DMT paid off. This was a six-year study involving over 5,000 MS patients treated with interferon beta or glatiramer compared to a British Columbia natural his-

www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 51

tory database and was the largest observational study to date in MS. DMT use was determined to be cost effective in preventing disability.7 An ongoing assessment of the study patients is planned for 10 years. One area of active research is preserving brain function in MS. Everyone’s brain is shrinking by 0.1 to 0.3 percent per year; this process is accelerated in MS. Additionally, hypertension, diabetes, smoking, and obesity all increase brain shrinkage in everyone. Over time, there is loss of neural circuits and brain plasticity (ability to adapt). A wellness program to maintain brain function is especially important in those with MS. This should include optimum body weight, no smoking, moderate alcohol intake, good sleep hygiene, a healthy diet, limited salt, and regular exercise several times a week (aerobic and muscle strengthening). Achieving goal blood pressure, glucose, and lipids and maintaining good dental health are additional ways to maintain CNS function. Lastly, regular mental exercise and socialization are important to preserving brain function. Encouraging this overall wellness program in those with MS will maximize the benefits of DMT. Memory training in a formalized program has been shown to be beneficial in patients with MS. In a pilot study evaluating 10 memory training sessions over five weeks in MS patients compared with placebo treatment, the memory training cohort showed improved memory and learning. Functional MRI showed increased patterns of cerebral activation. Memory improvement and increased cerebral activation was maintained over six months.8 Despite all the advances in the last few years, there are still unmet needs in MS management. There is no cure for MS, no effective therapies for neurodegeneration (progressive MS), nor therapies to reverse CNS damage. There is also widely variable individual therapeutic response to DMT. DMT does not guarantee a patient will feel better day to day; they will have fewer relapses but may still have significant quality of life detriment. This expectation of therapy has to be managed to have patient adherence. Because MS is likely heterogeneous with multiple damage mechanisms, clinicians cannot currently match patients with the best medication. Lastly, there is a need for additional safe, effective, and convenient therapies that are easy to adhere with. New therapies under study for MS include daclizumab, anti-CD20s, and progressive MS/repair strategies. Daclizumab is a humanized anti-CD25 monoclonal antibody that targets activated T cells and B cells and is already approved to prevent rejection in organ transplantation. A three-year, Phase III trial found a 45 percent decrease in annualized

relapse rate compared with interferon beta, a 54 percent decrease in new or enlarging brain lesions, and a 16 percent decrease in disability.9,10 This agent will be given as a once a month subcutaneous injection. Three anti-CD20 monoclonal antibodies – rituximab (Rituxan, already approved for rheumatoid arthritis and other indications), ocrelizumab, and ofatumumab – are under investigation. These are selective biologic agents that have potential for treating progressive MS.11 CNS repair strategies under investigation include remyelinating antibodies, stem cells, agents which protect axons/neurons/mitochondria, and reduced microglia activation. None of these agents are close to market. Conclusion

Although a devastating disease, there are effective disease-modifying medications for relapsing MS which should be initiated as soon as possible after diagnosis. Overall in treating relapsing MS, oral DMTs will increasingly be used in treatment naïve patients. The injectables will be reserved for second-line treatment. Anti-CD20 antibodies, once approved, will likely replace natalizumab, will be used first line in high disease activity/poor prognosis patients, and will be viewed as optimal switch agents. There is need for biomarkers to select and validate DMT choice. It is hoped that in the near future there will be better data to help clinicians select the most effective agent at the most effective dose for a given patient. The future should bring a concerted push for progressive MS therapies and CNS repair strategies. Patricia K. Coyle, MD, is Professor and Vice Chair (Clinical Affairs) and Director of the MS Comprehensive Care Center at the Stony Brook University Medical Center in Stony Brook, NY.

References 1. Scalfari A, Knappertz V, Cutter G, et al. Mortality in patients with multiple sclerosis. Neurology. 2013;81(2):184-92. 2. Manouchehrinia A, Weston M, Tench CR, et al. Tobacco smoking and excess mortality in multiple sclerosis: a cohort study. J Neurol Neurosurg Psychiatry. 2014;85(10):1091-5. 3. Multiple Sclerosis Coalition. The Use of Disease-Modifying Therapies in Multiple Sclerosis. Principles and Current Evidence. March 2015. Available at www.nationalmssociety.org. Accessed August 5, 2015. 4. Cross AH, Naismith RT. Established and novel disease-modifying treatments in multiple sclerosis. J Intern Med. 2014;275(4):350-63. 5. Rosenkranz T, Novas M, Terborg C. PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med. 2015;372(15):1476-8. 6. Tuohy O, Costelloe L, Hill-Cawthorne G, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015;86(2):208-15.

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7. Palace J, Duddy M, Bregenzer T, et al. Effectiveness and cost-effectiveness of

9. Oh J, Calabresi PA. Emerging injectable therapies for multiple sclerosis. Lan-

interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Shar-

cet Neurol. 2013;12(11):1115-26.

ing Scheme at 6 years: a clinical cohort study with natural history comparator.

10. Milo R. The efficacy and safety of daclizumab and its potential role in the

Lancet Neurol. 2015;14(5):497-505.

treatment of multiple sclerosis. Ther Adv Neurol Disord. 2014;7(1):7â&#x20AC;&#x201C;21.

8. Dobryakova E, Wylie GR, DeLuca J, Chiaravalloti ND. A pilot study exam-

11. Gasperini C, Haggiag S, Ruggieri S. Drugs in clinical development for

ining functional brain activity 6 months after memory retraining in MS: the

multiple sclerosis: focusing on anti-CD20 antibodies. Expert Opin Invest Drugs

MEMREHAB trial. Brain Imaging Behav. 2014;8(3):403-6.

2013;22(10):1243-53.

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Therapeutic Challenges in the Diagnosis and Management of Psoriasis Robert E. Kalb, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Psoriasis is a chronic, incurable inflammatory disease with systemic complications and a significant impact on patients. Effective medications and phototherapy can be used to significantly improve this disease. Data are accumulating that more aggressive therapy with systemic therapies including biologics is reducing long-term complications/comorbidities. • • • • • • •

Key Points Moderate to severe psoriasis has major impact on those affected and leads to significant comorbidities. To eliminate access barriers, managed care should consider the following: Eliminating phototherapy copayments Eliminating restrictions and prior authorizations for phototherapy or conventional systemic therapy (methotrexate, cyclosporine, acitretin) Changing biologic prior authorization policy to require only one prior systemic therapy failure Biologic agents are shifting the treatment paradigm in psoriasis, offering longterm safety and efficacy to a patient population that has long been underserved. Data are suggesting that treatment of psoriasis with biologics reduces the incidence of complications, including cardiovascular disease and joint damage.

PSORIASIS IS A CHRONIC INFLAMMATORY disorder that affects approximately 2 percent of the general population. With the development of very effective treatments that include biologics, disease control can be achieved. Psoriasis results in significant morbidity, including skin symptoms (itching, burning, and open areas of skin) and emotional/ psychological effects. Obesity, depression, psoriatic arthritis with joint deformities, and increased risk of cardiovascular disease are common comorbidities. Prevalence is roughly equal in men and women. Onset of psoriasis is most common between ages 15 to 35. Multiple genes are linked to the disease with linkages to other autoimmune diseases including diabetes, Lupus, and Crohn’s disease. Approximately 10 to 25 percent of patients have moderate to very severe disease. An estimated 100 to 125,000 patients

are currently being treated with systemic therapy. Clinicians tend to underestimate the impact of the disease on a particular patient. In a clinical study of etanercept (Enbrel®), patients perceived their disease at baseline to be much more severe than their physicians did.1 Physicians assessed approximately 22 percent of patients in this study as having marked or severe psoriasis. This assessment was based on the percentage of patients who had a baseline score of 4 (”marked”) or 5 (“severe”) on the Physician’s Static Global Assessment of Psoriasis. Scores were recorded on a scale of 0 to 5, with 0 indicating no evidence of disease and 5 indicating severe induration, erythema, and scaling. The perception of disease severity was different for patients, with approximately 75 percent assessing themselves as having marked or severe psoriasis.

www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 55

Exhibit 1: Psoriasis Therapy

Needs systemic therapy

The impact of psoriasis on a patient’s mental and physical function is comparable to that of major, systemic medical diseases, including cancer, arthritis, hypertension, heart disease, diabetes, and depression.2 Psoriasis causes as much disability as other major medical diseases.2 These findings are an indicator of how severely psoriasis can affect the day-today mental and physical functions of patients with the disorder. When considering treatment options, health care providers should consider psychological and social aspects of the disease as well as the severity of skin lesions. Psoriasis can be classified as mild, moderate, or severe based on the body surface area (BSA) affected. Mild psoriasis is defined as less than 2 percent BSA involvement and is isolated patches on knees, elbows, scalp, hands, and feet.3 Moderate and severe psoriasis are defined as covering 3 to 10 percent and greater than 10 percent of the body, respectively.3 Most prior authorization criteria used by managed care for certain treatments require 10 percent or more affected BSA. Even a modest amount of psoriasis based on body surface area can interfere with a patient’s quality of life (QOL) and should be treated. Studies use Psoriasis Area Severity Index (PASI) scores to identify efficacy of medications. The gold standard for a medication is to achieve a 75 percent reduction in the PASI score. Plaque psoriasis accounts for approximately 85 percent of all cases of psoriasis. The initial treatment selection involves a choice between a topical or system treatment. For patients with mild disease, topical treatment with corticosteroids, with or without a vitamin D analogue [Calcipotriene (Dovonex ®), Calcitriol (Vectical®)], is generally effective. Both vitamin D analogues are available generically. As the amount of BSA affected by psoriasis in-

Traditional Systemic Agents • Methotrexate • Cyclosporine • Acitretin • Apremilast Biologic Agents • Adalimumab Phototherapy • Etanercept • UVB • Infliximab • PUVA • Ustekinumab

creases, the likelihood that topical agents will be effective and, importantly, that patients will be compliant with therapy decreases. Therapies beyond the topical medications are likely to be needed to improve moderate and severe psoriasis. Traditional systemic agents, phototherapy and biologics, are the options for systemic treatment of psoriasis (Exhibit 1). Narrow band ultraviolet B phototherapy (NBUVB) is now the gold standard for phototherapy. This requires proper equipment and two to three times per week visits. It is a safe and effective treatment with few adverse effects. The two main issues with phototherapy are access and the cost of copayments. This type of phototherapy is not available in many areas. Most insurance plans charge for each session. With a $50 per session copay, a patient can have $600 a month in out-of-pocket costs. As shown in Exhibit 2, at home and office-based NBUVB have some of the lowest costs to achieve a significant treatment response.4 Methotrexate is given as once per week (~15 mg) oral therapy and is the gold standard therapy for psoriatic arthritis. Approximately 40 percent of patients will achieve a PASI 75 on methotrexate. Although this is an inexpensive therapy based on medication costs alone, there are some significant potential adverse effects (i.e., bone marrow and hepatic toxicity). Lab monitoring and alcohol avoidance are required. This agent can be given subcutaneously (Otrexup®), which appears to have fewer adverse effects and higher efficacy. Cyclosporine can be used to achieve a quick response. It is given orally as a daily dose (3 to 5 mg/ kg) with hypertension and renal toxicity being the most common adverse effects. The major issue with this agent is long-term use is limited; FDA labeling

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

Exhibit 2: Annual Cost to Achieve PASI 75 Response4

US$/PASI-75

A. 130,000 120,000 110,000 100,000 90,000 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 M H

S Cy I

li nf

n ki

lim

ab A Et

restricts use to one year of therapy. Acitretin (Soriatane® and Neotigason®) is an oral retinoid (Vitamin A) derivative that is not cytotoxic or immunosuppressive. This is an excellent maintenance medication, which has better efficacy when combined with phototherapy or other systemic therapy. It has typical retinoid dose-related side effects - nausea, headache, itching, dry, red or flaky skin, dry or red eyes, dry or chapped lips, swollen lips, dry mouth, thirst, depression, and hair loss. A phosphodiesterase (PDE) 4 inhibitor, apremilast (Otezla®), is the most recent systemic addition to the toolbox. It is an oral agent that produces a 33 percent PASI 75 response compared with 5 percent placebo response. It has no significant side effects, with only minor gastrointestinal issues. Although it costs about 75 percent less than biologics, it is less effective in achieving PASI 75 response. Advances in studies of the immunological basis of psoriasis, combined with progress in genetics, microbiology, and bioengineering, have resulted in a shift in therapeutic focus toward agents that interfere with the psoriatic disease process at the cellular level. These new biologic agents have the ability to interrupt the disease pathway through the modulation of T-cell response and cytokine levels and may, therefore, slow or halt disease progression. Biologics are becoming the treatment of choice for moderate to severe psoriasis, especially for patients for whom current therapies are no longer effective or cause unacceptable side effects. Biologic therapy for psoriasis includes tumor ne-

c er

ep Et

p ce

W A

f le

crosis factor (TNF) blocking agents [adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®)] and interleukin (IL) 12/23 blocking agents [ustekinumab (Stelara®)]. Etanercept is self-injected subcutaneously once or twice weekly. It is FDA approved for psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis. It is given as 100 mg once a week for the first 12 weeks for psoriasis, then 50 mg once per week. Adalimumab is also self-injected, but it is given once every other week. Because of greater demonstrated efficacy and an easier dosing schedule than etanercept, it is the most frequently used biologic for psoriasis. It is FDA approved for psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. Ustekinumab is very effective and use of this agent is increasing now that it is labeled for patient self-administration. It is dosed based on weight and is given at week 0, week 4, and then every 12 weeks. The infrequent dosing interval is helpful for patient adherence. The ultimate dosing interval can vary significantly from every eight weeks to much longer than 12 weeks. Exhibit 3 compares the various biologics. Psoriasis, as an inflammatory process, has several comorbidities, including cardiovascular (CV) disease, metabolic syndrome, hypertension, obesity, type II diabetes, and arthritis.5 Severe psoriasis is an independent risk factor for CV mortality (HR 1.57; 95% CI 1.26, 1.96), while mild psoriasis only modestly in-

www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 57

Exhibit 3: Biologic Agents for Psoriasis Adalimumab (Humira®)

Etanercept (Enbrel®)

Infliximab (Remicade®)

Ustekinumab (Stelara®)

Administration

SQ every other week

SQ 1x/week

2 hr IV infusion every 8 weeks after induction

SQ every 12 weeks

Type

Human monoclonal antibody TNFα

Receptor fusion protein TNFα

Chimeric monoclonal antibody TNFα

Human monoclonal antibody IL-12/23

Efficacy (PASI 75) at 12 wks, 1 year

~70% ~60%

~50% ~45%

~80% ~60%

~70% ~60 - 70%

Safety

Rare but serious side effects

Rare but serious side effects (? Less infections)

FDA Status

Psoriasis Psor Arth

Pediatric use for other indications

Yes

creases risk.6 Based on study data, treatment of psoriasis with biologic agents appears to reduce the risk of cardiovascular disease. In a retrospective longitudinal cohort study in Denmark over three years in 2,400 patients, biologic agents combined with MTX were associated with fewer events (death, myocardial infarction, stroke) compared to cyclosporine, retinoids, phototherapy, and topicals.7 A retrospective cohort study using data from the Kaiser Permanente health plan of 8,845 patients, found that use of TNF inhibitors for psoriasis was associated with a significant reduction in myocardial infarction risk and incident rate compared with treatment with topical agents.8 Overall, there is significant CV risk associated with severe skin disease (usually defined by having received systemic therapy for psoriasis). Current evidence suggests that treatment with conventional systemic or biologic therapy improves cardiovascular risk in psoriasis. Additionally, patients with severe psoriasis need intensive management of any other cardiovascular risk factors. Patients with psoriatic arthritis can have joint damage similar to rheumatoid arthritis. Biologic therapy prevents joint destruction in some patients. At this time, it is not well defined as to which patients with psoriatic arthritis would be spared joint damage. Standard therapy in this population is methotrexate and TNF inhibitor agents. Clinical criteria for starting a biologic include failure to respond to conventional therapy, adverse effects with conventional therapy, unstable disease, significant comorbidities, and psoriatic arthritis to possibly pre-

vent joint destruction. The annual cost of these agents is significant; it varies from $27,000/year for apremilast to over $70,000 for higher dose ustekinumab. Like phototherapy, there are access issues for biologic agents. Most plans require prior authorization for biologic therapy, but there are significant geographic variations. Blue Cross of California requires failure of phototherapy and two conventional systemic agents, along with 30 percent of body surface area affected for biologic approval. Because of superior efficacy and evidence for reduction of longterm complications, a better approach would be to change prior authorization criteria to require failure of one conventional systemic therapy. Managed care plans want information regarding cost-effectiveness of the psoriasis agents since systemic treatment options are burgeoning. Head-tohead efficacy trials have started to provide this data. Adalimumab and ustekinumab 45 mg and 90 mg each have similar efficacy.9 These biologics are more effective than etanercept and all conventional treatments. Head-to-head trials indicate the superiority of adalimumab and infliximab over methotrexate, the superiority of ustekinumab over etanercept, the nonsignificant superiority of cyclosporine over methotrexate, and the dose-dependent efficacy of etanercept and ustekinumab.9 Several additional biologic agents are under investigation. These include interleukin 17 blocking agents [brodalumab, ixekizumab, secukinumab], a janus kinase inhibitor already approved for rheumatoid arthritis [tofacitinib (Xeljanz®)] and p19 anti-

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

bodies (IL-23 blocker) [tildrakizumab, guselkumab]. Tofacitinib has efficacy similar to etanercept in the studies presented or published to date.

References 1. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349:2012-20. 2. Rapp SR, Feldman SR, Exum ML, et al. Psoriasis causes as much disability

Conclusion

as other major medical diseases. J Am Acad Dermatol. 1999;41:401-7.

Psoriasis can be a devastating disease, both physically and emotionally, but there is very effective treatment. Effective therapy is a control but not a cure. A choice between topical and systemic therapy should be based on the extent and impact of the disease on the individual. Biologic therapy has revolutionized psoriasis treatment, but there are still challenges in determining who would benefit most from the more expensive biologic therapy. Managed care could do several things related to medication coverage to improve psoriasis care, including eliminating phototherapy co-payments, having no restrictions or prior authorizations for phototherapy or conventional systemic therapy (methotrexate, cyclosporine, acitretin), and instituting a biologic prior authorization policy requiring only one prior systemic therapy failure.

3. National Psoriasis Foundation. How severe is my psoriasis? Available at https://www.psoriasis.org/about-psoriasis#severity. Accessed 7/1/2015. 4. Staidle JP, Dabade TS, Feldman SR. A pharmacoeconomic analysis of severe psoriasis therapy: a review of treatment choices and cost efficiency. Expert Opin Pharmacother. 2011;12(13):2041-54. 5. Kim N, Thrash B, Menter A. Comorbidities in psoriasis patients. Semin Cutan Med Surg. 2010;29(1):10-5. 6. Mehta NN, Azfar RS, Shin DB, et al. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J. 2010;31(8):1000-6. 7. Ahlehoff O, Skov L, Gislason G, et al. Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study. J Intern Med. 2013;273(2):197-204. 8. Wu JJ, Poon KY, Channual JC, Shen AY. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148(11):1244-50. 9. Schmitt J, Rosumeck S, Thomaschewski G, et al. Efficacy and safety of sys-

Robert E. Kalb, MD, is a Clinical Professor of Dermatology at SUNY

temic treatments for moderate-to-severe psoriasis: meta-analysis of randomized

at the Buffalo School of Medicine and the Buffalo Medical Group, P.C.

controlled trials. Br J Dermatol. 2014;170(2):274-303.

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www.namcp.org | Vol. 18, No. 4 | Journal of Managed Care Medicine 59

Whatâ&#x20AC;&#x2122;s keeping us from getting somewhere in pancreatic cancer? Merrimack is actively working to discover and develop new therapies that address the challenges in this disease. References: 1. Neesse A, Michl P, Frese KK, et al. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60(6):861-868. 2. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012;18(16):4266-4276. 3. Mielgo A, Schmid MC. Impact of tumour associated macrophages in pancreatic cancer. BMB Rep. 2013;46(3):131-138. 4. Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007; 67(19):9518-9527.

The Biology of Pancreatic Cancer is Complex1-4 Immunesuppressive cells

Extracellular Matrix

Stroma

Compressed Vasculature

Pancreatic Cancer Cells

Emerging Treatment Pathways in the Management of CINV Lee Schwartzberg 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 Control of CINV has improved significantly with better understanding of various neurotransmitters involved in the process and availability of medications targeting those neurotransmitters. The emetogenic potential for a given regimen and the individual patient’s risk factors must be considered when choosing a regimen. When highly and moderately emetogenic chemotherapy is given, good control requires medication combinations to cover both acute and delayed episodes. • • • •

Key Points Antiemetic guidelines are available for selecting effective regimens based on the emetogenic potential of a given chemotherapy regimen. Adherence with these guidelines improves response rates. Newer developments in this field include a combination product targeting two areas of CINV, the use of olanzapine, and the use of reduced dose dexamethasone to minimize adverse effects. Additional antiemetics and formulations of current agents are on the horizon.

CHEMOTHERAPY-INDUCED NAUSEA AND vomiting (CINV) is important to control. Without prevention, it is a major treatment-related adverse event experienced by 70% to 80% of cancer patients.1 Most patients cite CINV as the most feared side effect associated with chemotherapy, particularly before they have started chemotherapy.2 Controlling nausea or vomiting after it has occurred is much more difficult. Prevention is the key and there are very effective regimens. CINV has significant clinical impact. It is associated with the potential for treatment interruption/ abandonment and has negative implications on patient quality of life and activities of living. It also leads to increased use of health care resources.3,4 Physiologically, CINV can result in malnutrition, anorexia, weight loss, dehydration, and esophageal tears. There are patient or chemotherapy-related risk

factors for CINV. Patient factors which predispose to the development of CINV include low alcohol consumption (< 10 drinks/week), younger age (< 50), female gender, history of motion sickness, and poor control with prior chemotherapy. The patient-related factors may lead to the need for a higher level of antiemetic prophylaxis. The most important factor for determining whether CINV will occur is the emetogenic potential of the chemotherapy being given. Chemotherapy agents can be classified as having high, moderate, low, or minimal potential for inducing emesis (Exhibits 1).5 Examples of highly emetogenic chemotherapy (HEC) are cisplatin and doxorubicin. Because a moderate emetogenic chemotherapy (MEC) is defined as causing CINV in 30 to 80 percent of patients when no prophylaxis is given, some clinicians have begun dividing moder-

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Exhibit 1: Emetogenicity of IV Chemotherapy5

Emetogenic Classification

Incidence of Emesis

Index Agent

High

> 90%

Cisplatin

High-moderate

90%

Cyclophosphamide /Doxorubicin

Moderate

30% - 90%

Carboplatin, Oxaliplatin

Low

10% - 30%

5-Fluorouracil

Minimal

< 10%

Vincristine

ately emetogenic agents into high and low moderate categories. Examples of high moderate are the other platinum agents, carboplatin and oxaliplatin. Because combinations of chemotherapy agents are commonly given, the emetogenic potential of all the agents used have to be considered in choosing prophylactic therapy. Additionally, there are now many oral chemotherapy agents which can also cause CINV (Exhibit 2).5 There are four types of CINV. Acute CINV is nausea and vomiting that occurs within the first 24 hours after administration of chemotherapy. It occurs in 70 to 80 percent of patients given emetogenic chemotherapy without preventive medications. Delayed CINV starts more than 24 hours after administration of chemotherapy and typically lasts up to five days. Without prophylaxis, delayed CINV can occur in up to 80 percent of patients. Delayed CINV has been one of the unmet needs in managing CINV. Anticipatory CINV is a conditioned response that happens after a negative past experience with chemotherapy and has been reported in 33 percent of patients. Breakthrough CINV is that which occurs despite prophylaxis and requires rescue medications. The physiology of CINV has been extensively investigated. The emetic centers in the brain and gut are dependent on a host of neurotransmitters for this truly evolutionary protective response of ridding the body toxins. The understanding of the physiology of CINV has led to the use of three classes of agents - serotonin (5HT3) antagonists, corticosteroids, and neurokinin 1 (NK1) antagonists. The recommended regimens when HEC is given include all three. The 5HT3 antagonists include dolasetron (Anzemet ®), granisetron (Kytril®), ondansetron (Zofran®, generic), and palonosetron (Aloxi®) and provide coverage for acute CINV. Steroid receptors

are found in the brain and gut. Dexamethasone is the typical agent used in antiemetic regimens and provides efficacy for both acute and delayed CINV. Aprepitant (Emend®) is a selective high affinity antagonist of NK1 receptors used for delayed CINV. This agent is available as an oral dosage form (aprepitant) or intravenous (fosaprepitant). There are three major guidelines for managing CINV – National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and Multinational Association of Supportive Care in Cancer (MASCC).5-7 These guidelines have recommended regimens for each level of emetogenicity. Exhibit 3 provides the regimens for HEC regimens. For MEC, the recommended regimens are slightly different from the regimens for HEC. On the day of MEC administration, both a 5HT3 antagonist and dexamethasone are recommended. The addition of a NK-1 antagonist is recommended if the patient has risk factors for CINV or has failed previous therapy with two medication regimens.5 Olanzapine/palonosetron/dexamethasone is an alternative regimen.5 For moderately emetogenic chemotherapy, there are three options for therapy beyond day one. If a palonosetron or granisetron patch was used on day one as the serotonin antagonist, no further therapy needs to be given. The NCCN guidelines recommend either steroid monotherapy, a serotonin antagonist (other than palonosetron), aprepitant, or olanzapine be used for subsequent days of therapy.5 ASCO and MASCC recommend dexamethasone monotherapy for one to three days.6,7 For chemotherapy regimens with low emetic risk, the NCCN guidelines recommend dexamethasone, serotonin antagonist, metoclopramide, or prochlorperazine be started before chemotherapy and given daily during therapy.5 The ASCO guidelines rec-

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Exhibit 2: Emetogenicity of Oral Chemotherapy5

Emetogenic Classification

Incidence of Emesis

Index Agent

High

> 90%

Procarbazine

Moderate

30% - 90%

Temozolomide

Low

10% - 30%

Etoposide

Minimal

< 10%

Methotrexate

Exhibit 3: Highly Emetogenic Chemotherapy - Guideline Recommendations 5,6,7

Acute CINV

Delayed CINV (d 2-3)

Delayed CINV (d 4)

5HT3 + Dex + APR*

Dex + APR*

Dex

Palo/Net + Dex

Dex

Olanzapine + Palo + Dex

Olanzapine

ASCO

5HT3 + Dex + APR

Dex + APR*

Dex

MASCC§

5HT3 + Dex + APR

NCCN

Dex + APR*

* If fosaprepitant used, d 1 only; § Non-AC May also add Lorazepam and H2 blocker or proton pump inhibitor 5-HT3 = serotonin antagonist Dex = dexaethasone APR = aprepitant Palo/Net = palonosetron/netupitant Non-AC = non-anthracycline

ommend dexamethasone.6 For minimal emetogenic potential chemotherapy, all the guidelines agree that no prophylaxis needs to be given.5-7 In the NCCN guidelines, olanzapine is listed as an alternative to aprepitant and is substantially less expensive. This atypical antipsychotic blocks multiple neurotransmitters, including dopamine, serotonin, catecholamines, acetylcholine, and histamine. Olanzapine 10 mg once a day is given on days one to three instead of a NK-1 antagonist. Combined with a single dose of dexamethasone and a single dose of palonosetron, olanzapine was comparable to aprepitant at controlling acute and delayed CINV in patients receiving highly emetogenic chemotherapy. Olanzapine is useful for breakthrough CINV when someone has received a triple combination antiemetic regimen but still has problems. Netupitant, another NK-1 antagonist, was approved by the FDA in 2014 in a fixed-dose oral formulation with palonosetron (Akynzeo®). Netupitant has very high binding affinity for the NK-1 receptor

and a long half-life (90 h). The addition of netupitant to palonosetron/dexamethasone improves the overall no emesis rate by about 8 percent (80% vs 72%) in the face of HEC. It has also been studied for MEC, in which case, two pills are given before chemotherapy and nothing afterwards. This option is included in the NCCN guidelines. Like aprepitant, netupitant is a moderate inhibitor of CYP3A4. Rolapitant is an investigational, potent, selective, long-acting NK-1 receptor antagonist. The very long half-life (~180 hrs) of this agent suggests a single dose may be sufficient to prevent CINV during the entire five-day (0 to 120 hrs) at-risk period after chemotherapy. This agent has a reduced risk of drug interaction compared to the already approved NK-1 agents because it is not an inducer or inhibitor of CYP3A4. This agent will likely be FDA approved in the next year. Another area being studied is using less dexamethasone because of the adverse effects of corticosteroids. Two trials have shown that giving more

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than one day of dexamethasone does not provide additional benefits. Based on this data, clinicians are becoming comfortable only giving dexamethasone on day one. Although there are effective antiemetic regimens and evidence-based guidelines for prescribing these agents, clinicians do not always adhere with the guidelines. In a population-based study of patients in the Texas Cancer Registry-Medicare-linked database, overall adherence rate to NCCN recommendations when cisplatin was given was 78 percent for the 5HT3, 65 percent for dexamethasone, and aprepitant was barely used.10 For carboplatin (MEC), there was 83 percent adherence with 5HT3 prescribing, 66 percent for dexamethasone, and very minimal use for aprepitant. Giving antiemetic regimens based on guidelines has been shown to result in better response rates. In a prospective, observational, multicenter study in patients with solid tumors receiving HEC or MEC, two cohorts were identified: guideline-consistent and guideline-inconsistent. Guideline-consistent cases had higher rates of complete response [60% vs. 51%], no emesis [63% vs. 59% (NS)], no nausea [48% vs. 41% (NS)], and no CINV [43% vs. 34%].11. Importantly, this study points out that even with guideline-consistent antiemetic regimens, a significant portion of patients will still have problems with nausea and vomiting. One way to improve adherence with the antiemetic guidelines is to use computerized physician order entry. In a review of electronic medical records of 100 consecutive adult patients at a single tertiary care institution, there was a high degree of compliance to institutional guidelines in the delayed period (97%). This institution used automatic guideline-directed antiemetic order sets, but clinicians had the discretion to deviate from the recommendations. There was 100 percent compliance for patients receiving moderate or minimally emetogenic chemotherapy.12 Having a multidisciplinary team working on CINV prevention in cancer treatment settings is critical. There are multiple steps and providers who need to be involved. It is important to have an established protocol and that it is adhered with. Patients should be educated about CINV potential and the medication regimens that will be used before any chemotherapy is given. Clinicians need to take patient concerns and fears about CINV seriously. Some important patient education points include emetic risk of various chemotherapy agents, the stages of CINV, the institutionâ&#x20AC;&#x2122;s antiemetic protocols, potential adverse effects of antiemetics, and the need for reporting symptoms/ side effects promptly to a nurse or other oncology

team members. Conclusion

Although effective antiemetic regimens are available, control of CINV is not ideal. Improved adherence to CINV guidelines and improved patientclinician communication have the potential to decrease CINV rates. Several new medications have been approved or are in development that will hopefully continue to improve CINV prevention. Lee Schwartzberg, MD, FACP, is a Professor of Medicine and Chief of the Division of Hematology/Oncology at the University of Tennessee Health Science Center.

References 1. Jenns K. Importance of nausea. Cancer Nurs. 1994;17(6):488-93. 2. Hickok JT, Roscoe JA, Morrow GR, et al. Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics: a University of Rochester James P. Wilmot Cancer Center Community Clinical Oncology Program Study of 360 cancer patients treated in the community. Cancer. 2003;97(11):2880-6. 3. Wiser W, Berger A. Practical management of chemotherapy-induced nausea and vomiting. Oncology (Williston Park). 2005;19(5):637-45. 4. Bloechl-Daum B, Deuson RR, Mavros P, et al. Delayed nausea and vomiting continue to reduce patientsâ&#x20AC;&#x2122; quality of life after highly and moderately emetogenic

chemotherapy

despite

antiemetic

treatment.

Clin

Oncol.

2006;24(27):4472-8. 5. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 1.2015. Available at www.nccn.org. 6. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clinl Oncol. 2011;29:4189-98. 7. Multinational Association of Supportive Care in Cancer. MASCC/ESMO antiemetic guideline 2013. Available at www.mascc.org. 8. Aapro M, Fabi A, NolĂ¨ F, et al. Double-blind, randomised, controlled study of the efficacy and tolerability of palonosetron plus dexamethasone for 1 day with or without dexamethasone on days 2 and 3 in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy. Ann Oncol. 2010;21(5):1083-8. 9. Komatsu Y, Okita K, Yuki S, et al. Open-label, randomized, comparative, phase III study on effects of reducing steroid use in combination with Palonosetron. Cancer Sci. 2015;106(7):891-5. 10. Gomez DR, Liao KP, Giordano S, et al. Adherence to national guidelines for antiemesis prophylaxis in patients undergoing chemotherapy for lung cancer: a population-based study. Cancer. 2013;119(7):1428-36. 11. Aapro M, Molassiotis A, Dicato M, et al. The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol. 2012;23(8):1986-92. 12. Kadakia KC, Leal AD, Seisler DK, et al. Antiemetic prescribing practices using a computerized physician order entry system. Support Care Cancer. 2014;22(1):217-23.

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Metastatic Malignant Melanoma: Significant Treatment Advances Karl D. Lewis, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary The treatment of metastatic melanoma has undergone a paradigm shift from ineffective chemotherapy to immunotherapy and targeted therapy. Immunotherapy is producing durable responses in some patients. Targeted therapy, used in combinations to prevent resistance, is also improving overall survival rates. Additional treatments aimed at continuing to extend survival are under investigation. Key Points • Immunotherapy is an effective treatment for melanoma, resulting in durable re sponses in some patients. • The combination of immune therapies may further improve responses and survival. • Targeted therapy rapidly reduces tumor burden but tumor resistance develops quickly. • Combination targeted therapy can help delay the development of resistance and is the standard of care.

FOR THOSE LIVING IN THE UNITED STATES, the lifetime risk of developing cutaneous melanoma has risen from one in 1,500 in 1935 to one in 74 in 2,000. Currently, approximately 2.1 percent of men and women will be diagnosed with melanoma of the skin at some point during their lifetime.1 In Caucasians, the incidence of melanoma increased over 600 percent between 1950 and 2000.2 This is considered a true increase in incidence, not just an effect of increased awareness. Along with the increased melanoma incidence, there has been an increase in mortality of 165 percent during that same period. Patients may think that skin cancer is no big deal, but melanoma can lead to death. Although elderly Caucasian males have the highest risk of this disease, it does affect the young, and they do die from the disease. Melanomas arise from the melanocytes, which

give skin its pigmentation. The melanin produced by the melanocytes absorbs ultraviolet radiation (UV) from the sun. UVC, the shortest wavelength, is the most mutagenic followed by UVB and UBA, respectively. Like most other cancers, melanoma survival is related to the stage of disease at diagnosis.3 When the disease is localized to the skin (Stage 1 and 2), the survival is best. With Stage 3 disease, the median survival has historically been five years. Metastatic melanoma (Stage 4) has distant metastases and a historical median survival of nine to 12 months. Dacarbazine and high-dose interleukin 2 (IL-2) are both therapies that have been FDA approved for a number of years for metastatic melanoma. The response rate to dacarbazine is less than 10 percent in unselected Stage 4 melanoma patients; additionally, this agent does not improve survival. It has been

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

Exhibit 1: PD-1/PD-L1 Inhibiting Reagents in Clinical Development

Target PD-1

PD-L1

Agent

Class

Pidilizumab (CT‑011, CureTech-Teva)

IgG1 humanized antibody

AMP‑224 (Amplimmune-GSK)

Fc-PD-L2 fusion protein

BMS935559 (MDX‑1105, BMS-ONO)

IgG4 fully human antibody

MPDL3280A (Genentech)

IgG1 engineered fully human antibody

MEDI4736 (MedImmune, AZ)

IgG1 engineered fully human antibody

Exhibit 2: Adverse Effects of BRAF Inhibitors Vemurafenib

Dabrafenib

Squamous cell carcinoma

19%

10%

Photosensitivity

52%

Arthralgia

56%

19%

Elevated Liver Enzymes

26%

<10%

18% (Grade 30%, SAE 1%)

16% (Grade 33%, SAE 5%)

21%

Pyrexia Plantar-Palmar Hyperkeratoses

SAE = serious adverse effect

known for a long time that melanoma is recognized by the immune system. High-dose IL-2 stimulates the immune system to recognize and attack the melanoma. It results in a 16 percent response rate in highly selected Stage 4 melanoma patients but has no effect on median overall survival. Durable responses are seen in about 5 percent of patients, which is why it was approved by the FDA. Prior to the development of newer therapies, objective responses to therapy were very infrequent. The year 2011 was one of great importance in regard to the treatment of melanoma, with the approval of ipilimumab, an immune therapy, and vemurafenib, a targeted therapy for those patients who have proto-oncogene B-Raf (BRAF) mutations. These were the first agents to be shown to have a significant impact on survival. With these new agents, the course of the disease could be altered. To understand immune therapy for melanoma, it is helpful to review how the immune system

recognizes foreign antigens. T cells recognize antigens presented by the major histocompatibility complex on the surface of cancer cells through a T-cell receptor. This first signal is not enough to turn on a T-cell response, and a second signal delivered by the B7 costimulatory molecules B7-1 (or CD80) and B7-2 (or CD86) is required. Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is up-regulated shortly after T-cell activation and initiates negative regulation signaling on T cells (i.e., CTLA-4 can be considered the brakes on the immune system). When the costimulatory molecules bind to CD28, they provide activation signals; when they bind to CTLA-4, they provide inhibitory signals. The interaction between CTLA-4 and the costimulatory molecules happens primarily in the priming phase of a T-cell response within lymph nodes. Programmed death 1 (PD-1) inhibitory receptor is expressed by T cells during long-term antigen

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exposure and results in negative regulation on T cells during ligation with PD ligand 1 and 2 (PDL1, PD-L2), which are primarily expressed within inflamed tissues and the tumor microenvironment. The PD-1 interaction happens in the effector phase of a T-cell response in peripheral tissues. Its blockade with antibodies to PD-1 or PD-L1 results in the preferential activation of T cells with specificity for the cancer. Thus, CTLA-4, PD-1, and PD-L1 are targets of immune therapy. Ipilimumab (Yervoy®) is a monoclonal antibody that binds to CTLA-4 to keep T cells activated. In clinical trials, this agent does result in a 10 percent improvement in five-year survival rates and a fourmonth improvement in median overall survival. A durable immune response is seen in about 20 percent of patients. As with interleukin, it is not currently possible to predict which patients will have a durable response. Ipilimumab is given as four doses and commonly results in worsening of the disease initially. Significant toxicities occur because the brakes have been taken off the immune system so the immune system can attack normal tissues. Rash and colitis are the two problematic autoimmune adverse effects. Programmed death is the other immune target which prevents tumor cells from downregulating T cells. PD-1 antibodies are now approved for melanoma and other cancers. Nivolumab (Opdivo®) and pembrolizumab (Keytruda®) are FDA approved for use in adults to treat metastatic melanoma, following treatment with ipilimumab, or after treatment with ipilimumab and a BRAF inhibitor in patients who carry a BRAF mutation. These agents result in significant tumor load reductions with about 40 percent of patients having a durable response. These two agents result in fewer autoimmune responses than what is seen with ipilimumab. PD-L1 antibodies and additional PD-1 antibodies are under investigation (Exhibit 1). Overall, immunotherapy is an effective treatment for melanoma, resulting in durable responses in some patients, but toxicity can be great. Significant research is ongoing to better identify those patients who will respond. The PD-1 antibodies appear to result in larger numbers of patients benefiting compared with ipilimumab. The combination of agents (ipilimumab + PD-1 antibody) may result in greater benefit and is under investigation. Molecularly targeted therapies are different from immunotherapy. These agents target the cancer itself through blocking specific pathways required for cell growth. BRAF is a member of the Raf kinase family of growth signal transduction protein kinases. BRAF plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell

division and differentiation. BRAF gene mutations cause cancer by excessively signaling cells to grow. Approximately 50 percent of patients with melanoma have activating mutations in the BRAF gene.4 Two BRAF inhibitors, vemurafenib (Zelboraf ®) and dabrafenib (Tafinlar ®), have reached the market. Treatment with the two agents works rapidly to reduce tumor load but resistance develops. The tumor develops pathways around the BRAF blockade and resumes growing. The BRAF inhibitors improve median overall survival by about four months. Importantly, with these agents, brain metastases can be treated. The main difference between vemurafenib and dabrafenib is the toxicity profile (Exhibit 2). Dabrafenib leads to more grade 3 episodes of pyrexia but causes lower rates of other toxicities. Dose reductions because of adverse effects are needed in 38 percent of those who receive vemurafenib and 18 percent on dabrafenib. Six and 3 percent of patients have to discontinue vemurafenib and dabrafenib, respectively, because of adverse effects. Tumors have many ways of developing resistance to BRAF inhibition. One common pathway is to bypass BRAF and use mitogen-activated protein kinase (MEK) to continue growing. Trametinib (Mekinist ®), a MEK inhibitor, was approved in 2013 by the FDA as a single agent for treatment of BRAF mutation-positive metastatic melanoma but resistance develops within six months when monotherapy is used. The combination of a BRAF inhibitor with a MEK inhibitor can prevent the emergence of resistance and overcome acquired resistance.5,6 Combination therapy is now the standard of care in BRAF-mutated melanoma. The overall survival data with combination therapy are still being collected. Cobimetinib is an investigational MEK inhibitor being studied in combination with BRAF inhibitors. Overall, with targeted therapy there are very high response rates in select patients with the specific mutation, but resistance is a major problem. Unlike the immune therapies, a large number of patients will initially benefit, but the response will not be durable. Overcoming resistance for the long term is an area of active research. Costs of these agents are significant. Immunotherapy ranges from $7,500 for a pembrolizumab dose to $12,500 for an ipilimumab dose. Vemurafenib is $14,000 per month, dabrafenib $8,000 and trametinib $9,000. Conclusion

Major advances in the past few years have occurred for patients with advanced melanoma including immune and targeted therapy. For the first time, the natural

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

history of this disease can be altered. Research continues on how to further delay and/or prevent resistance and identifying which patients will respond to immunotherapy. Standard therapy for BRAF-mutated patients is a BRAF and MEK inhibitor combination. For those without the BRAF mutation or who fail targeted therapy, ipilimumab or PD-1 antibodies are the recommended therapy. Future therapies are likely to be ipilimumab in combination with PD-1 antibodies or PD-1 antibodies in combination with targeted combination therapy.

References. 1. SEER Stat Fact Sheets: Melanoma of the Skin. Available at www.seer.cancer. gov/statfacts/html/melan.html. 2. SEER Cancer Statistics Review 1950â&#x20AC;&#x201C;2000. Available at www.seer.cancer. gov/csr/1975_2000. 3. Balch CM, Buzaid AC, Soong S-J, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635-48. 4. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011, 29:1239-46. 5. Larkin J, Ascierto PA, DrĂŠno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-76.

Karl D. Lewis, MD, is an Assistant Professor of Medicine in the Division

6. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK in-

of Medical Oncology and is the Associate Director of the Melanoma

hibition versus BRAF inhibition alone in melanoma. N Engl J Med.

Research Clinics at the University of Colorado Denver (UCD).

2014;371(20):1877-88.

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Individualized Treatment Options in the Management of Metastatic 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 considered incurable, there are many treatment options for metastatic breast cancer. Despite significant advances in understanding the underlying biology of the disease and improved treatments, advances are needed in several areas, including overcoming treatment resistance, treating brain metastases, and management of triple-negative breast cancer. Key Points • Tumor biology and genetics dictate the choice of therapy. • Hormone-responsive disease is treated primarily with antiestrogen therapies. • HER2-positive disease is treated with targeted therapies in addition to chemo therapy. • Triple-negative disease is treated with chemotherapy. • PARP1 inhibitors are showing promise for BRCA+ disease.

ONCE METASTATIC, BREAST CANCER IS treatable, but not curable. Breast cancers have different molecular signatures depending on where they arise that dictate tumor biology and predict outcome, thus median overall survival (OS) varies depending on the type of cancer. OS for triplenegative breast cancer is 13 months and 36 to 48 months for human epidermal growth factor receptor 2 positive (HER2) and hormone receptor positive (HR+) breast cancer. There are approximately 40,000 deaths per year from breast cancer. Rather than treating all breast cancers as one disease, treatment is now selected based on tumor biology and genetics. Establishment of tumor biology, via a biopsy, upon recurrence is necessary due to the heterogeneity of disease, the discordance between primary and recurrent site biology, and the potential for treatment with targeted therapies. Sixty to 70 percent of breast cancer tumors will express hor-

mone receptors (either estrogen or progesterone), 20 to 25 percent will express HER2, and 15 percent will be triple-negative (no hormone receptors or HER2). Hormone receptor-positive metastatic breast cancer is treated primarily with anti-estrogen therapy. In pre and postmenopausal patients with estrogen receptor-positive disease, sequential endocrine agents are used until no longer effective. Treatment options include selective estrogen receptor modulators (tamoxifen), aromatase inhibitors [AI, anastrozole (Arimidex ®), letrozole (Femara®), exemestane (Aromasin®)]; or selective estrogen-receptor downregulators [fulvestrant (Faslodex ®)]. The choice of agent for metastatic disease will depend on the prior treatment the patient has received. In a continuing quest to improve treatment responses and delay the development of treatment resistance, a combination of various hormonal agents

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

Exhibit 1: EGFR 1 and (HER2) 2 Inhibition

Cetuximab

Trastuzumab

EGFR/HER

Lapatinib

Eriotinib

Signaling

Gefitinib

Cell Division/Tumor Growth

has been evaluated. Fulvestrant has been studied in combination with AIs. In the one trial of this combination, there was a statistically significant (1.5 months) difference in progression-free survival (PFS) and 6.4 months for OS; this study population was out of current context because 60 percent of the subjects had not previously received tamoxifen.1 The majority of contemporary patients with HR+ disease will have received tamoxifen earlier. A similarly designed European trial was negative.2 A trial in patients who progressed on an AI comparing fulvestrant and anastrozole, versus anastrozole alone, or exemestane alone, was also negative.3 Thus, the role of this combination is unclear. Combination therapy may be an option in the face of extensive disease at presentation or in patients who have not received tamoxifen previously. Many patients with HR+ disease will develop resistance to therapy over time and require a therapy switch because the disease will begin to regrow. One mechanism of endocrine resistance is aberrant signaling via the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway. mTOR is a pathway important for proliferation of HR+ breast cancer cells. mTOR can be activated independent of the PI3K pathway and mTOR can activate the ER receptor independent of estrogen.

Everolimus (Afinitor 速 ) is a potent oral inhibitor of mTOR. It is approved for advanced HR+, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. In the trial that led to FDA approval, everolimus treatment resulted in a prolongation in median PFS by four to six months, resulting in a 64 percent risk reduction of progression or death.4 The patients with the fewest mutations in the PI3k pathways benefited the most compared with those with multiple mutations. Adverse events are consistent with previous experience with everolimus, including stomatitis, fatigue, anemia, and hyperglycemia. A trial is ongoing evaluating fulvestrant alone versus fulvestrant and everolimus versus triple therapy with fulvestrant, everolimus and anastrozole. Selective cyclin D kinase 4/6 inhibitors are another class of targeted therapy under study for HR+ disease. Early data with one of these agents, PD 0332991, in combination with letrozole, showed a dramatic improvement in PFS (26.1 vs 7.5 months).5 In HER2+ breast cancer, the cancer cells have a gene mutation that makes an excess of the HER2 protein which drives cell growth. Trastuzumab (Herceptin速) was the first targeted therapy approved for this type of breast cancer. Trastuzumab, an EGFR-2 antibody, binds extracellularly to the tu-

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Exhibit 2: Current Therapy for Advanced HER2+ Breast Cancer11

Setting

Biologic Agent

Cytotoxic Agent

First-line

Pertuzumab + Trastuzumab

• •

Docetaxel Paclitaxel

• • • •

Paclitaxel + carboplatin Docetaxel Vinorelbine Capecitabine

•

Capecitabine

• •

Capecitabine Other

Trastuzumab

Previous trastuzumab

T-DM1 Lapatinib Lapatinib + trastuzumab Trastuzumab

mor cell (Exhibit 1). Adding trastuzumab to singlet or doublet chemotherapy provides an OS benefit. Resistance to trastuzumab occurs in a significant percentage of patients with HER2+ disease. When progression occurs on trastuzumab therapy, studies have shown that ongoing administration can provide a three to four month benefit.6 Current treatment options beyond trastuzumab include lapatinib, pertuzumab, and TDM-1. Other avenues of overcoming resistance are under study. Lapatinib (Tykerb® ) is a dual EGFR-1/HER2 inhibitor. It is a small-molecule oral tyrosine-kinase inhibitor. Lapatinib is able to bind intracellularly, thus offering a unique advantage in that it can inhibit the EGFR-1–, EGFR-2–, or HER2-receptor sites. It has been studied in combination with chemotherapy in those who have failed trastuzumab and provides a survival benefit.7 Trastuzumab and lapatinib can be combined for additional benefit (~4 months).8 The HER2 receptor can either dimerize with itself or an EGFR receptor leading to activation of downstream pathways and tumor cell growth. Pertuzumab (Perjeta®) targets the extracellular dimerization domain of HER2 and blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. Pertuzumab and trastuzumab can be combined for a more comprehensive HER2 blockade and to prevent resistance. In combination with trastuzumab and docetaxel as first-line therapy in HER2+ disease, the addition of pertuzumab improved PFS (6.1 months) and preliminary median OS. 9,10 Median

overall survival had not yet been reached for the pertuzumab group at the time of publication. Triple combination therapy of pertuzumab, trastuzumab, and taxane chemotherapy is the recommended firstline therapy for HER2+ metastatic disease.11 T-DM1 (Kadcyla®) is a combination of trastuzumab and emtansine (DM1) which is a derivative of maytansine, a very effective but highly toxic chemotherapy. Combined with trastuzumab, the emtansine enters the HER2+ cell only. T-DM1 administration results in significant improvement in OS compared with capecitabine/lapatinib.12 This agent is the standard of care for patients who progressed through first-line HER2 targeting therapy.11 T-DM1 has been studied in combination with pertuzumab but the results have not yet been published. Exhibit 2 presents the treatment options for HER2+ MBC.11 One area of HER2+ disease treatment that is lacking is treating brain metastases. It is common for this disease to recur with brain metastases. Current HER2-targeted therapies have limited potential to cross the blood-brain barrier. Some tumors do not have hormone or HER2 receptors and are thus termed triple negative breast cancer (TNBC). Because no validated targets have been identified for the majority of cases of TNBC, chemotherapy is still the standard of care. Single sequential chemotherapy is acceptable with combination therapy reserved for heavy visceral load or rapid progression. Much research is ongoing into identifying subsets of TNBC which may respond to specific therapies

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The majority of breast cancer gene mutation one and two (BRCA-1, BRCA-2) related breast cancers are triple-negative/basal-like subtype. Targeted treatments are under study for BRCA-mutated disease. When DNA is damaged by environmental causes or carcinogens, cells can repair themselves through two major mechanisms through homologous recombination through BRCA or by base excision repair through poly (ADP-ribose) polymerase (PARP). When a patient is treated with chemotherapy, DNA damage is the desired outcome of therapy because it leads to cell death but PARP or BRCA can “fix” the effects of chemotherapy. Because BRCA is nonfunctional in BRCA mutation disease, these tumors rely on PARP1 to repair DNA damage. PARP inhibitors that circumvent DNA repair after chemotherapy have shown activity in BRCA+ disease. PARP inhibitors in combination with platinum agents are being studied in BRCA1-mutated disease and appear to provide significant benefits.13-16 As with HER2+ disease, brain metastases occur in up to 30 percent of those with TNBC and are difficult to treat. One last agent to discuss is eribulin (Halaven®), a chemotherapy agent. This agent was FDA approved in 2010 for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. This agent is a synthetic form of a chemotherapeutically active compound derived from the sea sponge Halichondria okadai and is a microtubule inhibitor. Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade. It provides a modest survival benefit (2.5 months).17 Care for metastatic breast cancer is headed toward true personalized medicine. Many different mutations can be identified when breast cancer tissue is examined, and there are therapies targeting many different mutations. The question that needs to be answered is just because there is a therapy that targets a mutation will that treatment lead to a patient benefit. A benefit may not occur because of toxicity, medication ineffectiveness, additional mutations, or lack of impact in blocking/altering that particular mutation. Further delineation of molecular genetics of both primary and metastatic breast cancer sites are needed, inclusive of mutations, amplifications, and epigenetic changes. Participation in clinical trials should be available for all patients in order to continue the advances in the treatment of metastatic breast cancer.

Conclusion

Metastatic breast cancer is still incurable, but longterm disease control is feasible, with good quality of life. Both progression-free and overall survival have improved over the years with the availability of newer agents. Establishment of tumor biology, via a biopsy, upon recurrence is necessary due to the heterogeneity of disease, the discordance between primary and recurrent site biology, and the potential for treatment with targeted therapies. Targeted therapies are benefiting those with HR+ and HER2+ disease and are on the horizon for TNBC. George Somlo, MD, is a Professor in the Departments of Medical Oncology and Therapeutics Research and Hematology and Hematopoietic Cell Transplantation at the City of Hope Comprehensive Cancer Center in Duarte, CA.

References 1. Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367(5):435-44. 2. Bergh J, Jönsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30(16):1919-25. 3. Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013;14(10):989-98. 4. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-9. 5. Rocca A, Farolfi A, Bravaccini S, et al. Palbociclib (PD 0332991) : targeting the cell cycle machinery in breast cancer. Expert Opin Pharmacother. 2014;15(3):407-20. 6. von Minckwitz G, Schwedler K, Schmidt M, et al. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011;47(15):2273-81. 7. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-43. 8. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30(21):2585-92. 9. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-19. 10. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14(6):461-71. 11. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 3.2015. Available at www.nccn.org. 12. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-91. 13. Daemen A, Wolf DM, Korkola JE, et al. Cross-platform pathway-based

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analysis identifies markers of response to the PARP inhibitor olaparib. Breast

2013;14(9):882-92.

Cancer Res Treat. 2012;135(2):505-17.

16. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with

14. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase

recurrent high-grade serous or poorly differentiated ovarian carcinoma or tri-

inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced

ple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised

breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235-44.

study. Lancet Oncol. 2011;12(9):852-61.

15. Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) poly-

17. Cortes J, Oâ&#x20AC;&#x2122;Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treat-

merase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients

ment of physicianâ&#x20AC;&#x2122;s choice in patients with metastatic breast cancer (EMBRACE):

with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol.

a phase 3 open-label randomised study. Lancet. 2011;377(9769):914-23.

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Patients, Science, and Innovation are the foundation of everything we do. At Celgene, we believe in an unwavering commitment to medical innovation, from discovery to development. Our passion is relentlessâ&#x20AC;&#x201D;and we are just getting started.

ÂŠ 2015 Celgene Corporation

07/15

US-CELG150237b

The Next Generation of Wound Care

In a world where cost and waste reduction are critical, choose Grafix for fast wound closure Actual sizes shown 5 cm x 5 cm

4 cm x 4 cm

3 cm x 4 cm

2 cm x 3 cm

1.5 cm x 2 cm 14 mm

• Available in multiple sizes, helping to reduce waste and cost • Optimal wound coverage from initial application through wound closure • Flexible, conforming, and easy-to-use without the need for sutures Randomized multi-center trial comparing Grafix vs conventional care in 97 patients with diabetic foot ulcers1

• Grafix demonstrated significantly higher wound closure compared to control (62% vs 21%, p=0.0001) • Median time to closure: 42 days with Grafix vs 70 days with control (p=0.019) • 50% fewer infections with Grafix vs control (18% vs 36%, p=0.044)

n=97

p=0.0001

a Relative

improvement 3x greater than other wound therapies that have been used in multi-center randomized controlled trials Control (standard care) included surgical debridement, off-loading, and non-adherent dressings.

G15140

Reference: 1. Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, et al. The efficacy and safety of Grafix for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 2014:11(5):554-560.

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