AHDB Oct 2011 Vol4 No 6

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ SEPTEMBER/OCTOBER 2011

VOLUME 4, NUMBER 6

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

EDITORIAL

From Asheville to Hickory: transforming our “sick care” system into a true “health care” model Daniel G. Garrett, RPh, MS, FASHP

CLINICAL

The Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project model ™

Barry A. Bunting, PharmD, DSNAP; Grover Lee, PharmD, BCMCM; Grant Knowles, PharmD; Christine Lee, PharmD, BCPS, CLS; Paul Allen, PhD, MBA

Stakeholder Perspective by Rick Miller BUSINESS

Health resource utilization and direct costs associated with angina for patients with coronary artery disease in a US managed care setting Judy Kempf, PhD; Erin Buysman, MS; Diana Brixner, RPh, PhD

Stakeholder Perspective by Michael F. Murphy, MD, PhD

Review of strategies to enhance outcomes for patients with type 2 diabetes: payers’ perspective Rhonda Greenapple, MSPH

Stakeholder Perspective by Charles E. Collins, Jr, MS, MBA PERSPECTIVES

Adapting to market changes: beyond healthcare reform F. Randy Vogenberg, PhD, RPh

The era of personalized medicine in oncology: novel biomarkers ushering in new approaches to cancer therapy Steve Stricker, PharmD, MS, BCOP

©2011 Engage Healthcare Communications, LLC www.AHDBonline.com

DEXILANT WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

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

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

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

24

HRS

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

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

Conclusions of comparative efficacy cannot be drawn from this information.

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

Average patient costs for DEXILANT are less than all other branded Rx PPIs†‡§ †Based on average out-of-pocket costs for commercially insured patients.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Nonclinical Toxicology], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Advise the patient to follow the dosing instructions in the Patient Information Leaflet and inform the patient that: • DEXILANT is available as a delayed release capsule.

• DEXILANT may be taken without regard to food.

• DEXILANT should be swallowed whole.

• Alternatively, DEXILANT capsules can be administered as follows: – Open capsule; – Sprinkle intact granules on one tablespoon of applesauce; – Swallow immediately. Granules should not be chewed.

– Do not store for later use.

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

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

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

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

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

EDITORIAL BOARD

CLINICAL EDITOR

HEALTH INFORMATION TECHNOLOGY

PHARMACY BENEFIT DESIGN

Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

GOVERNMENT EDITOR

Victor J. Strecher, PhD, MPH Professor and Director, Center for Health Communications Research University of Michigan Schools of Public Health and Medicine, Ann Arbor Founder and Chief Visionary Officer HealthMedia, Johnson & Johnson

William J. Cardarelli, PharmD Director of Pharmacy, Atrius Health Harvard Vanguard Medical Associates

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Senior Counselor, Fleishman-Hillard Washington, DC ACTUARY

David Williams Milliman Health Consultant Windsor, CT AGING AND WELLNESS

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

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University Immediate Past President, ACCC Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems CARDIOLOGY RESEARCH

HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director, Outcomes Research Center, University of Utah College of Pharmacy, Salt Lake City Gordon M. Cummins, MS Director, IntegriChain Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL HEALTH & VALUE PROMOTION

Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Milwaukee

Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York

Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL

EMPLOYERS

MANAGED MARKETS

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharon, MA

MANAGED CARE & GOVERNMENT AFFAIRS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Branded Specialty Pharmacy Programs, US Specialty Customers, Pfizer, Specialty Care Business Unit, PA Charles E. Collins, Jr, MS, MBA Vice President, Managed Markets Strategy Fusion Medical Communications PATIENT ADVOCACY

William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University, Spokane, WA

ENDOCRINOLOGY RESEARCH

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ

PERSONALIZED MEDICINE

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation

EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Vice President, Research Operations Center for Health Research Geisinger Health System, Danville, PA

Vol 4, No 6

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PHARMACOECONOMICS

Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

September/October 2011

www.AHDBonline.com

Leslie S. Fish, PharmD Senior Director of Pharmacy Services Fallon Community Health Plan, MA Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals, Chadds Ford, PA Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Associate Scientist, RAND Health Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality & biomedical research J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago RESEARCH & DEVELOPMENT

Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, HarvardMIT Division of Health Sciences and Technology, Cambridge, MA SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

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American Health & Drug Benefits

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SEPTEMBER/OCTOBER 2011

VOLUME 4, NUMBER 6

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS EDITORIAL

336 From Asheville to Hickory: Transforming Our “Sick Care” System into a True “Health Care” Model Daniel G. Garrett, RPh, MS, FASHP CLINICAL

343 The Hickory Project: Controlling Healthcare Costs and Improving Outcomes for Diabetes Using the Asheville Project Model Barry A. Bunting, PharmD, DSNAP; Grover Lee, PharmD, BCMCM; Grant Knowles, PharmD; Christine Lee, PharmD, BCPS, CLS; Paul Allen, PhD, MBA 350 Stakeholder Perspective by Rick Miller BUSINESS

353 Health Resource Utilization and Direct Costs Associated with Angina for Patients with Coronary Artery Disease in a US Managed Care Setting Judy Kempf, PhD; Erin Buysman, MS; Diana Brixner, RPh, PhD

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Director of Client Services Mark Timko 732-992-1897 Associate Editors Brett Kaplan Lara J. Lorton 732-992-1892 Editorial Assistant Jessica A. Smith Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Founding Editor-in-Chief Robert E. Henry

361 Stakeholder Perspective by Michael F. Murphy, MD, PhD

Mission Statement 377 Review of Strategies to Enhance Outcomes for Patients with Type 2 Diabetes: Payers’ Perspective Rhonda Greenapple, MSPH 386 Stakeholder Perspective by Charles E. Collins, Jr, MS, MBA Continued on page 334 American Health & Drug Benefits is included in the following indexing and database services: EMBASE/Elsevier Bibliographic Database SCOPUS/Elsevier Bibliographic Database Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases Standard Periodical Directory MEMBER: Committee on Publication Ethics (COPE) BPA Worldwide membership applied for August 2010.

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www.AHDBonline.com

American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare.

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

Contact Information: For subscription information and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1892 F: 732-992-1881

September/October 2011

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Vol 4, No 6

moving millimeters

See how many millimeters you can move with EDARBI EDARBI 80 mg was statistically superior to DIOVAN® 320 mg and BENICAR® 40 mg in reducing 24-hr mean ambulatory and clinic SBP1 REDUCTIONS IN 24-HR MEAN AMBULATORY SBP AT WEEK 61,2 Mean ambulatory baseline: Study 1=144.9 mm Hg

▼ Similar results were observed across two other comparator studies: Study 2 vs BENICAR 40 mg and Study 3 vs DIOVAN 320 mg

STUDY 1

▼ Clinic SBP differences between EDARBI and active comparators were consistent with mean ambulatory results Study 1 Design: A 6-week, randomized, double-blind, placebo-controlled, forced-titration study in patients (N = 1,291) with clinic SBP ≥150 mm Hg and ≤180 mm Hg and 24-hr mean SBP ≥130 mm Hg and ≤170 mm Hg. The primary endpoint was change in 24-hr mean ambulatory SBP. Placebo lowered 24-hr mean ambulatory SBP by 0.3 mm Hg. Data shown are placebo corrected.

IMPORTANT SAFETY INFORMATION WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue EDARBI as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ▼ Avoid fetal or neonatal exposure.

DIOVAN 320 mg

-10.0 mm Hg BENICAR 40 mg

-11.7 mm Hg EDARBI 80 mg

-14.3 mm Hg P<0.001 vs DIOVAN 320 mg P=0.009 vs BENICAR 40 mg References: 1. EDARBI Prescribing Information. 2. White WB, Weber MA, Sica D, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension.

Hypertension. 2011;57:413-420.

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

For further information, please see adjacent Brief Summary of Prescribing Information.

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

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

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

Trademarks are the property of their respective owners. ©2011 Takeda Pharmaceuticals North America, Inc. All rights reserved. LXA-00482 09/11

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

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

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

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

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

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

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

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

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

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

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

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

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

If oligohydramnios is observed, Edarbi should be discontinued unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

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

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

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

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

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

Similar results may be anticipated in patients treated with Edarbi.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PK

Fold Change and 90% CI

Recommendation

AGE

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

No dose adjustment

Severe/Normal

Cmax AUC

No dose adjustment

ESRD/Normal

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

No dose adjustment

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

HEPATIC IMPAIRMENT

Severe/Normal

NO EXPERIENCE NO EXPERIENCE

PEDIATRIC

0.5

1.0

1.5

2.0

Change relative to reference

2.5

3.0

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

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

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

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

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

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

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

SEPTEMBER/OCTOBER 2011

VOLUME 4, NUMBER 6

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

PERSPECTIVES

368 Adapting to Market Changes: Beyond Healthcare Reform F. Randy Vogenberg, PhD, RPh 387 The Era of Personalized Medicine in Oncology: Novel Biomarkers Ushering in New Approaches to Cancer Therapy Steve Stricker, PharmD, MS, BCOP 396 PhRMA President Calls Obama Policy ‘Wrongheaded’: Curtailing Patients Will Cripple R&D on Pharmaceuticals, Industry Warns Paige Winfield Cunningham

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Printed in the United States of America.

DEPARTMENTS

INDUSTRY TRENDS 403 Building Your Automated Bundled Payment for an Episode-of-Care Initiative Douglas Moeller, MD DIABETES TYPE 2 PIPELINE 410 Drugs in Phase 3 Clinical Trials for Type 2 Diabetes ADA 2011 HIGHLIGHTS 412 Cutting-Edge Data Presented at ADA 2011 Highlight the Diabetes–Cardiovascular Disease Link

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EDITORIAL

From Asheville to Hickory: Transforming Our “Sick Care” System into a True “Health Care” Model Daniel G. Garrett, RPh, MS, FASHP Vice President, Health Care Programs, American Health Care

I

t is only 75 miles from Asheville, NC, to Hickory, NC. The article by Bunting and colleagues, titled “The Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project model” and appearing in this issue of the journal,1 offers a new perspective on the journey from Asheville to Hickory and its significance in transforming our current “sick care” system into a true healthcare system.

The concept of what is now known as the Asheville Project was developed by a think-tank group of North Carolina pharmacy leaders in Chapel Hill between 1994 and 1996, to demonstrate that community pharmacists could improve clinical outcomes and lower healthcare costs for people with chronic conditions.2 The Asheville Project started with 1 self-insured employer—the city of Asheville—and 47 patients with diabetes participating in a voluntary program working with pharmacists in the Asheville community. Today in Asheville, there are 9 employers offering that program as an employee benefit and more than 1800 people are participating in programs for those with diabetes, high blood pressure, dyslipidemia, asthma, and depression. A multidisciplinary team of care managers is working collaboratively to help patients self-manage their chronic conditions.3 As chronicled in the current Hickory Project article,1 the Asheville Project model has been replicated at many sites across the country with varying degrees of success.

In 2005, I pondered, “Beyond the Asheville Project: are we in the middle of a tipping point?”4 The Asheville model has been discussed in the Washington Post,5 is taught in most pharmacy colleges, and is touted by leaders of national and state healthcare business coalitions.6 We have had 3 visits to Asheville by groups from Japan, and the program was featured on NBC’s Nightly News.7 Despite this notoriety and widespread replication in more than 35 states from Charleston, SC, to Honolulu, HI, the Asheville Project has yet to be readily accepted and eagerly adopted. I would suggest that we are still waiting for the tipping point.

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What is delaying the acceptance of the Asheville model? Thomas Kuhn postulated that it takes 17 years from the discovery and announcement of new scientific knowledge to a paradigm shift and widespread implementation.8 Based on this logic, the first Asheville Project scientific articles were published in 2003, meaning we will be waiting until 2020 for the model to be common practice. Is it just a matter of time, or are there barriers that can be overcome? What strategies are needed to achieve further expansion of the Asheville model that can be learned from the Hickory Project?

Barriers to Acceptance of the Asheville Model Solid data on return on investment for payer decision makers are lacking. No studies, other than the Asheville Project and now the Hickory Project, have published data as compelling or that demonstrate savings approaching those found in these 2 projects. In the patient self-management program, which included 5 sites based on the Asheville model, the savings were $918 per patient per year (PPPY), and the savings in the 10 sites in the Diabetes Ten City Challenge were $1079 PPPY. These savings were in comparison with the projected increased cost trend, not in comparison with baseline costs.9,10 In both studies, not enough data were captured. If more data had been captured, the results would have likely been better.

Medical claims administrators’ and pharmacy benefit managers’ reluctance to share data. In my experience, the greatest barrier to capturing meaningful data to identify cost-savings is the need to obtain data from third-party administrators and pharmacy benefit managers who are unwilling to share the data. This is especially frustrating for self-insured payers, who ultimately own these data, and all that is required is a standard paid claims report in a format that can be exported.

Enrollment and engagement of participants. Enrolling potential participants is challenging. Even with incentives for waived or reduced copays for conditionrelated medications, enrollment is generally less than

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50% in the initial year of a program. Much of this is dependent on the culture of trust with the employer. Furthermore, once enrolled, getting people truly engaged in setting personal health goals and in self-management of their conditions is often difficult.

Healthcare system territories and professional turf.

A recent article by Rideout summarizes the challenges we face in overcoming inefficiencies of the current US healthcare system.11 Although accountable care organizations, patient-centered medical homes, and value-based benefit design are currently being promoted, the system remains provider-centric, and competition between healthcare professionals for payment still prevails.

Health benefit consultants and brokers still selling the current system. The US healthcare system is our most change-averse industry,12 and although the Affordable Care Act has passed, it is now being challenged and its future is uncertain. Economic incentives are now in place to keep the current system intact, and until consultants and brokers buy into new models such as the Asheville or Hickory Projects, such programs may not get the consideration they deserve.

Investment in current on-site clinic and health and wellness programs. The health and wellness industry is expected to reach $600 billion in 2011, and growth for products and services in this area is one of the few bright spots in the economic downturn.13 This should be sufficient to have employers and payers amenable to the Asheville model and the Hickory Project. But because payers have made commitments to invest in wellness programs and on-site clinics, they do not think they need an intensive program for the 15% of their health plan members with chronic conditions who are driving 85% of the sick care costs.

Lessons Learned from the Hickory Project: Strategies for Success Data systems should consistently collect measures and report meaningful results. A distinct advantage of the Hickory Project over the original Asheville Project was the provision of a web-based virtual medical record that incorporated guidelines for care, medical claims, and pharmacy claims. This system was developed using the experience of the Asheville Project care managers and is now used by Mission Health System hospitals in Asheville to enhance data collection and consistency of care for current participants in the Asheville model.14 Having a system such as the one used in the Hickory Project is critical for ensuring standardized care in multiple sites and for generation of reliable reports for decision makers to demonstrate the long-term cost-savings and program sustainability.

Payers must insist the data are theirs and demand

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to share them freely. In both the Asheville and Hickory projects, employers require their medical and pharmacy claims administrators to supply the necessary data for ongoing patient care and outcomes analysis. If a selfinsured payerâ&#x20AC;&#x2122;s claims administrator will not or cannot share the data in a usable format, the payer needs to change to an administrator who will do this, and requests for proposals for future claims administration need to establish the data-sharing expectations.

Having the patient actively participate in a collaborative support system in which financial incentives are aligned for patients, providers, and payers is what turns the system from a sick care model into a true healthcare model.

Provide incentives to drive high-enrollment rates and care management that engages participants in self-management. In the Hickory Project, once the initial financial savings were apparent to the employer, and it was noted that enrollment was not as high as desired, medical benefit plan contribution options were identified. After legal review and approval from management, medical benefits were structured to drive enrollment, and participation increased significantly.

Patient engagement has been enhanced in the Asheville and Hickory Projects, where care managers received training in intrinsic coaching.15 This has resulted in the participants accessing their â&#x20AC;&#x153;best thinkingâ&#x20AC;? for self-management of their conditions through goals they set for themselves, which results in improved personal outcomes.

Involving the patient as the focus of the system, promoting stakeholder collaboration, and realigning payment structure. Crucial to the Hickory Project results were the lessons learned from the Asheville Project and adhering to the principles of that care model.16 Having the patient actively participate in a collaborative support system in which financial incentives are aligned for patients, providers, and payers is what turns the system from a sick care model into a true healthcare model.

Cultivating consultants and brokers as champions of health. Key to the Hickory Project was that the health benefit consultant was also a consultant to employers who participated in the Asheville Project. A small group of consultants/brokers is now comprehending how the model works, and they are beginning to present the model as a transformative system.17-19 Having a group of champions from this area is key to communicating the

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model to payers who are inundated by proposals with differing degrees of success or failure.

Understanding the full continuum of employee health benefits and how they work together. The employers in Asheville and Hickory who implemented the program had existing wellness and health clinic programs, and they knew their programs were not making an impact on the rising costs of chronic diseases.

Through the Asheville and Hickory projects, they learned how to get the best from both efforts and create a continuum of benefits to support all members of their health plan, regardless of their current state of health.

Key to the Hickory Project was that the health benefit consultant was also a consultant to employers who participated in the Asheville Project.

Transforming the Care Continuum The model is beginning to gain renewed momentum.

At the recent Centers for Disease Control and Prevention’s (CDC’s) Heart Disease and Stroke Prevention Practitioners Training, we presented a workshop that featured the Asheville model and how it is being replicated.20 It included presentations on the Maryland P3 Program, the South Carolina Department of Health and Environmental Control Stroke Belt Project, an overview of replication across the country, and data from the Hickory Project.20 The discussion stimulated interest from many states on how the Asheville model improves chronic care management and ultimately reduces the rate of heart attacks and strokes.

The CDC’s interest in spreading the model is timely: the CDC’s Million Hearts campaign was launched the same week.21 The meeting included a dialogue on how communities replicating the Asheville model will contribute to the national goal of preventing 1 million heart attacks and strokes in the next 5 years.

The data from the Hickory Project represent a milestone in transforming the sick care system into a healthcare system. Having these data in hand, and the

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lessons learned, will shorten the journey to implementing a chronic health management project named for your community. ■

References 1. Bunting BA, Lee G, Knowles G, et al. The Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project model. Am Health Drug Benefits. 2011;4:343-350.

2. Garrett DG. The answer to how is when: the genesis of the Asheville Project.

Pharm Times. 1998;suppl:4-5.

3. Kiser S. Where are we at and where are we going. Presented at the Asheville Project and Beyond: A Next Generation of Health and Wellness Initiatives; January 14-16, 2009; Asheville, NC. 4. Garrett DG. Beyond the Asheville Project: are we in the middle of a tipping point?

Pharm Times. 2005;suppl:5-6.

5. Connolly C. In N.C. improving worker health—and cutting costs. Washington Post.

August 20, 2002:A01. www.pharmacist.com/AM/Template.cfm?Section=Asheville_ Project&Template=/CM/ContentDisplay.cfm&ContentID=21294. Accessed September 30, 2011.

6. American Pharmacists Association. National Business Coalition on Health and APhA Foundation partner to improve management of chronic health care conditions. May 8, 2007. www.pharmacist.com/AM/Template.cfm?Section=News_ Releases2&template=/CM/ContentDisplay.cfm&ContentID=12237. Accessed September 30, 2011.

7. NBC Nightly News. The Asheville Project and Diabetes Ten City Challenge.

January 21, 2007. www.theashevilleproject.net/in_the_news. Accessed September 30, 2011.

8. Kuhn TS. The Structure of Scientific Revolutions. 1st ed. Chicago, IL: University of Chicago Press; 1962.

9. Garrett DG, Bluml BM. Patient self-management program for diabetes: first-year clinical, humanistic, and economic outcomes. J Am Pharm Assoc (2003). 2005;45: 130-137.

10. Fera T, Bluml BM, Ellis WM. Diabetes Ten City Challenge: final economic and clinical results. J Am Pharm Assoc (2003). 2009;49:383-391.

11. Rideout J. Systematic health management: the time has come to do the right thing for each person. Am Health Drug Benefits. 2011;4:152-154.

12. Christensen CM, Bohmer R, Kenagy J. Will disruptive innovations cure health care? Harv Bus Rev. 2000;78:102-112, 199.

13. JD Ford and Company. Resilience and continued growth expected in global health & wellness industry. Global Health & Wellness: State of the Industry. 2009. www.jdford.com/pdfs/JDF_Comp_Health_Wellness_09.pdf. Accessed September 30, 2011.

14. Little F. The Asheville Project: A Proven Model to Improve Outcomes and Reduce Costs. Presented at the Corporate Benefits Summit; March 7, 2011; Amelia Island, FL. 15. Totally Coached, Inc. Articles. www.totallycoached.com/en/library/articles/.

Accessed September 30, 2011.

16. Bunting BA, Garrett DG, Martin JP, et al. What it takes to replicate the Asheville Project. Pharm Times. 2005;suppl:7-9.

17. Miller R, Garrett DG. Making the case for health care instead of sick care: the Hickory Project case study. Presented at the Pharm Benefit Management Institute Conference; March 5, 2009; Phoenix, AZ. 18. Cohn S. Why implement the Asheville Model? Pharm Times. 2005;suppl:17-18.

19. Dail JA. Employer perspective. Presented at the Asheville Project and Beyond: A Next Generation of Health and Wellness Initiatives; January 15, 2009; Asheville, NC. 20. Mukhtar Q, Ntatin A, Rush C, et al. Building connections for health care systems and communities through collaboration with community pharmacists and community health workers (CHWs). Presented at the Centers for Disease Control and Prevention’s Disease and Stroke Prevention Practitioners Training meeting; September 15, 2011; Decatur, GA. 21. Centers for Disease Control and Prevention, Centers for Medicare & Medicaid Services. Million Hearts. http://millionhearts.hhs.gov. Accessed October 4, 2011.

www.AHDBonline.com

September/October 2011

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Vol 4, No 6

WELCHOL KNOCKS DOWN ®

TWO WITH ONE

FDA-approved, in addition to diet and exercise, for use in adults with T2DM* and primary hyperlipidemia1 Lowers both A1C & LDL-C, without systemic absorption Flexible dosing options: Oral Suspension and Tablet formulations Once-daily dosing

*Type 2 diabetes mellitus.

Welchol for Oral Suspension can now be mixed with fruit juices and diet soft drinks, in addition to water

IMPORTANT INFORMATION ABOUT WELCHOL (colesevelam HCI) Indications Welchol is indicated as an adjunct to diet and exercise to: – reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethylglutaryl-coenzyme (HMG CoA) reductase inhibitor (statin) – improve glycemic control in adults with type 2 diabetes mellitus Important Limitations of Use – Welchol should not be used for glycemic control in type 1 diabetes or for the treatment of diabetic ketoacidosis – Welchol has not been studied in type 2 diabetes as monotherapy or in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones – Welchol has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias Contraindications Welchol is contraindicated in individuals with a history of bowel obstruction, those with serum triglyceride (TG) concentrations of >500 mg/dL, or with a history of hypertriglyceridemia-induced pancreatitis.

Warnings and Precautions The effect of Welchol on cardiovascular morbidity and mortality has not been determined.

Welchol can increase serum TG concentrations particularly when used in combination with sulfonylureas or insulin.

Caution should be exercised when treating patients with TG levels >300 mg/dL.

Welchol may decrease the absorption of fat-soluble vitamins A, D, E, and K. Patients on vitamin supplements should take their vitamins at least 4 hours prior to Welchol. Caution should be exercised when treating patients with a susceptibility to vitamin K or fat-soluble vitamin deficiencies.

Caution should also be exercised when treating patients with gastroparesis, gastrointestinal motility disorders, a history of major gastrointestinal tract surgery, and when treating patients with dysphagia and swallowing disorders.

Welchol reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam (cyclosporine, glyburide, levothyroxine, and oral contraceptives [ethinyl estradiol, norethindrone]) should be administered at least 4 hours prior to Welchol. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol.

Alternatively, the physician should monitor drug levels of the co-administered drug.

To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form.

Due to tablet size, Welchol for Oral Suspension is recommended for, but not limited to, any patient who has difficulty swallowing tablets.

Phenylketonurics: Welchol for Oral Suspension contains 48 mg phenylalanine per 3.75 gram dose.

Adverse Reactions In clinical trials, the adverse reactions observed in ≥2% of patients, and more commonly with Welchol than placebo, regardless of investigator assessment of causality seen in:

– Adults with Primary Hyperlipidemia were: constipation (11.0% vs 7.0%), dyspepsia (8.3% vs 3.5%), nausea (4.2% vs 3.9%), accidental injury (3.7% vs 2.7%), asthenia (3.6% vs 1.9%), pharyngitis (3.2% vs 1.9%), flu syndrome (3.2% vs 3.1%), rhinitis (3.2% vs 3.1%), and myalgia (2.1% vs 0.4%) – Adult patients with Type 2 Diabetes were: constipation (8.7% vs 2.0%), nasopharyngitis (4.1% vs 3.6%), dyspepsia (3.9% vs 1.4%), hypoglycemia (3.0% vs 2.3%), nausea (3.0% vs 1.4%), and hypertension (2.8% vs 1.6%) Post-marketing experience: Due to the voluntary nature of these reports it is not possible to reliably estimate frequency or establish a causal relationship: – Increased seizure activity or decreased phenytoin levels have been reported in patients receiving phenytoin concomitantly with Welchol – Reduced International Normalized Ratio (INR) has been reported in patients receiving warfarin concomitantly with Welchol – Elevated thyroid-stimulating hormone (TSH) has been reported in patients receiving thyroid hormone replacement therapy Pregnancy Welchol is Pregnancy Category B.

Please see brief summary of the full Prescribing Information about Welchol on next page.

Reference: 1. Welchol (colesevelam HCI). Prescribing Information. Daiichi Sankyo, Inc., Parsippany, NJ, 2011. ©2011 Daiichi Sankyo, Inc.

Printed in USA

09/11

DSWC11001413-1

www.welchol.com

WELCHOL (colesevelam hydrochloride) Initial U.S. Approval: 2000 BRIEF SUMMARY: See package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.1 Primary Hyperlipidemia WELCHOL is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin).

WELCHOL is indicated as monotherapy or in combination with a statin to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: a. LDL-C remains ≥ 190 mg/dL or b. LDL-C remains ≥ 160 mg/dL and • there is a positive family history of premature cardiovascular disease or • two or more other CVD risk factors are present in the pediatric patient.

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate [See Clinical Studies (14.1) in the full prescribing information].

In patients with coronary heart disease (CHD) or CHD risk equivalents such as diabetes mellitus, LDL-C treatment goals are <100 mg/dL. An LDL-C goal of <70 mg/dL is a therapeutic option on the basis of recent trial evidence.

If LDL-C is at goal but the serum triglyceride (TG) value is >200 mg/dL, then non-HDL cholesterol (non-HDL-C) (total cholesterol [TC] minus high density lipoprotein cholesterol [HDL-C]) becomes a secondary target of therapy. The goal for non-HDL-C in persons with high serum TG is set at 30 mg/dL higher than that for LDL-C. 1.2 Type 2 Diabetes Mellitus WELCHOL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [See Clinical Studies (14.2) in the full prescribing information].

Diabetes mellitus is considered a CHD risk equivalent. In addition to glycemic control, intensive lipid control is warranted [See Indications and Usage (1.1) and Warnings and Precautions (5.2)].

1.3 Important Limitations of Use • WELCHOL should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis.

• WELCHOL has not been studied in type 2 diabetes as monotherapy or in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones.

• WELCHOL has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

• WELCHOL has not been studied in children younger than 10 years of age or in pre-menarchal girls.

4 CONTRAINDICATIONS WELCHOL is contraindicated in patients with • A history of bowel obstruction [See Warnings and Precautions (5.4)] • Serum TG concentrations >500 mg/dL [See Warnings and Precautions (5.2)] • A history of hypertriglyceridemia-induced pancreatitis [See Warnings and Precautions (5.2)] 5 WARNINGS AND PRECAUTIONS 5.1 General The effect of WELCHOL on cardiovascular morbidity and mortality has not been determined.

5.2 Serum Triglycerides WELCHOL, like other bile acid sequestrants, can increase serum TG concentrations.

WELCHOL had small effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia [See Adverse Reactions (6.1) and Clinical Studies (14.1) in the full prescribing information].

In clinical trials in patients with type 2 diabetes, greater increases in TG levels occurred when WELCHOL was used in combination with sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas) and when WELCHOL was used in combination with insulin (median increase 22% compared to placebo in combination with insulin) [See Adverse Reactions (6.1) and Clinical Studies (14.2) in the full prescribing information]. Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. In patients with type 2 diabetes, the effect of WELCHOL on LDL-C levels may be attenuated by WELCHOL’s effects on TG levels and a smaller reduction in non-HDL-C compared to the reduction in LDL-C. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL. Because most patients in the

WELCHOL clinical trials had baseline TG <300 mg/dL, it is unknown whether patients with more uncontrolled baseline hypertriglyceridemia would have greater increases in serum TG levels with WELCHOL. In addition, the use of WELCHOL is contraindicated in patients with TG levels >500 mg/dL [See Contraindications (4)]. Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting WELCHOL and periodically thereafter. WELCHOL should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemia-induced pancreatitis [See Adverse Reactions (6.1)].

5.3 Vitamin K or Fat-Soluble Vitamin Deficiencies Precautions Bile acid sequestrants may decrease the absorption of fat-soluble vitamins A, D, E, and K. No specific clinical studies have been conducted to evaluate the effects of WELCHOL on the absorption of co-administered dietary or supplemental vitamin therapy. In non-clinical safety studies, rats administered colesevelam hydrochloride at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency.

Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to WELCHOL. Caution should be exercised when treating patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins.

5.4 Gastrointestinal Disorders Because of its constipating effects, WELCHOL is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal tract surgery and who may be at risk for bowel obstruction. Because of the tablet size, WELCHOL Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, WELCHOL for Oral Suspension should not be taken in its dry form. Always mix WELCHOL for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting.

5.5 Drug Interactions WELCHOL reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam should be administered at least 4 hours prior to WELCHOL. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to WELCHOL. Alternatively, the physician should monitor drug levels of the co-administered drug [See Drug Interactions (7) and Clinical Pharmacology (12.3) in the full prescribing information].

5.6 Phenylketonurics WELCHOL for Oral Suspension contains 24 mg phenylalanine per 1.875 gram packet and 48 mg phenylalanine per 3.75 gram packet [See Description (11) in the full prescribing information].

6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice.

In the lipid-lowering trials, 807 adult patients received at least one dose of WELCHOL (total exposure 199 patient-years). In the type 2 diabetes trials, 566 patients received at least one dose of WELCHOL (total exposure 209 patient-years).

In clinical trials for the reduction of LDL-C, 68% of patients receiving WELCHOL vs. 64% of patients receiving placebo reported an adverse reaction. In clinical trials of type 2 diabetes, 60% of patients receiving WELCHOL vs. 56% of patients receiving placebo reported an adverse reaction.

Primary Hyperlipidemia: In 7 double-blind, placebo-controlled, clinical trials, 807 patients with primary hyperlipidemia (age range 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with WELCHOL 1.5 g/day to 4.5 g/day from 4 to 24 weeks.

Table 1 Placebo-Controlled Clinical Studies of WELCHOL for Primary Hyperlipidemia: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) WELCHOL Placebo N = 807 N = 258 Constipation 89 (11.0) 18 (7.0) Dyspepsia 67 (8.3) 9 (3.5) Nausea 34 (4.2) 10 (3.9) Accidental injury 30 (3.7) 7 (2.7) Asthenia 29 (3.6) 5 (1.9) Pharyngitis 26 (3.2) 5 (1.9) Flu syndrome 26 (3.2) 8 (3.1) Rhinitis 26 (3.2) 8 (3.1) Myalgia 17 (2.1) 1 (0.4)

Pediatric Patients 10 to 17 Years of Age: In an 8-week double-blind, placebo-controlled study boys and post-menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (heFH) (n=192), were treated with WELCHOL tablets (1.9-3.8 g, daily) or placebo tablets [See Clinical Studies (14.1) in the full prescribing information].

(median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL).

Two (0.4%) patients on WELCHOL and 2 (0.4%) patients on placebo developed TG elevations ≥1000 mg/dL. In all WELCHOL clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with WELCHOL [See Contraindications (4) and Warnings and Precautions (5.2)].

Cardiovascular adverse events: During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the WELCHOL group and 2% (10/562) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown.

Hypoglycemia: Adverse events of hypoglycemia were reported based on the clinical judgment of the blinded investigators and did not require confirmation with fingerstick glucose testing. The overall reported incidence of hypoglycemia was 3.0% in patients treated with WELCHOL and 2.3% in patients treated with placebo. No WELCHOL treated patients developed severe hypoglycemia.

Table 2 Placebo-Controlled Clinical Study of WELCHOL for Primary Hyperlipidemia in heFH Pediatric Patients: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) WELCHOL Placebo N = 129 N = 65 Nasopharyngitis 8 (6.2) 3 (4.6) Headache 5 (3.9) 2 (3.1) Fatigue 5 (3.9) 1 (1.5) Creatine Phosphokinase Increase 3 (2.3) 0 (0.0) Rhinitis 3 (2.3) 0 (0.0) Vomiting 3 (2.3) 1 (1.5) The reported adverse reactions during the additional 18-week open-label treatment period with WELCHOL 3.8 g per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%) [See Clinical Studies (14.1) in the full prescribing information].

6.2 Post-marketing Experience The following additional adverse reactions have been identified during post-approval use of WELCHOL. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drug Interactions with concomitant WELCHOL administration include: • Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Phenytoin should be administered 4 hours prior to WELCHOL. • Reduced International Normalized Ratio (INR) in patients receiving warfarin therapy. In warfarin-treated patients, INR should be monitored frequently during WELCHOL initiation then periodically thereafter.

• Elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy. Thyroid hormone replacement should be administered 4 hours prior to WELCHOL [See Drug Interactions (7)].

Gastrointestinal Adverse Reactions Bowel obstruction (in patients with a history of bowel obstruction or resection), dysphagia or esophageal obstruction (occasionally requiring medical intervention), fecal impaction, pancreatitis, abdominal distension, exacerbation of hemorrhoids, and increased transaminases.

Laboratory Abnormalities Hypertriglyceridemia

Type 2 Diabetes Mellitus: The safety of WELCHOL in patients with type 2 diabetes mellitus was evaluated in 4 double-blind, 12-26 week, placebocontrolled clinical trials. These trials involved 1128 patients (566 patients on WELCHOL; 562 patients on placebo) with inadequate glycemic control on metformin, sulfonylurea, or insulin when these agents were used alone or in combination with other anti-diabetic agents. Upon completion of the pivotal trials, 492 patients entered a 52-week open-label uncontrolled extension study during which all patients received WELCHOL 3.8 g/day while continuing background treatment with metformin, sulfonylurea, or insulin alone or in combination with other anti-diabetic agents.

A total of 6.7% of WELCHOL-treated patients and 3.2% of placebo-treated patients were discontinued from the diabetes trials due to adverse reactions.

This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation.

One patient in the pivotal trials discontinued due to body rash and mouth blistering that occurred after the first dose of WELCHOL, which may represent a hypersensitivity reaction to WELCHOL. Table 3 Placebo-Controlled Clinical Studies of WELCHOL Add-on Combination Therapy with Metformin, Insulin, Sulfonylureas: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) WELCHOL Placebo N = 566 N = 562 Constipation 49 (8.7) 11 (2.0) Nasopharyngitis 23 (4.1) 20 (3.6) Dyspepsia 22 (3.9) 8 (1.4) Hypoglycemia 17 (3.0) 13 (2.3) Nausea 17 (3.0) 8 (1.4) Hypertension 16 (2.8) 9 (1.6)

Hypertriglyceridemia: Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the phase 3 diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the WELCHOL group and 177 mg/dL in the placebo group. WELCHOL therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively [See Warnings and Precautions (5.2) and Clinical Studies (14.2) in the full prescribing information]. In comparison, WELCHOL resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial [See Clinical Studies (14.1) in the full prescribing information].

Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 4.1% of WELCHOL-treated patients compared to 2.0% of placebo-treated patients. Among these patients, the TG concentrations with WELCHOL

7 DRUG INTERACTIONS Table 4 lists the drugs that have been tested in in vitro binding or in vivo drug interaction studies with colesevelam and/or drugs with postmarketing reports consistent with potential drug-drug interactions. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to WELCHOL. Alternatively, the physician should monitor drug levels of the co-administered drug.

Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports Drugs with a known interaction with Cyclosporinec, glyburidea, levothyroxinea, colesevelam and oral contraceptives containing ethinyl estradiol and norethindronea Drugs with post-marketing reports phenytoina, warfarinb consistent with potential drug-drug interactions when coadministered with WELCHOL Drugs that do not interact with cephalexin, ciprofloxacin, digoxin, warfarinb, fenofibrate, lovastatin, colesevelam based on in vitro or in vivo testing metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil a

Should be administered at least 4 hours prior to WELCHOL No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR).

[See Post-marketing Experience (6.2)] c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. b

In an in vivo drug interaction study, WELCHOL and warfarin coadministration had no effect on warfarin drug levels. This study did not assess the effect of WELCHOL and warfarin coadministration on INR. In postmarketing reports,

concomitant use of WELCHOL and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating WELCHOL and frequently enough during early WELCHOL therapy to ensure that no significant alteration in INR occurs. Once the INR is stable, continue to monitor the INR at intervals usually recommended for patients on warfarin. [See Post-marketing Experience (6.2)] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies of colesevelam use in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of fetal harm. Requirements for vitamins and other nutrients are increased in pregnancy. However, the effect of colesevelam on the absorption of fat-soluble vitamins has not been studied in pregnant women. This drug should be used during pregnancy only if clearly needed.

In animal reproduction studies, colesevelam revealed no evidence of fetal harm when administered to rats and rabbits at doses 50 and 17 times the maximum human dose, respectively. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

8.3 Nursing Mothers Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract.

8.4 Pediatric Use The safety and effectiveness of WELCHOL as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with heFH [See Clinical Studies (14.1) in the full prescribing information]. The adverse reaction profile was similar to that of patients treated with placebo.

In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo [See Adverse Reactions (6.1)].

Due to tablet size, WELCHOL for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when WELCHOL is administered to children 10 to 17 years of age.

WELCHOL has not been studied in children younger than 10 years of age or in pre-menarchal girls.

8.5 Geriatric Use Primary Hyperlipidemia: Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ≥65 years old, and 58 (4%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Type 2 Diabetes Mellitus: Of the 1128 patients enrolled in the four diabetes studies, 249 (22%) were ≥65 years old, and 12 (1%) were ≥75 years old.

In these trials, WELCHOL 3.8 g/day or placebo was added onto background anti-diabetic therapy. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No special considerations or dosage adjustments are recommended when WELCHOL is administered to patients with hepatic impairment.

8.7 Renal Impairment Type 2 Diabetes Mellitus: Of the 1128 patients enrolled in the four diabetes studies, 696 (62%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 53 (5%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl ≥50 mL/min (n=1075).

10 OVERDOSAGE Doses of WELCHOL in excess of 4.5 g/day have not been tested. Because WELCHOL is not absorbed, the risk of systemic toxicity is low. However, excessive doses of WELCHOL may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses.

17 PATIENT COUNSELING INFORMATION Dosing: Patients should be advised to take WELCHOL Tablets with a meal and liquid. WELCHOL can be taken as 6 tablets once daily or 3 tablets twice daily. Patients should be advised to take WELCHOL for Oral Suspension as one 3.75 gram packet once daily or one 1.875 gram packet twice daily.

To prepare, empty the entire contents of one packet into a glass or cup.

Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. WELCHOL for Oral Suspension should be taken with meals.

To avoid esophageal distress, WELCHOL for Oral Suspension should not be taken in its dry form. Always mix WELCHOL for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting. [See Dosage and Administration (2) in the full prescribing information] Drug interactions: Drugs with a known interaction with colesevelam (e.g., cyclosporine, glyburide, levothyroxine, oral contraceptives) should be administered at least 4 hours prior to WELCHOL. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index (e.g., phenytoin), should also be administered at least 4 hours prior to WELCHOL. Alternatively the physician should monitor blood levels of the coadministered drug. [See Drug Interactions (7)] Gastrointestinal: WELCHOL can cause constipation. WELCHOL is contraindicated in patients with a history of bowel obstruction. WELCHOL is not recommended in patients who may be at risk of bowel obstruction, including patients with gastroparesis, other gastrointestinal motility disorders, or a history of major gastrointestinal surgery. Patients should be instructed to consume a diet that promotes bowel regularity. Patients should be instructed to promptly discontinue WELCHOL and seek medical attention if severe abdominal pain or severe constipation occurs. Because of the tablet size, WELCHOL Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, WELCHOL for Oral Suspension should not be taken in its dry form. Always mix WELCHOL for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting.

[See Warnings and Precautions (5.4)] Hypertriglyceridemia and pancreatitis: Patients should be instructed to discontinue WELCHOL and seek prompt medical attention if the hallmark symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting). [See Warnings and Precautions (5.2)] 17.1 Primary Hyperlipidemia Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet.

17.2 Type 2 Diabetes Mellitus General: Patients should be advised that it is important to adhere to dietary instructions, a regular exercise program, and regular testing of blood glucose.

Hypertriglyceridemia and cardiovascular disease: Patients receiving a sulfonylurea or insulin should be informed that WELCHOL may increase serum triglyceride concentrations and that the long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. [See Warnings and Precautions (5.2)]

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CLINICAL

ORIGINAL RESEARCH

The Hickory Project: Controlling Healthcare Costs and Improving Outcomes for Diabetes Using the Asheville Project Model Barry A. Bunting, PharmD, DSNAP; Grover Lee, PharmD, BCMCM; Grant Knowles, PharmD; Christine Lee, PharmD, BCPS, CLS; Paul Allen, PhD, MBA Background: The results of the Asheville Project have shown the success of a community-based, chronic disease management model in improving clinical outcomes in patients with chronic disease while reducing annual costs of care per participant. The question arose whether other programs using a similar management model and implemented in other communities could replicate the success of the Asheville Project in improving clinical outcomes and reducing costs for patients with a chronic disease.

Objective: To assess the long-term clinical and financial outcomes of a chronic care management model for patients with diabetes, using the Asheville care management model that was successful in the management of several chronic diseases.

Study design: Longitudinal, 3-year (2007-2009), quasi-experimental, multisite, pre-/postenrollment study.

Methods: Self-insured health plan members with diabetes agreed to meet on a regular basis (ie, an average of every 3 months) with a healthcare professional. Participants received reduced copayments on diabetes-related medications and supplies as an incentive for participating in the study. Providers utilized a web-based electronic medical record system that provided updated medical and prescription data and highlighted gaps in care based on national standards. Program providers included community pharmacists, population health management company pharmacists, and nurses at on-site clinics, trained in use of evidence-based guidelines of care. Providers assessed patientsâ&#x20AC;&#x2122; medications, knowledge level, and lifestyle; provided patient education and goal setting; and referred patients for physician follow-up and recommendations to physicians. The majority of the encounters were face-to-face.

Results: The study included 95 plan members in the clinical cohort participating for 1 year or more, and 54 members in the financial cohort who have been participating in the program for 3 years. At the end of 3 years, the percentages of those achieving guideline goals increased from baseline to the latest follow-up included, respectively, reaching target hemoglobin A1c levels, 38% to 53%; low-density lipoprotein cholesterol, 46% to 67%; systolic blood pressure (BP), 55% to 72%; diastolic BP, 60% to 71%; annual eye examination, 37% to 61%; and self-testing blood glucose, 79% to 97%. Total healthcare costs decreased by an average of $2704 per participant per year. The programâ&#x20AC;&#x2122;s return on investment was $4.89 to every $1 spent (including program costs).

Conclusion: The Hickory Project shows that it is possible to produce sustained improvements in clinical outcomes and reductions in healthcare costs for patients with diabetes using a chronic care model that provides frequent patient follow-up, a focus on appropriate medication therapy, adherence to clinical practice guidelines, and a reduction in prescription copayments for antidiabetes medications as an incentive for patients to participate in the program.

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2011;4(6):343-350 www.AHDBonline.com Disclosures are at end of text

Dr Bunting is Vice President, Clinical Services; Dr Grover Lee is Chief Executive Officer; Dr Knowles was Senior Clinical Manager; Dr Christine Lee is Chief Clinical Officer; Dr Allen was Chief Operating Office; all at American Health Care, Rocklin, CA.

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his follow-up study was conducted to determine if a previously successful, community-based, chronic disease management model, known as the Asheville Project, could be replicated in other communities in the country.

In 1997, the North Carolina Association of Pharmacists initiated a research study to determine if specially trained community pharmacists engaged in individual, appointment-based consultations with patients with chronic medical conditions could improve care and decrease healthcare costs. That study, the Asheville Project, began with a diabetes program for health plan members of the City of Asheville. It subsequently involved 8 additional employers in the community and 4 additional chronic conditions—asthma, hypertension, hyperlipidemia, and depression.

The unique aspects of this model consisted of (1) voluntary participation, (2) community-based program, (3) appointment-based patient follow-up, (4) face-to-face counseling by pharmacists and diabetes educators, (5) long-term period, (6) reduced prescription copayment incentive, (7) a focus on appropriate medication therapy, and (8) adherence to evidence-based guidelines.

In 2003, the first in a series of peer-reviewed publications on the Asheville Project was published.1,2 The initial publication was a 5-year study of 187 patients with diabetes.1,2 In 2006, the results of a 5-year study of 207 patients with asthma were published3; in 2008, a 6year study of 620 patients with hypertension and hyperlipidemia was published.4 Each of these 4 studies demonstrated significant clinical and financial outcome improvements using this chronic care, community-based model.

The diabetes study showed a $1200 to $1872 per participant per year (PPPY) decrease in direct healthcare costs compared with baseline and significant improvements in clinical laboratory measures.1,2 The asthma study showed a $1995 PPPY decrease in costs (direct and indirect). The results also showed a significant decrease in the rates of asthma-related emergency department visits and hospitalization (from 22 events per 100 patients annually to 3 events per 100 patients annually).

The 6-year cardiovascular (CV) study demonstrated a 53% decrease in the risk of having a CV event and a 46.5% decrease in the average cost of a CV event when it did occur. The number of myocardial infarctions (heart attacks) decreased from 23 to 6 for equivalent historical versus study time periods. Given the success of this model in one community, it was important to determine if the model could be replicated in other communities.

Research Design and Methods In 2005, American Health Care decided to replicate

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KEY POINTS ➤

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The Asheville Project demonstrated significant clinical and financial outcome improvements using a chronic care, community-based model.

The Hickory Project was initiated to determine if such a model could be replicated in other communities in the setting of patients with diabetes.

In this study, the percentages of patients reaching target hemoglobin A1c levels increased from 38% at baseline to 53% at 3 years; other clinical outcomes also improved, including low-density lipoprotein cholesterol and blood pressure levels, and more patients were self-testing their blood glucose.

After 3 years, total spending on prescriptions increased by an average of $2947 per person per year (PPPY) from baseline. By contrast, medical expenses decreased by $6583 per participant from baseline to year 3, resulting in a decrease from baseline of an average of $3636 PPPY in total healthcare costs.

The conservative (nonprojected) return on investment in the Asheville Project was $4 for every $1 spent on the program.

The Hickory Project adds to the growing evidence that it is possible for a chronic care management program to improve clinical outcomes and to decrease the cost of care by incorporating access to the patient’s electronic medical record, patient education, and evidence-based management plan.

the Asheville model in other communities. The company, which provides clinical pharmacy services, subsequently published 2 preliminary articles on their effort with a nationwide manufacturer,5,6 and this present article is an update at the 3-year point of this ongoing Hickory Project study. In a parallel and independent effort, the American Pharmacists Association Foundation also implemented a replication of the Asheville model known as the Diabetes Ten City Challenge.7,8 The current study, the Hickory Project, is a report on the results of the first 3 years of working with Hickory Springs Manufacturing Company, which is headquartered in Hickory, NC. The company has 4500 self-funded health plan members located in more than 60 operational facilities in the United States. In collaboration with Wells Fargo Insurance Services, the employer’s benefits consultant, American Health Care implemented a program for which it provided information technology, clinical administration, and outcomes reporting.

American Health Care recruited, trained, and monitored the healthcare professionals, who were referred to as “intensive chronic care managers.”

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Participants, for whom face-to-face care management was not possible because of a lack of providers in some communities, were provided management via telephone calls. Training, tools, and guideline-based protocols were developed by American Health Care. Intensive chronic care managers received training in best practices, patient counseling, and documentation.

An enhancement of the Asheville model was the provision of an electronic medical record (EMR) system that provided guidelines of care and a complete record of all medical and prescription claims. In the Asheville Project, care managers used paper charts and did not have access to a complete medical and prescription claims history.

As in the Asheville model, participants in the Hickory Project were provided one-on-one counseling, blood pressure (BP) assessment, medication assessment, laboratory review, health knowledge assessment, lifestyle education, and goal setting. Recommendations were made to the patient’s physician when deficiencies were identified. Patients were referred back to their physicians when deficiencies warranted further assessment or when therapy changes had to be considered. In this model, the physician continues to be the primary decision maker.

American Health Care’s role was to (1) provide a web-based, secure EMR; (2) integrate and update all medical and prescription claims data into the EMR monthly; (3) build guidelines of care into the EMR; (4) identify the eligible population; (5) inform eligible patients of the option of having a chronic care manager, intended health benefits of the program, financial incentives, and requirements of participation (to meet with their chronic care provider as frequently as once per month); (6) ensure that the requirements for laboratory testing were followed; (7) follow up with the patient’s physician; and (8) provide outcomes reporting of clinical and financial progress to the employer and health plan on a regular basis.

The intensive chronic care manager’s role was to schedule sessions with patients on a regular basis (ie, an average of every 3 months) to determine if there was a treatment plan in place by their physician and to determine: • What is the plan?

• Is the plan appropriate?

• Does the patient understand the plan?

• Is the patient following the plan?

• And, most important, is the plan working?

When the answer to any of these questions was negative, educating the patient, providing guidelines and personal goals, and referring the patient back to the physician for a change in therapeutic plan needed to be considered.

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Of the manufacturer’s 4500 plan members, 522 (12%) are currently participating in programs for diabetes, high BP, and/or high cholesterol levels, which is comparable with enrollment rates in the Asheville Project.

This article shows the clinical outcomes of the 95 plan members with diabetes who have been participating in the program for 1 year or longer, as well as the financial outcomes of the 54 plan members with diabetes who were participating in the program for the entire 3 years (2007-2009) and for whom complete financial data were available.

The method used to analyze the data for financial outcomes was to compile, review, and tabulate all medical and prescription claims filed for the participants for 2 years before the start of the program and 3 years after the start of the program. This is reported as PPPY cost and is what the plan paid for annual care for the average individual in the program. Plan savings is reported as net plan savings and includes the costs of the program.

To calculate the return on investment (ROI), the following components were determined or calculated the: • Average annual health plan costs before the start of the program for the 54 patients who participated in the 3-year program • Average health plan costs for each of the 3 years of the study • Difference between the average health plan historical annual costs and the average for each of the 3 subsequent years of the study • Average US healthcare cost trend during the 3-year study period and historical health plan costs • Total program management costs, including administrative fees, reduced prescription copayment incentives, and care manager fees.

ROI was then calculated by dividing the total calculated health plan savings (baseline costs plus 8% annual trend) by the total health plan costs for the program.

“Trend” refers to the participant’s actual total health plan costs relative to what would have been expected if the participant’s costs had tracked at an 8% trend increase.

The US healthcare trend over this time period was more than 9% (based on PricewaterhouseCoopers Health Research Institute data for this study period).9 We used a more conservative 8% trend based on the employer’s health plan experience. Clinical data were measured at the beginning of the program and annually, and reported as baseline compared with the latest result at the end of the study period.

Primary Outcomes The study had 2 separate primary outcomes groups— financial and clinical. Financial outcomes include (1) the participants’ healthcare costs (ie, all medical and

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Medical and Prescription Costs for Patients Figure 1 Enrolled for 3 Years Medical cost, PPPY Prescription cost, PPPY $11,848 $1741

$10,235 $8974

$8212

Cost, $

$4002 $4332

$4688

$10,107 $6233 1 year before enrollment

Year 1

$4642

$3524

Year 2

Year 3

Study participation

PPPY indicates per participant per year.

Cost Comparison per Participant per Year: Figure 2 Projected versus Actual Average total cost, projected Average total cost, actual 16,000

$14,925 $13,819

14,000

$12,796

12,000

Cost, $

$10,235 10,000

$8974

$8212

8000 6000 4000 2000 0 Year 1

Year 2

Year 3

Study participation

Projected total health plan costs assuming no program versus actual observed total health plan costs. The projection cost shown was calculated from the average cost of participants for the year before enrollment ($11,848) using a historical plan trend of 8%.

prescription claims paid by the health plan) for each of the 3 years of the program versus their historic average; (2) the participantsâ&#x20AC;&#x2122; healthcare costs versus the national trend; (3) the participantsâ&#x20AC;&#x2122; healthcare costs versus zero trend; (4) net health plan savings; and (5) ROI. Clinical outcomes include (1) the percentage of participants achieving the American Diabetes Association (ADA) goal of hemoglobin (Hb) A1c <7%; (2) the percentage of participants with diabetes achieving the

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low-density lipoprotein cholesterol (LDL-C) goal of <100 mg/dL; (3) the percentage of participants with diabetes achieving the ADA-recommended goals of systolic BP <130 mm Hg and diastolic BP <80 mm Hg; (4) the percentage of those receiving recommended annual eye examinations; (5) the percentage of patients monitoring their own blood glucose daily; and (6) the percentage of patients conducting foot selfexaminations at least weekly.

Results A total of 180 patients with diabetes were enrolled during the first 3 years of the program. Of these, 21 patients were dropped from the program for failure to keep care manager appointments, 2 decided they no longer wished to participate, and 103 lacked either a 1-year history of claims data or a full 3 years of program period claims data. A total of 95 patients were in the program for 1 year or longer. Of these, 54 patients participated all 3 years and had at least a 1-year history of claims data plus 3 years of program period claims data.

The percentage of patients who achieved the ADA HbA1c <7% goal increased from 38% at the start of the study (or at enrollment) to 53%. The percentage of patients who achieved the recommended LDL-C goal of <100 mg/dL increased from 46% to 67%. The percentage of patients achieving the recommended systolic BP goal of <130 mm Hg increased from 55% to 72%. The percentage of patients achieving the recommended diastolic BP goal of <80 mm Hg increased from 60% to 71%.

Only 37% of the patients entering the study had the ADA-recommended annual eye examination in the year before the study, which increased to 61% by the end of the study.

The number of patients regularly self-testing blood glucose levels increased from 79% at baseline to 97% at the end of the study. The ROI average during the 3 years of this study was $8.48 for every $1 spent on the program using a trended/projected cost comparison. Applying the same approach using nontrended data resulted in an ROI of $4.89 for every $1 spent on the program. Both ROI calculations include all program costs.

Figure 1 shows the medical and prescription costs for the 54 individuals enrolled for the full 3 years of the study. A significant decrease in the total health plan costs from a preprogram average of $11,848 PPPY to $8212 PPPY by the end of year 3 was observed. Also, the percentage of health plan dollars being spent on medical costs versus prescription costs decreased from 85% to 43% by the end of year 3. Total spending on prescriptions increased considerably, by an average of $2947 PPPY from baseline to year 3. However, medical expenses decreased by $6583 per participant from baseline to

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Discussion The strengths of this study are several, including its length (ie, 3 years); its ability to confirm the results of previous studies; and the finding that at baseline the study group’s healthcare costs were comparable with national norms, but the national costs were rising whereas the study group’s costs were falling during the course of the study.

The need for improvement in the management of chronic illnesses was summarized in the following statement by the National Committee for Quality Assurance: “The fact that many Americans do not receive appropriate preventive care and care for chronic conditions like diabetes and hypertension, also means that annually there are thousands of preventable second heart attacks, kidney failures, and other conditions, such as painful and debilitating fractures from osteoporosis.”10 According to national authorities, a handful of such conditions account for more than 50% of US medical costs.11,12 Even a perfect medical plan has little value if it is not followed. Physicians caring for patients with chronic medical conditions can do all the right tests, say all the right things, and make excellent treatment plans.

Researchers can produce safe and effective medications,

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Average Savings per Participant per Year, Based on Figure 3 Projected Costs 8000 $6713

7000

Cost, $

6000 $4845

5000 4000 3000

$2561

2000 1000 0 Year 1

Year 2

Year 3

Study participation

Projected Annual and Cumulative Savings for Figure 4 54 Participants Enrolled for 3 Years

Cost, $

year 3. This resulted in a net (nonprojected) savings of $3636 PPPY between the baseline year and year 3 and an average annual savings of $2704 PPPY over the entire 3-year study period.

Figure 2 shows a projected cost comparison (projected vs actual) over 3 years for the 54 participants.

An average healthcare cost trend increase of 8% annually, based on previous plan experience, was used for this comparison. As seen in Figure 2, the study population’s costs consistently decreased relative to the projected costs. It is important to point out that the study group’s costs at the start of the program were virtually identical to the national average for patients with diabetes in the United States. Therefore, a projection of 8% for the study group, at a time when the national trend was even higher (more than 9%)9 is a conservative approach.

Figure 3 shows the cost-savings average for the 54 participants for each of the 3 years of the study. The projected savings in the first, second, and third year were $2561, $4845, and $6713 PPPY, respectively (relative to what would have been expected if their health plan costs had tracked at an 8% increase each year).

Figure 4 shows the projected annual and cumulative savings over 3 years for the 54 participants. The cumulative net health plan savings for the 3 years of the program was estimated to be $762,426.

900,000 800,000 700,000 600,000 500,000 400,000 300,000 200,000 100,000 0

Annual savings Cumulative savings $762,426

$399,924

$362,502

$261,630 $138,294

Year 1

Year 2

Year 3

Study participation

and national organizations can produce well-thoughtout guidelines from evidence-based studies. But if patients then do not follow the plan, take the medicine, and succeed on an individual level, the clinical outcomes will not improve on the national level.

We believe the key to successful management of many chronic medical conditions is to ensure that an evidence-based management plan is being followed, and that it is working appropriately. Traditional primary care models, however, appear to be better at formulating treatment plans than at ensuring that the plans are being followed and are succeeding, as is evidenced by the low medication adherence rates reported in the United States.13,14 Therefore, programs that provide frequent contact with patients (between physician office visits) by other healthcare professionals who are more accessi-

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Table Comparison of the Asheville Project and the Hickory Project Outcomes Asheville Project: baseline vs latest follow-up, % at goal

Hickory Project: baseline vs latest follow-up, % at goal

HbA1c <7%

42%-60%

38%-53%

LDL-C <100 mg/dL

37%-58%

46%-67%

Systolic BP <130 mm Hg

Not reported

55%-72%

Diastolic BP <80 mm Hg

Not reported

60%-71%

Daily self-testing of blood glucose

Not reported

79%-97%

Annual eye examination

Not reported

37%-61%

Weekly foot examination

70%-99%

79%-97%

Asheville Project

Hickory Project

Nontrended average PPPY decrease in total health plan cost over 3 years

$1288

$2704

Return on investment

$4.00 : $1

$8.48 : $1

Clinical target

Cost outcomes

BP indicates blood pressure; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol; PPPY, per participant per year.

ble and cost less than primary care visits have the potential to improve care and lower costs. The program used in our study represents such a model.

The Hickory Project adds to the growing evidence that it is possible for a chronic care approach to not only improve the quality of care for patients with diabetes but also to decrease costs. In addition, there is growing evidence that this particular chronic care model is effective.

As in the original Asheville Project diabetes study,1,2 in the Hickory Project we observed improvements in several objective measures of diabetes care.

The percentage of patients achieving HbA1c goals increased from 38% to 53%; the percentage of patients achieving LDL-C goal increased from 46% to 67%; the percentage of patients achieving BP goals increased from 55% to 72% (systolic BP) and 60% to 71% (diastolic BP); the percentage of patients having an annual eye examination increased from 37% to 61%; daily self-test-

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ing of blood glucose increased from 79% to 97%; and regular foot self-examination increased from 79% to 97%.

The Table provides a concise comparison of the Asheville Project and the Hickory Project outcomes.

Both studies observed an interesting shift in healthcare dollar spending; at the end of both studies, more dollars were spent on prescription medications and less on medical expenses. However, the savings on the medical side were significantly greater than the increased spending on prescription drugs. In both studies, the plans had historically been spending approximately $0.80 of each healthcare dollar on medical expenses for the study patients and $0.20 of every $1 on prescriptions. After 3 years in both studies, this changed to $0.40 per $1 spent on medical expenses and $0.60 per $1 spent on prescription drugs. Most important, fewer dollars were being spent overall. In the present study, the prescription spending increased (by $2947 PPPY), but this was more than offset by a $6583 PPPY decrease in medical spending, resulting in a net savings of $3636 PPPY at the end of year 3.

It is possible that we are observing a correlation between getting patients on more effective medication regimens and lowering healthcare costs, which is logical.

Pharmaceutical manufacturers spend billions of dollars proving that their medications work, but then the medications are not consistently and appropriately prescribed, not consistently taken by patients, or not adjusted to the desired outcome. It is, therefore, not surprising that a program that emphasizes appropriate medication therapy would improve outcomes and lower costs on the medical side.

The Asheville diabetes study observed an average health plan savings of $2951 PPPY (projected) for 74 patients during the first 3 years of study. The Hickory Project showed an even greaterâ&#x20AC;&#x201D;$4706 PPPY (projected)â&#x20AC;&#x201D; health plan savings for 54 patients during its first 3 years.

Additional evidence that this model lowers healthcare costs was the $1079 PPPY (projected) cost-savings reported in the Diabetes Ten City Challenge study.8 In all 3 studies, using similar models, impressive reductions were seen in total healthcare costs, with the current Hickory Project study reporting the greatest savings.

Even if a conservative approach is used, which would assume that no increases in healthcare costs would have occurred during the 3 years of this study using routine care, the calculated savings in the Hickory Project is an average of $2704 PPPY over the 3 years of the study.

The conservative (nonprojected) ROI reported for the Asheville Project was $4 for every $1 spent on the program. The conservative (nonprojected) ROI for the Hickory Project study was $4.89 for every $1 spent on the program, which includes all program costs.

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Limitations It is important for a pre-/postenrollment study comparison design to address the possibility that the group of patients might have experienced the statistical phenomenon known as “regression to the mean,” meaning that the patient population had an extreme year before the start of the program and would have, on average, improved even without the program. To determine if this was a significant risk for this study, we calculated what the study group’s mean costs were for 2 years before the start of the program. We were also able to determine the US mean healthcare costs for patients with diabetes at the time of the study. The study group’s mean healthcare costs at the time the study began were not extreme relative to what they had been historically or in comparison to the national norm. The study group’s historical mean cost was actually $798 below the national average. The historical mean cost for the group for the 2 years before the program was $10,946 annually, and the national mean at the time for individuals with diabetes in the United States was $11,744, based on a 2007 study by the ADA.15 Selection bias is another potential risk. Individuals who were more motivated to take care of themselves might have been more motivated to enroll. Offsetting this tendency to enroll a healthier, more motivated population, patients with harder-to-control diabetes would be expected to be receiving more medications and be more motivated to enroll, because of the prescription incentive. A comparison with nonparticipants was not done. This might have further clarified if a selection bias was a factor in this study.

An additional potential design bias was the requirement to keep appointments to continue to receive the prescription incentive, which means we might have selected more compliant patients. Of the original 180 participants in the group, 21 were dropped because of failure to keep care manager appointments, and 2 decided they no longer wanted to participate, which might have affected the findings.

Another limitation is the relatively low number of patients in this study. A total of 95 patients were included in the clinical cohort and 54 patients in the financial cohort, which limits the type of analysis possible and the ability to identify unique elements of the program that contributed most to the cost-savings. The Asheville model, however, has now been studied across several communities and in more than 1000 people over a 10year period, demonstrating consistent and favorable results for this disease management model.

A final limitation is that we were unable to determine the extent to which each of the program elements contributed to the observed clinical and financial improvements.

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Conclusions This study describes the outcomes of an approach to the management of diabetes that incorporates pharmacists and nurses, resources already available in most communities. Although these are not traditional roles, especially for pharmacists, according to our experience, when given the opportunity to be paid to provide such services, a critical mass of interested individuals are available.

Also based on our experience, a growing number of health plans appear to be willing to pay for such services.

Healthcare costs continue to climb in our current healthcare system, and there are few success stories when it comes to actually controlling healthcare costs. The Asheville Project model, however, is one such success story. The Asheville model was successfully replicated by the Hickory Project for a manufacturer with multiple locations across the United States and resulted in improved clinical outcomes and significantly decreased healthcare costs for a group of patients with diabetes. It is reasonable to pursue and expand models that have shown promise in controlling healthcare costs in critical populations. ■ Acknowledgments The authors wish to thank Louis Deibert and the information technology staff at American Health Care for their support in providing data analysis for this study.

American Health Care Foundation provided the funding for this study.

Author Disclosure Statement Dr Bunting, Dr Grover Lee, Dr Knowles, Dr Christine Lee, and Dr Allen have reported no conflicts of interest.

References 1. Cranor CW, Bunting BA, Christensen DB. The Asheville Project: long-term clinical and economic outcomes of a community pharmacy diabetes care program. J Am Pharm Assoc (Wash). 2003;43:173-184.

2. Garrett DG, Martin LA. The Asheville Project: participants’ perceptions of factors contributing to the success of a patient self-management diabetes program. J Am Pharm Assoc (Wash). 2003;43:185-190.

3. Bunting BA, Cranor CW. The Asheville Project: long-term clinical, humanistic, and economic outcomes of a community-based medication therapy management program for asthma. J Am Pharm Assoc (2003). 2006;46:133-147.

4. Bunting BA, Smith BH, Sutherland SE. The Asheville Project: clinical and economic outcomes of a community-based long-term medication therapy management program for hypertension and dyslipidemia. J Am Pharm Assoc (2003). 2008;48:23-31.

5. Lee GC, Mick T, Lam T. The Hickory Project builds on the Asheville Project— an example of community-based diabetes care management. J Manag Care Pharm.

2007;13:531-533.

6. Mick ET, Lee G, Lam T. Multidisciplinary approach to disease management: preliminary findings of the Hickory Project. Diabetes Trends. 2007;5-9.

7. Garrett DG, Bluml BM. Patient self-management program for diabetes: first-year clinical, humanistic, and economic outcomes. J Am Pharm Assoc (2003). 2005;45: 130-137.

8. Fera T, Bluml BM, Ellis WM. Diabetes Ten City Challenge: final economic and clinical results. J Am Pharm Assoc (2003). 2009;49:383-391.

9. PricewaterhouseCoopers. Behind the numbers: medical cost trends for 2009. June 2008. www.pwc.com/us/en/healthcare/publications/behind-the-numbers-medicalcost-trends-for-2009.jhtml. Accessed May 19, 2011.

10. National Committee for Quality Assurance. The state of health care quality: 2004. www.ncqa.org/Portals/0/Publications/Resource%20Library/SOHC/SOHC_ 2004.pdf. Accessed September 16, 2011.

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11. Centers for Disease Control and Prevention. Chronic disease overview: costs of chronic disease. www.cdc.gov/nccdphp/overview.htm. Accessed September 16, 2011.

12. Mensah G, Brown DW. An overview of cardiovascular disease burden in the United States. Health Aff (Millwood). 2007;26:38-48.

13. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.

14. World Health Organization. Adherence to long-term therapies: evidence for action. 2003. www.who.int/chp/knowledge/publications/adherence_full_report.pdf.

Accessed September 19, 2011.

15. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007.

Diabetes Care. 2008;31:596-615.

STAKEHOLDER PERSPECTIVE Keeping a Lid on Health Plan Costs, One Patient at a Time EMPLOYERS/HEALTH PLANS: As the country and Congress debate the course of healthcare reform, medical plan sponsors are left to tackle the problem one patient at a time.

So it goes with the Hickory Project discussed in the present article—an effort initiated by the pharmaceutical management company American Health Care (AHC) to replicate the results of a 14-year diabetes management program in Asheville, NC, and by our client, Hickory Springs Manufacturing Company, to keep a lid on health plan costs in these dire times.

When we approached Hickory Springs with the idea of removing prescription copays for plan members who agreed to meet with a diabetes health coach, Group Health and Workers Compensation Manager Tim Isenhower focused on a single statistic reported

by Barry Bunting, PharmD: that none of the Asheville Project members who were enrolled in the program at the time had started kidney dialysis.

Kidney failure is one of the harsh impacts uncontrolled diabetes can have. “We’ll waive $500 in copays to keep someone from a $500,000 treatment,” I recall Isenhower saying at a 2006 meeting in which Bunting talked about the Asheville Project’s success.

From the onset, the management team that I work with knew they were having an impact, based on the employees who thanked them for making treatment affordable, and the early findings that A1c, low-density lipoprotein cholesterol (LDL-C), and blood pressure (BP) levels were improving. In 2008 they decided to expand.

They decided to open more clinics, use them for coaching where appropriate, and reward all participating and complying employees with lower paycheck contributions for health coverage. Smokers had to enroll in a program to quit. They were not required to quit to get the lower cost, but they had to finish the program. Likewise, employees with high

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LDL-C, high BP, or diabetes had to enroll and comply to keep the lower plan cost, and—for diabetes— reduced copays.

Sure, there were complaints, but there were also good results: a 4:1 return on investment (ROI) without trending and an 8:1 ROI using a modest 8% annual medical trend. The cumulative savings estimate reported by AHC totals >$760,000.

Crucial to this success is that the intensive care managers are not in any way an attempt to circumvent or replace the role of a patient’s treating physician. Rather, they complement that role: making treatment plans relevant to a patient’s busy life, making sure they comply with medication regimens, and ensuring that the treatment is working.

This model is gaining traction across the country as employers realize that following evidence-based guidelines costs less, and providers realize that following evidence-based guidelines is how they will increase their compensation. Mercer’s 2010 National Survey of Employer-Sponsored Health Plans revealed that 69% of employers were offering some form of health risk assessment, with 35% of those tying completion to an incentive.

Hickory Springs supplies foam and components to the furniture industry. Their business is very competitive, and holding down health plan costs is a key strategy to staying in the game. As we look to expand on our success, we want to reach out to spouses and dependents. We may tie their participation to lower plan costs and other incentives, or devise a way to make the face-to-face sessions more convenient.

Whatever we decide, we are confident that success will come one patient at a time.

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Rick Miller Senior Vice President, Employee Benefits Wells Fargo Insurance Services, Roanoke, VA

September/October 2011

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Overall Survival Advantage Sustained at 3-Year Median Follow-up In Previously Untreated Multiple Myeloma (MM) VISTTA* OVERALL SURVIV VAL AL (OS) (OS S) ANAL LY YSIS: VcMP† vs MP VISTA* SURVIVAL ANALYSIS: (36.7-month median follow-up) MEDIAN OS NOT REACHED FOR VcMP

100 90

% PPatients atients Without Event

80 70 60 50 40 30 20 10

■ VELCADE+MP VELCADE+MP (n=344) ■ MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); PP=0.00084 = =0 =0.00084

0 0

3

6

9

12

15

18

21

24

Months Ka Kaplan-Meier plan-Meier estima estimate. te.

▼ ▼ ▼

27

30

33

36

39

42

45

48

51

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

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

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone.

The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.

Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.

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

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

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

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

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

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

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

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

V-11-0041

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ORIGINAL RESEARCH

Health Resource Utilization and Direct Costs Associated with Angina for Patients with Coronary Artery Disease in a US Managed Care Setting Judy Kempf, PhD; Erin Buysman, MS; Diana Brixner, RPh, PhD Background: Angina is often a first symptom of coronary artery disease (CAD); however, the specific burden of illness for patients with CAD-associated angina in managed care has not been reported.

Objective: To determine the clinical and cost burden of illness for patients with CAD-associated angina in a managed care environment.

Study design: A retrospective database analysis in a nationwide commercial managed care plan.

Methods: This study included patients with International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic or procedure codes for CAD between July 1, 2004, and June 30, 2006, who had data available for the period 6 months before and 12 months after the index date. The primary analyses for patients classified as having CAD with angina were based on a 3-algorithm patient-identification model (combined positive predictive value of 89%, 95% confidence interval, 0.79-0.95). Utilization measures for the 12-month postindex period, annual CAD-related direct costs, and total all-cause costs (ie, medical plus pharmacy) were determined. A generalized linear model was used to compare CAD-related costs and overall costs.

Results: Of the 246,227 patients with CAD, the 3-algorithm model assigned 230,919 patients (93.8%) to the CAD-without-angina cohort and 15,308 (6.2%) to the CAD-with-angina cohort.

Patients with angina were more likely than patients without angina to be hospitalized (41% vs 11%, respectively; P <.001), to visit the emergency department (34% vs 12%, respectively; P <.001), to have office visits (94% vs 79%, respectively; P <.001), and to have more revascularization procedures (35% vs 8%, respectively; P <.001). Average CAD-related inpatient costs were $9536 versus $2169, and pharmacy costs were $1499 versus $891, for patients with and without angina, respectively. Total average CAD-related medical and pharmacy costs for patients with angina were $14,851 versus $4449 for patients with CAD without angina, and the average all-cause per-patient cost was $28,590 versus $14,334, respectively.

Conclusion: Based on these results, US patients with CAD plus angina in a managed care setting use significantly more healthcare services and incur higher costs than patients who have CAD without angina. Revascularization procedures are a major driver of these increased costs for those with CAD and angina.

C

hest pain, or angina pectoris, is the primary symptom of coronary artery disease (CAD), or chronic heart disease, a leading cause of morbidity and mortality in the United States. An estimated

Stakeholder Perspective, page 361

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2011;4(6):353-361 www.AHDBonline.com Disclosures are at end of text

17.5 million Americans have CAD, 9 million have angina pectoris, and approximately 500,000 new cases of angina are diagnosed annually.1,2 Current evidence-based treatment guidelines for patients with stable ischemic

Dr Kempf was Executive Director, Outcomes Research, CV Therapeutics (Gilead), Palo Alto, CA, at the time of the study and is currently an employee of Genzyme; Ms Buysman is Associate Director, Observational Research, OptumInsight, Eden Prairie, MN; Dr Brixner is Professor and Chair, Department of Pharmacotherapy, and Executive Director, Outcomes Research Center, University of Utah, Salt Lake City.

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KEY POINTS ➤

➤

➤

➤

➤

➤

Approximately 17.5 million Americans have coronary artery disease (CAD) and 9 million have angina, which is often the initial symptom of CAD. There are limited data on healthcare resource utilization and direct costs for patients with CAD plus angina, and CAD without angina.

This study used real-world data to compare treatment patterns and costs for patients who have CAD with and without angina in a managed care setting.

Average CAD-related inpatient costs were $9536 for those with angina versus $2169 without angina; total average CAD-related medical and pharmacy costs for patients with angina were $14,851 versus $4449 for those without angina.

Overall, patients with CAD plus angina used considerably more healthcare resources than those without angina, including hospitalization, emergency department visits, outpatient visits, and cardiovascular drug regimens.

In addition, patients with CAD and angina were significantly more likely to have a revascularization procedure—a major cost driver—than patients without angina.

heart disease recommend lifestyle changes, drug therapy, and revascularization procedures.3,4 Current treatment strategies are to identify and treat underlying conditions that may contribute to angina symptoms, modify risk factors, improve a patient’s health and survival through pharmacologic and nonpharmacologic means, and utilize revascularization procedures through evidence-based practice.5 To date, several studies have examined resource utilization in patients with angina pectoris. These studies have examined the direct costs of chronic angina using national health statistics, as well as information in 2 large clinical trials—the COURAGE and MERLIN-TIMI 36 trials.1,6,7 However, no data exist comparing the manifestation of CAD with or without documented angina.

Few US studies have examined treatment patterns, resource utilization, and the cost of care for patients with CAD plus angina. Javitz and colleagues, who conducted the only database study to investigate the annual direct medical costs of chronic angina, reported annual costs ranging from $1.9 billion to $74.8 billion, depending on the way in which angina was defined.8 The study was conducted from a societal perspective, using the National Center for Health Statistics’ publicuse databases. Given the considerable burden of stable ischemic heart disease and the paucity of information

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about its economic impact, with particular emphasis in the public healthcare sector, the objective of the current study was to compare real-world treatment patterns and costs of CAD with angina versus CAD without angina in a large, commercially insured, managed care population.

Methods Data Source This large, retrospective database analysis used eligibility, medical, and pharmacy claims data from a nationwide commercial managed care plan affiliated with OptumInsight that covers more than 13 million individuals. Procedures for selecting study participants were in compliance with the Health Insurance Portability and Accountability Act of 1996.9,10 This study was approved by the privacy board associated with the New England Institutional Review Board.

Study Sample Patients in the study population had physician or hospital claims between July 1, 2004, and June 30, 2006, that included International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic,11 or ICD-9-CM Current Procedural Terminology (CPT), or Healthcare Common Procedure Coding System (HCPCS) procedure codes (in any position) consistent with a diagnosis of CAD (ICD-9-CM codes 410.xx, 411.x, 412, 414.xx, 429.2, 429.5, 429.6, 429.7x, 996.03, V45.81, V45.82; ICD-9-CM procedure codes 36.0x, 36.1x, 36.2, 36.3x; CPT codes 33140, 33141, 33510-33523, 33533-33536, 33572, 92975, 92996, 93540; or HCPCS codes G0290, G0291, S0340-S0342, S2205-S2209).

Eligible patients were enrolled in the plan for 6 months before receiving their ICD-9-CM code (ie, the index date) and for 12 months after the index date (ie, postindex period).

A subgroup of these patients was identified as having CAD with angina. Patient identification was based on 6 algorithms used in the study by Javitz and colleagues.8 After those algorithms were modified to be more reflective of the patient population in the current study, a medical chart review was conducted. This review determined the positive predictive value of each algorithm for identifying the greatest number of patient charts with an angina diagnosis relative to the total number of charts reviewed.

Stratification of the algorithms by their positive predictive values (Table 1) showed that 3 had high values (algorithms 1, 3, and 5: 80%-95%), 1 had an intermediate value (algorithm 2: 67%), and 2 had low values (algorithms 4 and 6: 52% and 25%, respectively).

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The primary analyses for this study were based on a 3-algorithm patient-identification model (using algorithms 1, 3, and 5), which had a combined positive predictive value of 89% (95% confidence interval [CI], 0.79-0.95). Secondary analyses were based on a 4-algorithm model (using algorithms 1, 2, 3, and 5), which had a combined positive predictive value of 83% (95% CI, 0.73-0.90).

Patients were divided into 2 cohorts. The first cohort, consisting of patients with CAD with angina, included individuals who were identified by the 3-algorithm model (primary analyses) or by the 4-algorithm model (secondary analyses). The second cohort, consisting of patients with stable ischemic heart disease without angina, included patients who were identified by algorithms with an intermediate or low positive predictive value and those who were not identified by any of the algorithms.

Outcome Variables Healthcare utilization and direct costs during the 12 months after the identification index date were determined for each patient in both cohorts. Utilization measures included the number of physician and other outpatient visits, emergency department visits, hospitalizations, and revascularization procedures, as well as the number of prescriptions filled. Annual CAD-related direct costs were measured for outpatient visits, hospitalizations, and pharmacy costs, and the total costs (medical plus pharmacy) were calculated. Total all-cause costs (medical plus pharmacy), including CAD-related and non–CAD-related costs, were also calculated. Costs were not consumer-price adjusted to the current year, and reflect the costs in the year in which the services occurred. Indirect costs were not evaluated, because such costs are not available in the database used.

Table 1 Assessment of Algorithms for Positive Predictive Value in Identifying Patients with Angina Algorithm

Description a

Frequency, N (%)

Positive predictive value

95% CI

5987 (13)

0.95

0.74-0.99

12,405 (28)

0.67

0.45-0.84

3246 (7)

0.80

0.59-0.93

11,112 (25)

0.52

0.31-0.73

1

2 angina diagnoses and 2 nitrates (≥30-day gap)

2

2 angina diagnosesa and • 2 beta-blockers (≥30-day gap) or • 2 calcium channel blockers (≥30-day gap)

3

1 angina diagnosis and 2 nitrates (≥30-day gap)

4

1 angina diagnosis and • 2 beta-blockers (≥30-day gap) or • 2 calcium channel blockers (≥30-day gap)

5

2 nitrates (30-150 days apart) and • 2 CAD diagnosesa and • 2 chest pain diagnosesa

6075 (14)

0.95

0.75-0.99

6

1 nitrate and • No angina diagnosis and • No CAD diagnosis and • No chest diagnosis and • No hydralazine and isosorbide prescription filled within 90 days of each other

5861 (13)

0.25

0.07-0.52

1, 3, 5

Combination of 3 groups

15,308

0.89

0.79-0.95

1, 2, 3, 5

Combination of 4 groups

27,713

0.83

0.73-0.90

Total

All 6 groups

44,686

—

—

a

Patients included in the study had 2 claims with a diagnosis in the ICD-9-CM primary or secondary position on different dates for any setting (other than laboratory) or 1 diagnosis in the primary position during an inpatient stay.

CAD indicates coronary artery disease; CI, confidence interval; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.

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Table 2 Demographic and Clinical Characteristics of the Study Population CAD without CAD with angina angina (N = 230,919) (N = 15,308) P valuea

Variable

59 (11.50)

61 (11.27)

<.001

35-44 yr

23,642 (10)

855 (6)

<.001

45-54 yr

61,027 (26)

3630 (24)

<.001

55-64 yr

86,324 (37)

6093 (40)

<.001

â&#x2030;Ľ65 yr

59,926 (26)

4730 (31)

<.001

Male

145,230 (63)

10,037 (66)

<.001

Female

85,689 (37)

5271 (34)

<.001

Baseline

0.81 (1.29)

1.30 (1.65)

<.001

Follow-up

1.51 (1.80)

2.44 (2.16)

<.001

Age, yr, mean (SD) Age-group, N (%)

Gender, N (%)

CCI score, mean (SD)

a

P value for comparison between the CAD-without-angina and CAD-with-angina cohorts.

CAD indicates coronary artery disease; CCI, Charlson comorbidity index; SD, standard deviation.

The extent of clinically significant comorbidity was determined using the Charlson comorbidity index (CCI).12 A patientâ&#x20AC;&#x2122;s CCI score reflects the cumulative increase in the likelihood of 1-year mortality as a result of severity of comorbidity, with higher scores indicating a greater risk for death. The CCI has been modified for use with administrative databases, including the ICD-9CM database.13,14 CCI scores before and after a patientâ&#x20AC;&#x2122;s index date were determined.

Statistical Analysis All study variables, including baseline and follow-up measures, were analyzed descriptively using the SAS version 9.1.3 (SAS Institute, Cary, NC) data analysis system. Dichotomous variables were analyzed using chisquare tests, and continuous variables were compared using t-tests.

Healthcare costs of study participants were highly variable, with some accruing thousands and others accruing millions of dollars in costs. Therefore, a generalized linear model was used to compare CAD-related costs and overall costs between the cohort with CAD and angina and the group with CAD without angina.

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The model controlled for the effect of other confounding variables, including age, sex, health plan region, CCI score, and measures of baseline utilization. A generalized linear model assuming a gamma distribution and using a log link was employed to estimate adjusted costs for the 2 cohorts. Generalized linear modeling was conducted using Stata version 9 (Stata Corporation, College Station, TX).

Results Of 246,227 patients with CAD, the 3-algorithm model assigned 230,919 (93.8%) to the CAD-withoutangina cohort and 15,308 (6.2%) to the CAD-withangina cohort (Table 2). Patients identified as having angina were significantly older than, but not clinically differentiated from, those without angina (mean age, 61 vs 59 years, respectively; P <.001). Both cohorts had a preponderance of men, because women tend to have a lower incidence of CAD than men until more advanced age.15 In both cohorts, the mean CCI score was higher during the 12 months after the index date than in the 6 months before the index date, but baseline (preindex) and follow-up (postindex) CCI scores were significantly higher (P <.001) in patients with angina than in those without angina, suggesting an increased burden of comorbidity in patients with angina.

Resource Utilization The CAD-with-angina cohort used considerably more resources than the cohort of patients with CAD without angina (Figure 1). Patients with CAD and angina were significantly more likely to be hospitalized (41% vs 11%, respectively; P <.001). Compared with 12% of patients with CAD without angina, 34% of those with angina visited the emergency department during the follow-up year (P <.001). The proportion of patients who visited a physician or other outpatient healthcare provider at least once during the follow-up period was 94% in the CAD-with-angina cohort and 79% in the CAD-without-angina cohort (P <.001), and the average number of outpatient visits was higher for patients with angina than for those without angina (6.7 vs 2.6 visits, respectively; P <.001).

Figure 2 shows the proportion of patients who received at least 1 prescription for cardiovascular medications during the follow-up period. Across all categories, patients who had CAD with angina were more likely to receive a prescription than those without angina.

Patients with CAD and angina had a significantly higher rate of revascularization procedures during the follow-up period than those without angina (35% [5288/15,308] vs 8% [19,466/230,919], respectively;

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Resource Utilization in Patients with and Figure 1 without Angina during the 12-Month Follow-Up Period

Proportion of Patients with/without Angina Who Figure 2 Received at Least 1 Prescription for Cardiovascular Medication during Follow-Up Period

100

Patients prescribed medication, %

Resource use by patients during postindex follow-up year, %

CAD without angina (N = 230,919) CAD with angina (N = 15,308) 94% 79% 75

50 41% 34% 25 11%

12%

0 Hospitalizations

Emergency department visits

CAD without angina (N = 230,919) CAD with angina (N = 15,308)

98%

100 90

85%

80 70

60%

60 50

44%

40 30 20

20%

18%

10 0 Lipidlowering agents

Betablockers

ACE inhibitors

AT-II receptor blockers

Calcium channel blockers

P <.001 for CAD without angina versus CAD with angina.

ACE indicates angiotensin-converting enzyme; AT-II, angiotensin-II; CAD, coronary artery disease.

P <.001). Analysis of first revascularization interventions showed that percutaneous coronary intervention (PCI) or stent procedures were common in both cohorts, but that a significantly greater percentage of patients who had CAD with angina had such a procedure compared with those without angina (84% [4422/5288] vs 73% [14,300/19,466], respectively; P <.001). Among patients with CAD who had a revascularization procedure during the follow-up period, 57% (2994/5288) of the patients with angina compared with 53% (10,406/19,466) of those without angina had more than 1 procedure (data not shown in this article).

Direct Costs The greater resource utilization by patients in the CAD-with-angina cohort is reflected in the direct costs of treating a patient with angina during the follow-up period. Comparison of 12-month CAD-related, perpatient costs showed that patients with angina had significantly higher costs than those without angina in all resource categories (Figure 3).

Average inpatient costs were higher for patients who had CAD with angina than for those without angina ($9536 vs $2169, respectively; P <.001). Emergency department and outpatient costs were also higher for patients with angina. Because patients who had CAD with angina were more likely to receive prescription

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21%

Medications

P <.001 for CAD without angina versus CAD with angina.

CAD indicates coronary artery disease.

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31% 17%

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Nitrates

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medication, average annual pharmacy costs were higher for patients with angina than for those without angina ($1499 vs $891, respectively; P <.001).

During the 12-month follow-up period, average medical and pharmacy costs were $14,851 for patients who had CAD with angina compared with $4449 for patients who had CAD without angina (P <.001). Comparison of all-cause total medical and pharmacy costs revealed a similar pattern. The average per-patient all-cause cost was $28,590 for patients who had CAD with angina compared with $14,334 for patients who had CAD without angina. This almost 2-fold increase in per-patient costs among patients with angina probably reflects the increased burden of comorbidity in this cohort.

The general linear model results in adjusted stable ischemic heart diseaseâ&#x20AC;&#x201C;related costs of $4418 for CAD without angina and $14,357 for CAD with angina. The adjusted all-cause costs were $14,415 for CAD without angina and $27,239 for CAD with angina (P <.001 for both).

Results Obtained with the 4-Algorithm Model Although the patient cohorts identified by the 3algorithm model were used for the primary study analyses, additional analysis based on the 4-algorithm model was conducted to assess the sensitivity of the results on cohort selection. Results based on the 4-algorithm model were similar to those obtained with the 3-algo-

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rithm model. For example, the proportion of patients with angina who had a revascularization procedure during the follow-up period was 35% using the 3-algorithm model and 34% using the 4-algorithm model.

artery bypass graft. Both CAD-related and nonâ&#x20AC;&#x201C;CADrelated medical and pharmacy costs were considerably higher in patients who had CAD with angina.

The implications of our study support that ischemic heart disease continues to account for the vast majority of cardiac disease, including hospitalizations for myocardial infarctions, unstable angina, and evaluation and treatment of stable chest pain syndromes. Of note, our study provides further evidence that patients with active symptoms remain at increased risk for morbidity, revascularization procedures, and polypharmacy, with a substantial increase in healthcare resource utilization compared with patients with CAD without angina.

Results similar to those obtained in this US-based study have previously been reported for studies conducted in the United Kingdom,16,17 Sweden,18,19 Switzerland,20 Australia,21 and Italy.22 Although these studies showed that pharmacy costs and physician and emergency department visits contribute to the high and steadily growing annual healthcare costs of patients with chronic angina, the increasing use of revascularization procedures is the major contributor to these costs. This point is confirmed by the evaluation of the relative cost and cost-effectiveness of PCI compared with an optimal

Discussion Whereas managed care pharmacy directors are often aware of the costs associated with managing CAD, they may not be as familiar with the additional incremental burden associated with angina. In evaluating therapies specifically for angina, this can be important information for making appropriate formulary decisions.

Our study shows that the CAD-with-angina cohort consumed more healthcare resources than the CADwithout-angina cohort, which is probably associated with an increase in the burden of comorbidities in this cohort. Compared with patients with CAD without angina, those with angina were more likely to be hospitalized, to visit the emergency department, to visit a physician or other outpatient healthcare provider, and to receive polypharmacy cardiovascular drug regimens.

Similarly, patients who had CAD with angina were more likely than those without angina to have a first-time revascularization procedure or a first-time coronary

Figure 3 CAD-Related per-Patient Direct Medical/Pharmacy Costs for Patients with/without Angina during the Follow-Up Period

Yearly average per-patient costs, $

30,000

$28,590

CAD without angina (N = 230,919) CAD with angina (N = 15,308) $24,244

25,000

20,000 $14,851

15,000

$14,334

$13,352 $11,686 $9536

10,000

5000 $2169 $60 $235

0

D CA

t en ati p in

D CA

rtm pa e yd nc e g er em

t en D CA

$3211 $1208

ory lat u b am

$4449

$3558

$4346 $2648

$891 $1499

D CA

al dic e m D CA

arm ph

y ac

D CA

t ot

al -ca All

e us

al dic e m

rm ha p e us -ca l l A

y ac

et us a c All

ot a

l

Costs

P <.001 for CAD without angina versus CAD with angina.

CAD indicates coronary artery disease.

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treatment strategy from the COURAGE trial.6 The addition of PCI to optimal medical therapy was not found to be a cost-effective initial management strategy for symptomatic chronic CAD.6 The findings of the present study are confirmed by a systematic review of 47 studies of the economic burden of illness for patients with CAD and angina, conducted

by Reynolds and colleagues.23 In addition to showing that revascularization procedures were the major determinant of healthcare costs for patients with chronic angina, that review suggested that these procedures had only a modest and transient beneficial effect on patients’ work status.23 In many studies, the increase in the proportion of patients who were employed 6 months to 1 year after revascularization was less than 25%, and the results of studies with multiyear follow-up periods suggested that most patients who initially returned to work were no longer employed within several years of the initial procedure. Planned departure from the workforce upon reaching retirement age seems to have had only a minor impact on patients’ employment status.

Although our study did not directly address the indirect costs of CAD, those costs are important. Indirect costs of lost workdays, reduced productivity, and longterm medications may be as great as the direct costs measured by this present study, as suggested by Shaw and colleagues.24 A more recent study—a substudy of the MERLINTIMI 36 trial investigating the economic impact of angina after acute coronary syndrome (ACS)—showed that patients with CAD plus angina had a >2-fold increase in resource utilization and an additional $4000 in incremental costs at 8 months of follow-up after an ACS event.7 The difference was mostly attributable to higher rates of hospitalization and revascularization procedures among patients admitted for ACS with more severe angina.

The magnitude of this problem is estimated to be in the tens of billions of dollars.

In our database study, we used a rigorous methodology to identify patients with angina. We hypothesized that identifying patients in a claims database would be challenging for several reasons. For example, physicians may use angina codes during the screening of patients eventually found to have other causes of chest discomfort, and various ICD-9-CM diagnostic and medication codes are routinely used for patients with angina.

Although the use of managed care claims data is attractive, because it shows real-world practice patterns, it does not explain why clinicians selected a particular code for a diagnosis or medication, nor does it permit an assessment of the accuracy of these codes for identifying a specific disease.

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A typical method for identifying a patient with a particular disease in a claims database is to find 2 separate events with a primary ICD-9-CM disease diagnostic code combined with at least 2 claims with the medication code for the drug most often used to treat that disease. When we considered the best approach for identifying patients with angina, we realized that this symptom could be described as either “angina” or “chest pain.”

Although nitrates are the primary drug treatments for angina, many other medications may also be prescribed.

We therefore assumed that we would fail to identify a large proportion of patients with angina if we used only the diagnostic code for angina and the medication codes for nitrates.

To increase the likelihood of obtaining a representative sample of patients with angina, we examined the algorithms used in the study by Javitz and colleagues,8 modified them to reflect the composition of our database, and based on the results of a medical chart review, stratified the 6 algorithms according to their positive predictive value. We then defined our 2 study cohorts using a model that incorporated the 3 algorithms with the highest positive predictive value (a combined value of 89%), although we performed some secondary analyses using a 4-algorithm model with a combined positive predictive value of 83%.

When we compared the outcomes of patients identified as having angina by the 3- and 4-algorithm models, we observed only minor differences. Both models revealed significantly higher rates of resource utilization and significantly higher CAD-related and non–CADrelated direct costs for patients with angina than for those without angina. The 3-algorithm patient-identification model was chosen because of its higher positive predictive value, indicating that the 3-algorithm model selects patients with true angina with a higher probability than other algorithms.

We found that the outcome measures we used were essentially unrelated to the slightly different definitions of angina in the 2 models, adding to the robustness of our findings. Therefore, in the 3-algorithm model used in this article, 35% of angina patients underwent revascularization compared with 34% in the 4-algorithm model.

Limitations This study shares the limitations inherent to all administrative claims studies. Claims data are collected for the purpose of determining reimbursement rather than of facilitating research, and the extent to which these data can accurately capture a diagnosis is limited.25-34 In contrast, claims data provide a snapshot of a real-world treatment environment based on the actual use of healthcare resources and their costs. Admin-

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istrative data have demonstrated reasonably good concordance with medical record or patient survey data.25-35 The cause of the incremental cost differences is difficult to assess; for example, some of the increased burden associated with patients who have CAD with angina may be because of increased physician contact and services resulting from the additional diagnosis, and not specifically from angina.

The results of this study can be generalized only to a limited extent. The managed care database on which the study was based represents a population of commercially insured patients. Therefore, these patients are relatively younger (ie, non-Medicare population), with a lower burden of comorbidity than would typically be found in databases of Medicare recipients.

The results of this study are relevant to the treatment of cardiovascular disease in a managed care setting.

Conclusion This study demonstrates that among commercially insured US patients diagnosed with and treated for CAD in a managed care setting, patients with angina make significantly greater use of healthcare resources than patients without angina. In the year after their CAD diagnosis, patients with angina are considerably more likely to have a revascularization procedure than those without angina. This greater resource utilization, if not based on evidence-based practice, may result in significantly higher annual direct costs for patients with angina. Additional analyses are warranted to further evaluate the impact of these findings as they relate to medical practice and pharmacy services, perhaps via prospective trial designs and/or observational research.

The pattern of healthcare utilization observed in this study suggests that patients with angina may seek care, obtain incomplete relief of their symptoms, and then continue to seek care. For patients treated in a managed care environment, therapeutic approaches that are consistent with current treatment guidelines and reduce the frequency and severity of angina attacks could result in substantial savings in terms of resource usage and direct economic costs in managed care organizations. ■ Acknowledgment This study was supported by funding from Gilead Pharmaceuticals (formerly CV Therapeutics).

Author Disclosure Statement Dr Kempf was employed by CV Therapeutics (Gilead) when this article was written; Ms Buysman is an employee of OptumInsight, which was contracted by CV Therapeutics (Gilead) to conduct this research; Dr Brixner has received consultant support for this research.

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References 1. Lloyd-Jones D, Adams RJ, Brown TM, et al, for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation.

2010;121:e46-e215. Erratum in Circulation. 2010;121:e260.

2. Mensah GA, Brown DW. An overview of cardiovascular disease burden in the United States. Health Aff (Millwood). 2007;26:38-48.

3. Gibbons RJ, Abrams J, Chatterjee K, et al, for the American College of Cardiology and American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article. J Am Coll Cardiol. 2003;41:159-168.

4. Fraker TD Jr, Fihn SD, Gibbons RJ, et al, for the American College of Cardiology, American Heart Association, and American College of Cardiology/American Heart Association task force on practice guidelines writing group. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina. Circulation. 2007;116:2762-2772. Epub 2007 Nov 12.

5. Lucas FL, DeLorenzo MA, Siewers AE, Wennberg DE. Temporal trends in the utilization of diagnostic testing and treatments for cardiovascular disease in the United States, 1993-2001. Circulation. 2006;113:374-379.

6. Weintraub WS, Boden WE, Zhang Z, et al, for the Department of Veterans Affairs Cooperative Studies Program No. 424 (COURAGE Trial) investigators and study coordinators. Cost-effectiveness of percutaneous coronary intervention in optimally treated stable coronary patients. Circ Cardiovasc Qual Outcomes. 2008;1:12-20.

7. Arnold SV, Morrow DA, Lei Y, et al. Economic impact of angina after an acute coronary syndrome: insights from MERLIN-TIMI 36 trial. Circ Cardiovasc Qual Outcomes. 2009;2:344-353. Epub 2009 Jun 2.

8. Javitz HS, Ward MM, Watson JB, Jaana M. Cost of illness of chronic angina. Am J Manag Care. 2004;10(suppl 11):S358-S369.

9. Health Insurance Portability and Accountability Act of 1996. Public Law No. 104-191, 110 Stat 1936;1996. www.cms.gov/hipaageninfo/downloads/hipaalaw.pdf.

Accessed September 13, 2011.

10. Gunn PP, Fremont AM, Bottrell M, et al. The Health Insurance Portability and Accountability Act privacy rule: a practical guide for researchers. Med Care. 2004; 42:321-327.

11. CDC. Coding Clinic for ICD-9-CM: Official Guidelines for Coding and Reporting. www.cdc.gov/nchs/data/icd9/icd9cm_guidelines_2011.pdf. Accessed September 13, 2011.

12. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-383.

13. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613-619.

14. Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43:1130-1139.

15. Vaccarino V, Parsons L, Every NR, et al. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med. 1999;341:217-225.

16. Stewart S, Murphy NF, Walker A, et al. The current cost of angina pectoris to the National Health Service in the UK. Heart. 2003;89:848-853.

17. Sculpher M, Smith D, Clayton T, et al. Coronary angioplasty versus medical therapy for angina. Health service costs based on the second Randomized Intervention Treatment of Angina (RITA-2) trial. Eur Heart J. 2002;23:1291-1300.

18. Andersson F, Kartman B. The cost of angina pectoris in Sweden. Pharmacoeconomics. 1995;8:233-244.

19. Zethraeus N, Molin T, Henriksson P, Jönsson B. Costs of coronary heart disease and stroke: the case of Sweden. J Intern Med. 1999;246:151-159.

20. Claude J, Schindler C, Kuster GM, et al, for the Trial of Invasive versus Medical therapy in the Elderly (TIME) investigators. Cost-effectiveness of invasive versus medical management of elderly patients with chronic symptomatic coronary artery disease. Findings of the randomized trial of invasive versus medical therapy in elderly patients with chronic angina (TIME). Eur Heart J. 2004;25:2195-2203.

21. Calver J, Brameld KJ, Preen DB, et al. High-cost users of hospital beds in Western Australia: a population-based record linkage study. Med J Aust. 2006;184:393-397.

22. Conti A, Pieralli F, Sammicheli L, et al. Updated management of non-ST-segment elevation acute coronary syndromes: selection of patients for low-cost care: an analysis of outcome and cost effectiveness. Med Sci Monit. 2005;11:CR100-CR108.

23. Reynolds MW, Frame D, Scheye R, et al. A systematic review of the economic burden of chronic angina. Am J Manag Care. 2004;10(suppl 11):S347-S357.

24. Shaw LJ, Merz CN, Pepine CJ, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health—National Heart, Lung, and Blood Institute—sponsored Women’s Ischemia Syndrome Evaluation. Circulation. 2006;114:894-904. Epub 2006 Aug 21.

25. Rawson NS, Malcolm E. Validity of the recording of ischaemic heart disease and chronic obstructive pulmonary disease in the Saskatchewan health care datafiles. Stat Med. 1995;14:2627-2643.

26. Humphries KH, Rankin JM, Carere RG, et al. Co-morbidity data in outcomes research: are clinical data derived from administrative databases a reliable alternative to chart review? J Clin Epidemiol. 2000;53:343-349.

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27. Romano PS, Roos LL, Luft HS, et al. A comparison of administrative versus clinical data: coronary artery bypass surgery as an example. Ischemic Heart Disease Patient Outcomes Research Team. J Clin Epidemiol. 1994;47:249-260.

28. Jollis JG, Ancukiewicz M, DeLong ER, et al. Discordance of databases designed for claims payment versus clinical information systems: implications for outcomes research. Ann Intern Med. 1993;119:844-850.

29. Dans PE. Looking for answers in all the wrong places. Ann Intern Med. 1993;119:855-857.

30. Jollis JG. Utility and limitations of claims data [letter]. Ann Intern Med. 1994;120:1049-1051.

31. Muhajarine N, Mustard C, Roos LL, et al. Comparison of survey and physician claims data for detecting hypertension. J Clin Epidemiol. 1997;50:711-718.

32. Fowles JB, Lawthers AG, Weiner JP, et al. Agreement between physiciansâ&#x20AC;&#x2122; office records and Medicare Part B claims data. Health Care Financ Rev. 1995;16:189-199.

33. Quan H, Parsons GA, Ghali WA. Validity of procedure codes in International Classification of Diseases, 9th revision, clinical modification administrative data.

Med Care. 2004;42:801-809.

34. Quan H, Truman C, Jin Y, Ghali WA. Combination of hospital discharge and physician claims data improves detection of procedures. Presented at the AcademyHealth Annual Research Meeting, June 26-28, 2005; Boston, MA. Abstract 3388.

35. Tang PC, Ralston M, Arrigotti MF, et al. Comparison of methodologies for calculating quality measures based on administrative data versus clinical data from an electronic health record system: implications for performance measures. J Am Med Inform Assoc. 2007;14:10-15. Epub 2006 Oct 26.

STAKEHOLDER PERSPECTIVE Medical Claims Data Can Inform Coverage Decisions in Managed Care Health Plans RESEARCHERS: Actionable information within a healthcare setting is predicated on access to data and analyses relevant to patients and healthcare providers in that setting. The original research by Kempf and colleagues in this article provides a superb example of exploiting an administrative claims database to inform decisions regarding coverage and program design in patients with coronary artery disease (CAD) with or without angina in a nationwide commercial managed care plan.

Richly annotated, the article provides excellent descriptions of case ascertainment procedures within the limitations of a claims database, develops a coherent analytic model for adjusted analyses, and evaluates the impact of alternative methods of analyses on results and conclusions. The authorsâ&#x20AC;&#x2122; examination of the challenges associated with administrative claims research using this study as a model is particularly instructive.

The precautionary note regarding generalization of results beyond the demographic of participants in a commercial managed care setting within the United States is laudable.

PAYERS: Even with adjustments controlling for confounding variables, physician and other outpatient visits, emergency department visits, hospitalizations, revascularization procedures, and prescription medication differ significantly and appreciably between patient cohorts. Particularly notable, the increase in all-cause direct medical and pharmacy costs driven by revascularization procedures and increased physician contact in CAD patients with angina is corroborated by analyses conducted internationally, as well as by results from substudies in prospective interventional research. Convergent observations across study designs

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and geographic locations emphasize the methodologic rigor that characterizes this study and reinforce the importance of aggressive management of active symptomatology in the treatment of patients with stable chest pain syndromes.

The data strongly suggest that programmatic interventions may be most effective in the year after initial CAD diagnosis, and they generate testable hypotheses regarding day-to-day angina self-management skills for future inquiry.

PATIENTS: The analyses do not address direct (out-of-pocket) costs incurred by patients with CAD with and without angina. However, both indirect (time-related) and direct costs incurred by patients and family members resulting from increased contacts with healthcare providers and utilization of other healthcare resources can be deduced from the conclusions of the study. These include adverse impacts on leisure and household work activities, as well as on workplace attendance and productivity resulting from an increased frequency of physician contact on the part of patients with CAD who obtain incomplete symptom relief, and therefore, repetitively seek medical care and eventually require procedural intervention for symptom control.

The results of this study also heighten awareness regarding the importance of self-management education activities, including medication, exercise/diet, symptom monitoring, and particularly, decisions about seeking emergency medical assistance.

Michael F. Murphy, MD, PhD Chief Medical & Scientific Officer Worldwide Clinical Trials, King of Prussia, PA

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Celgene is now joining the battle against metastatic breast cancer

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

If you need help accessing ABRAXANE for your patients, please call Celgene Patient Support ® at 800-931-8691 or visit www.abraxane.com.

Please see Important Safety Information on adjacent page.

Please see brief summary of full Prescribing Information on the following pages.

ABRAXANE® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation

03/11

ABR11012

ABRAXANEÂŽ for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

IMPORTANT SAFETY INFORMATION WARNING ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drugâ&#x20AC;&#x2122;s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. ADDITIONAL WARNINGS s The use of ABRAXANE has not been studied in patients with renal dysfunction.

In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL Pregnancy-Teratogenic Effects: Pregnancy Category D s ABRAXANE can cause fetal harm when administered to a pregnant woman s If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus s Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE Use in Males: s Men should be advised to not father a child while receiving treatment with ABRAXANE Albumin (human): s ABRAXANE contains albumin (human), a derivative of human blood PRECAUTIONS Drug Interactions: s No drug interaction studies have been conducted with ABRAXANE s Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 Hematology: s ABRAXANE therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3 s It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE s Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3 s In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended Nervous System: s Sensory neuropathy occurs frequently with ABRAXANE s The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification s If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE Hepatic Impairment: s Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution

s The starting dose should be reduced for patients with moderate and severe hepatic impairment Injection Site Reaction: s Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial s Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration Nursing Mothers: s It is not known whether paclitaxel is excreted in human milk s Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE therapy Ability to Drive and Use Machines: s Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines ADVERSE EVENTS s Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial s These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension s Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely s During postmarketing surveillance, rare reports of congestive heart failure and left ventricular dysfunction were observed, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%), infections (24%), vomiting (any 18%; severe 4%), and mucositis (any 7%; severe <1%).

Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), renal dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). In clinical trials and during postmarketing surveillance, dehydration was common and pyrexia was very common. Rare occurrences of severe hypersensitivity reactions have also been reported during postmarketing surveillance.

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

Rx Only

(paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Brief Summary of Full Prescribing Information.

WARNING ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. INDICATION: ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

CONTRAINDICATIONS: ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.

WARNINGS: Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity. ABRAXANE should not be administered to patients with baseline neutrophil counts of < 1,500 cells/mm3. Frequent monitoring of blood counts should be instituted during ABRAXANE treatment. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.

The use of ABRAXANE has not been studied in patients with renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. Pregnancy – Teratogenic Effects: Pregnancy Category D: ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women using ABRAXANE®. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Use in Males Men should be advised to not father a child while receiving treatment with ABRAXANE (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of effects of ABRAXANE exposure on male fertility and embryonic viability).

Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

PRECAUTIONS: Drug Interactions No drug interaction studies have been conducted with ABRAXANE. The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4 (see CLINICAL PHARMACOLOGY).

Hematology ABRAXANE® therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended (see DOSAGE AND ADMINISTRATION).

Nervous System Sensory neuropathy occurs frequently with ABRAXANE. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate and severe hepatic impairment. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION, Hepatic Impairment) Injection Site Reaction Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of ABRAXANE has not been studied.

Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Administration of paclitaxel protein-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately

1 to 5% of the daily maximum recommended human exposure on a mg/m2 basis). Testicular atrophy/ degeneration has also been observed in single-dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m2 and dogs administered 175 mg/m2 (see WARNINGS).

Pregnancy: Teratogenic Effects: Pregnancy Category D: (See WARNINGS section).

Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Following intravenous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE® therapy.

Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE, 11% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among elderly patients who received ABRAXANE. Ability to Drive and Use Machines Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines.

ADVERSE REACTIONS: The following table shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE® or paclitaxel injection for the treatment of metastatic breast cancer.

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE® Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 1 <1 < 8 g/dL 24 20 Infections Febrile Neutropenia 2 1 Bleeding 2 2 Hypersensitivity Reactione All 4 12 2 Severef 0 Cardiovascular Vital Sign Changesg Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsf 3 4 Abnormal ECG All patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsf 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsf 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsf 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsf 0 <1 Gastrointestinal Nausea Any symptoms 30 22 Severe symptomsf 3 <1 Vomiting Any symptoms 18 10 Severe Symptomsf 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsf <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsf <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 (continued)

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule, Continued Percent of Patients ABRAXANE® Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225) Hepatic (Patients with Normal Baseline) AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade. b ABRAXANE dose in mg/m2/duration in minutes. c paclitaxel injection dose in mg/m2/duration in hours. d paclitaxel injection pts received premedication. e Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. f Severe events are defined as at least grade 3 toxicity. g During study drug dosing.

Myelosuppression and sensory neuropathy were dose related.

Adverse Event Experiences by Body System Unless otherwise noted, the following discussion refers to the primary safety database of 229 patients with metastatic breast cancer treated with single-agent ABRAXANE® in the randomized controlled trial. The frequency and severity of important adverse events for the study are presented above in tabular form. In some instances, rare severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hematologic Neutropenia, the most important hematologic toxicity, was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2.

In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and 1% of patients in the paclitaxel injection arm.

Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding episodes were reported in 2% of the patients in each treatment arm.

Anemia (Hb <11 g/dL) was observed in 33% of patients treated with ABRAXANE in the randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with normal baseline hemoglobin, 31% became anemic on study and 1% had severe anemia.

Rare reports of pancytopenia have been observed in clinical trials and during postmarketing surveillance of ABRAXANE. Hypersensitivity Reactions (HSRs) In the randomized controlled metastatic breast cancer study, Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE® in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients in the randomized metastatic breast cancer trial. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.

Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension.

Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients in the metastatic breast cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study.

The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.

During postmarketing surveillance, rare reports of congestive heart failure and left ventricular dysfunction have been observed among individuals receiving ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory Reports of dyspnea (12%) and cough (6%) were reported after treatment with ABRAXANE in the randomized trial. Rare reports (<1%) of pneumothorax were reported after treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of radiation pneumonitis have been received in paclitaxel injection patients receiving concurrent radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy.

Neurologic The frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents.

In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent ABRAXANE®. In the randomized trial, sensory neuropathy was observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2% severe) in the paclitaxel injection arm.

The frequency of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients in the randomized trial. In the randomized comparative study, 24 patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.

No incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial.

Cranial nerve palsies and vocal cord paresis have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.

Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel injection safety.

Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in single arm and randomized trials and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients in a single arm study who received higher doses than those recommended (300 or 375 mg/m2).

These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection have suggested persistent optic nerve damage.

Arthralgia/Myalgia Forty-four percent of patients treated in the randomized trial experienced arthralgia/ myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after ABRAXANE® administration, and resolved within a few days.

Hepatic Among patients with normal baseline liver function treated with ABRAXANE in the randomized trial, 7%,

36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Gastrointestinal (GI) Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%, and 7% of ABRAXANE treated patients in the randomized trial.

Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction Injection site reactions have occurred infrequently with ABRAXANE and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported rarely.

Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Asthenia Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE® in the randomized trial.

Asthenia included reports of asthenia, fatigue, weakness, lethargy and malaise.

Other Clinical Events Rare cases of cardiac ischemia/infarction and thrombosis/embolism possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no patients had severe edema. In clinical trials and during postmarketing surveillance of ABRAXANE, dehydration was common and pyrexia was very common.

The following rare adverse events have been reported as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and pruritis have been observed. Additionally, there have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.

Accidental Exposure No reports of accidental exposure to ABRAXANE® have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

OVERDOSAGE: There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

DOSAGE AND ADMINISTRATION: After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel.

Patients should not receive ABRAXANE if AST > 10 x ULN or bilirubin > 5.0 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 4. The dose of ABRAXANE can be increased up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. Patients should be monitored closely. (See CLINICAL PHARMACOLOGY: Hepatic Impairment and PRECAUTIONS: Hepatic Impairment) Table 4: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Levels Bilirubin Levels ABRAXANE a Mild <10 x ULN >ULN to ≤ 1.25 x ULN 260 mg/m2 Moderate <10 x ULN AND 1.26 to 2.0 x ULN 200 mg/m2 Severe <10 x ULN 2.01 to 5.0 x ULN 130 mg/m2 b > 10 x ULN OR > 5.0 x ULN not eligible a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance.

Dose Reduction Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE. HOW SUPPLIED: Product No. 103450 NDC No. 68817-134-50 100 mg of paclitaxel in a single use vial, individually packaged in a carton.

Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light.

Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

This Brief Summary is based on the ABRAXANE Full Prescribing Information Revised: March 2010

ABRAXANE and Abraxis are registered trademarks of Abraxis BioScience, LLC. ©2010 Abraxis BioScience, LLC. All Rights Reserved.

U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006

CALL FOR PAPERS Improving Outcomes in Oncology American Health & Drug Benefits will be publishing a special Theme Issue on Improving Outcomes in Oncology in May 2012.

Readers are invited to submit articles for publication in this theme issue on topics relevant to the clinical, business, and policy aspects of cancer care amidst an economic downturn and inconsistent healthcare outcomes. Original research, white papers, evidence-based comprehensive reviews, cost and utilization evaluations, and case studies are of particular interest.

The editors invite all healthcare stakeholders—actuaries, employers, economists, manufacturers, patients, payers, policymakers, providers, purchasers, regulators, and researchers—to present their data, best practices, innovations, and initiatives to facilitate patient-centered management strategies and benefit design models to improve outcomes and reduce overall costs in the management of patients with cancer.

Readers are invited to submit original, outcomes-based research, white papers, evidence-based comprehensive reviews, and case studies on topics such as: Benefit designs to improve outcomes in cancer management • Best practices in oncology • Comparative research analyses of cancer therapies and diagnostics • Cost-effectiveness of cancer therapies • Employers’ strategies to enhance wellness of employees who are cancer survivors • Emerging and new trends in cancer therapy • End-of-life issues •

Health plan initiatives for controlling costs of cancer care • Palliative care • Pathways and clinical outcomes • Personalized medicine in oncology • Review of current practice guidelines • Targeted cancer therapies • Therapy-associated toxicities • Translational analyses in oncology •

Submission deadline for this issue is February 6, 2012. Articles submitted by January 9 will be given publication priority. All articles will undergo the Journal’s standard peer-review process.

Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com) For more information contact editorial@ahdbonline.com, or call 732-992-1889

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Adapting to Market Changes: Beyond Healthcare Reform F. Randy Vogenberg, PhD, RPh Principal, Institute for Integrated Healthcare, Sharon, MA, Senior Fellow, Jefferson School of Population Health, Philadelphia, PA

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hange in the marketplace cannot be stopped and, therefore, organizational development should not only reflect what is happening today but also prepare each organization to appropriately identify emerging changes in market conditions to best benefit from the opportunities for proper management and growth through change or account management.

This article reviews past and current trends in market changes to encourage those involved in prescribing, paying for, or developing drugs, devices, or diagnostic products to embrace the need to adapt to changes in the healthcare marketplace. Established training methods have delivered high return on investment performance during the past decade for various healthcare organizations and manufacturers. The need for training and for developing capability in healthcare organizations remains timely and perhaps even greater today than in the past.

Training for Market Changes Many market changes or shifts in the US healthcare marketplace since the last World War in the 1950s have required retraining or updated education on a new environment toward patient care management. In the current economic state of tight budgets and the emphasis on return on investment for every dollar spent, it is natural for organizations to resist the notion of having to adapt to yet another change in course occurring in the US healthcare system.

And yet, as the need to positively address organizational development with applied training programs is mounting, and change in healthcare has slowly begun to take place, every healthcare organization is more or less exposed to the consequences of those changes, depending on its product portfolio or other variables directly related to market conditions.

From the perspective of personnel training and development needs, if an organization relies on only an immediate, needs-based approach to change or regards healthcare reform as a matter in the distant future, how will organizational development be determined when change is here, and it is clearly time to start training for that change?

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The following brief review of market changes over the years establishes the case for decision makers in healthcare of the need to address the new reality that highlights the impetus for training for the emerging changes in the healthcare marketplace.

Transitions through Government Initiatives in Healthcare Approximately 30 years after the economic crises brought on by the Great Depression, the Social Security Act of 1965 positioned the US government back at the forefront of healthcare. Medicare and Medicaid not only made the US government a purchaser of healthcare, they also placed the cost of healthcare under public scrutiny, as healthcare itself became an increasingly larger part of the gross domestic product.

If Social Security set the stage for managed care, the Health Maintenance Organization Act of 1973, signed by then-president Nixon, opened a viable economic stream for the development of the managed healthcare marketplace. However, it was not until the 1980s that significant insurance models were developed and truly became a part of the American lexicon.

To this day there remains a lack of consensus among healthcare stakeholders about some of the key concepts embedded in a managed care approach to care, such as a “system of care,” “highest quality care,” and “cost-effective and cost-efficient healthcare.” Such private-sector transitions in the way the “business of healthcare” was conducted were enabled by government regulation over a period of years; these new regulations required education and training for healthcare manufacturer sales personnel and other healthcare stakeholders to be in the most effective position to respond to market opportunities as they developed.

Managed Care Emerges: Payers’ Tactical Decisions The use of case management emerged from the managed care trends prevalent in the 1980s, which successfully reduced costs by removing unnecessary hospitalizations, as well as through the introduction of new and innovative pharmaceuticals that allowed the settings of patient care to change.

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The principles of risk management, cost minimization, and the search for positive outcomes converged over the previous 3 decades to provide a winning formula for purchasers of healthcare and for managed care payers. Such changes in day-to-day operations affected medical decision-making at several levels, including the use of acute versus ambulatory care facilities within the community.

These tactical decisions also required retraining of medical personnel and other healthcare stakeholders with regard to the optimal use of medical care resources, including drugs, devices, and diagnostics, as well as the setting for care delivery to the patient.

Commercial Payers Determine Plan Strategy Such a change does not happen without dilemmas facing key market stakeholders. For example, politicians were loath to allow aggressive managed care management that limited patient choice, as well as purchasers’ insistence on lower cost despite the lack of improvement in patient outcomes. It is the payer environment—government, employers, union funds, and third-party administrators and health plans—that is driving the healthcare system in the United States. Various healthcare manufacturers, including pharmaceutical companies, are reacting to payers’ behavior that is often in conflict with the payers’ and manufacturers’ customer mix, making a win-win situation difficult, at best, for all parties.

For example, pharmacy benefits illustrate an intrinsic tie between pharmaceutical manufacturers and managed care payers. Because of the direct relationship between the success of a medication in the marketplace, or an effective plan management for patient care and the managed care organization, drug therapy itself has become a common denominator between the 2 organizations within the context of a benefit design.

However, too few managed care executives and pharmaceutical manufacturer sales or account teams truly understand the dynamics in which they are forced to operate. As biotechnology and pharmaceutical manufacturers merge, strategic approaches will become increasingly important as the so-called specialty pharmacy dollars represent bigger investments or offsets within a larger part of healthcare spending, namely, medical benefits.

Harkening back to risk management, cost minimization, and seeking positive outcomes, training for the future must include preparation for the anticipated changes rather than focusing on what has happened in the marketplace until now. A critical success factor missed by manufacturers is the ability to develop strategies, define performance, and assess talent to build the market capability to implement, sustain, and build on successful tactics. To be successful in that manner

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requires meaningful training and organizational development efforts at all levels of the organization, including the executive suite.

Healthcare Reform: The Affordable Care Act With the signing of the Patient Protection and Affordable Care Act of 2010 (ACA) and the subsequent Health Care and Education Reconciliation Act, the business of US healthcare was changed. Although some immediate changes were mandated in 2010 (Table), most of the changes would not begin before 2012 or 2014, and then through the end of this decade.

Congress is currently deadlocked on funding the implementation of many key portions of the ACA, but the market has already begun to change in response to commercial plan sponsor initiatives and the anticipated shifts in care coverage requirements in the early part of this decade.

Commercial plan sponsors are free to innovate and have already begun implementing changes related to integrated health management, even before any federal or state healthcare reform implementation.

Even with the 2000-plus pages of congressional legislation, most decisions on what will occur in the marketplace fall to a variety of regulatory agencies in the federal and state governments. Some 159 new boards, bureaucracies, and programs are contained within the healthcare reform legislation, making this one of the most complex pieces of legislation we have seen since the New Deal legislation of the 1930s. This means that true clarity regarding what is required in the marketplace by all stakeholders will not be available for most of this decade.

Therefore, for all manufacturer organizations in particular, reorienting organizational education and continued training to build managed market capability to effectively manage all the coming market changes are requisite to maintaining or optimizing business success through this decade. In particular, commercial plan sponsors are free to innovate and have already begun implementing changes related to integrated health management, even before any federal or state healthcare reform implementation.

Evolution through Biologics, Biotechnology, and Theranostics New technologies represent advances in healthcare

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solutions that offer the desired combination of risk management, cost minimization, and positive outcomes; nevertheless, the anticipated cost of these new technologic solutions remains troublesome for most healthcare stakeholders. Biologic-based products and combinations of diagnostic tests and/or devices that target therapies (known as theranostics or personalized medicine) represent the emerging wave in the healthcare manufacturer research pipelines, but much of what is needed on a dayto-day basis is not new.

Reimbursement experts, new insurance programs,

and other healthcare specialists continue to exist, reinventing themselves and reemerging. New products, new methods of payment, new ways to mitigate risk, new ways to cover costs and share them, new sales forces that provide solutions, and new marketing strategies that seek to educate and improve outcomes are all parts of the continuing change seen in healthcare today. However, it is the increased pace of change that should have grabbed the attention of manufacturers seeking to identify aligned opportunities for improved outcomes.

Table Patient Protection and Affordable Care Act Implementation Overview 2010 • Eliminate preexisting condition for insurance access • Prohibit rescissions and extend dependent coverage • Eliminate lifetime limits and restrict use of annual limits • Part D doughnut hole rebates • Coverage for preventive health services and improving efforts • Small business tax credit • Healthcare fraud initiatives • Improving consumer assistance and new independent appeals process

2012 • Medicare cuts to dialysis center, home health, and inpatient psychiatric hospital reimbursement • Allow accountable care organizations that voluntarily meet quality thresholds to share in achieved cost-savings • Reduce rebates for Medicare Advantage plans but provide bonus payments to high-quality Medicare Advantage plans • Create Medicaid demonstration projects around bundled payments for episodes of care • Reduce Medicare payments for excess preventable hospital readmissions

2011 • Pharmaceutical manufacturers provide 50% discount on brands filled during the doughnut hole period, and phase-in start for federal subsidies for generics in the same doughnut hole period of Medicare Part D • Prohibit Medicare Advantage higher cost-sharing in traditional fee-for-service program • Reduce annual market-basket updates for Medicare providers • Create the Innovation Center within the Centers for Medicare & Medicaid Services • Develop a national quality improvement strategy, with priorities to improve the delivery of healthcare services, patient health outcomes, and population health • Exclude over-the-counter drug cost reimbursement through a health reimbursement account or health flexible-spending account on a tax-free basis

2013 • Start phase-in of federal subsidies for brand prescriptions in Medicare Part D • Require disclosure of financial relationships between healthcare entities, including all licensed professionals, manufacturers, and covered-product distributors • Eliminate tax deduction for employers who receive Medicare Part D retiree drug-subsidy payments 2014 • Require US citizens to have qualifying health coverage and health plans to meet new standards and operating requirements • Impose fees on health plans • Require Medicare Advantage plans to have medical loss ratios no lower than 85% • Insurers cannot impose any coverage restrictions on preexisting conditions • Limits to out-of-pocket cost-sharing

Sources: Committees on Ways & Means, Energy & Commerce, and Education & Labor. Affordable healthcare for America. Health insurance reform at a glance implementation timeline. April 2, 2010. http://docs.house.gov/energy commerce/TIMELINE.pdf. Accessed August 15, 2011. The Henry J. Kaiser Family Foundation. Health Reform Source. Implementation timeline. http://healthreform.kff.org/Timeline.aspx. Accessed August 15, 2011.

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The central themes of adapting proactively to change remain the same, as does the need for lifelong learning—to adapt and survive. Each organization may be more or less exposed to the changing healthcare ecosystem based on the change at hand; therefore, a cost-effective approach may lie in a more sound sequential and developmentally focused organizational development and training strategy, not tactic.

Strategies involve longer-term issues, whereas tactics are very short-term. Who will be affected first in the emerging and changing healthcare market? Are those groups ready now? What will they need to know?

What will good training to meet anticipated near-term and future market needs look like?

Knowing the members or customers and their goals will provide the clues and direction needed to build relevant, enabling programs within each healthcare organization. A clear organizational alignment—with goals and objectives that provide structures and support to enable performance—is the foundation for effective training.

Contemporary business acumen, and addressing a clear strategy for building capability while adapting to market changes, must be embedded into all levels of organizational training to succeed in executing a successful corporate plan. Finally, measurements and metrics of progress made through building marketplace capability drive the market-driven lifelong learning program, as well as talent development.

Conclusion Change in the US marketplace is inevitable and, therefore, effective, and high return on investment and organization development–aligned training should not only reflect what is happening today but also prepare the organization for the next 6 to 18 months. This strategic approach will help an organization to appropriately identify changing marketplace conditions and to best manage the opportunities for enhanced product or patient outcomes and management.

As seen in the evolution of managed care to date, Medicare Part D, and shifts in Medicaid coverage over the past 10 years, reactive or incomplete training failed to adequately support the organization to achieve a valuable return on investment for manufacturer organizations in healthcare.

Understanding the significance of the ACA among other commercial, sponsor-driven marketplace changes, including the emergence of various nongovernment plan sponsors, will only grow in importance over the coming months and through this decade. Based on past experience and proved models for successful, high–return on investment training, the time to start applying an organizational development–driven training system toward effectively managing the healthcare marketplace changes is now. ■ Author Disclosure Statement Dr Vogenberg has reported no conflicts of interest.

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Vol 4, No 6

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ISTODAX® (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Important Safety Information WARNINGS AND PRECAUTIONS:

• Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Due to the risk of QT prolongation, ensure that potassium and magnesium are within the normal range before administration • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) • ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%),

thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).

Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.

The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

Introducing choice in treating PTCL ISTODAX® is now indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated

Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 06/11 IST11004

For more information: Please visit www.ISTODAX.com or call 1-888-423-5436

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information.

1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

• Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the therapy.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)].

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.

Due to the risk of QT prolongation, potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse outcomes.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

5.6 Use in Women of Childbearing Potential Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. An in vitro binding assay determined that romidepsin competes with ß-estradiol for binding to estrogen receptors [See Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1.

Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1.

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) (continued)

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8)

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).

Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome.

Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsorconducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) (continued)

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience.

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors.

Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital)

may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort.

7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse developmental outcomes. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential harm to the fetus.

In an animal reproductive study, pregnant rats received daily intravenous romidepsin during the period of organogenesis up to a dose of 0.06 mg/kg/day (0.36 mg/m2/day). This dose in rats is approximately equivalent to 18% the estimated human daily dose based on body surface area and resulted in 5% reduction in fetal weight. Embryofetal toxicities associated with the use of ISTODAX were not adequately assessed in this study.

8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of endstage renal disease on romidepsin pharmacokinetics has not been studied.

Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].

10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal

vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose.

Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [See References (15)].

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling.

17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients.

Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)].

• Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)].

• Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flulike symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)].

• Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)].

• Use in Women of Childbearing Potential If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling.

ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogencontaining contraceptives [See Warnings and Precautions (5.6)].

• Patients should be instructed to read the patient insert carefully.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.002/PPI.002 06/11

BUSINESS

REVIEW ARTICLE

Review of Strategies to Enhance Outcomes for Patients with Type 2 Diabetes: Payersâ&#x20AC;&#x2122; Perspective Rhonda Greenapple, MSPH Background: Diabetes and its clinical consequences exact a great toll on patients and on society in terms of its effects on morbidity and mortality and its staggering economic impact.

Objective: To review various programs and strategies that aim at enhancing adherence to antihyperglycemic therapy and suggest the best approach to improving patient outcomes and reducing healthcare costs.

Discussion: Treatment goals for patients with diabetes have been defined, and multiple safe and effective medications are available. Nevertheless, the majority of patients with diabetes fail to achieve treatment goals, because of difficulty with adherence to medication regimens and lifestyle modifications, and because of economic barriers. This article discusses various initiatives developed to improve patient outcomes, including consumer-driven health plans and wellness and prevention programs. Furthermore, economic incentives to patients, such as value-based insurance design, may increase adherence; nevertheless, evidence suggests that such programs alone provide only modest gains. Primary providers in disease management programs can include nurses, case managers, or pharmacists. Supportive interventions across several modalities have been shown to be effective.

Conclusion: An approach that uses a combination of strategies designed to impact patientsâ&#x20AC;&#x2122; health-related behaviors across a variety of modalities may help to improve outcomes and reduce costs. Additional novel, innovative interdisciplinary initiatives are necessary to effect meaningful change that can facilitate improved health outcomes for patients with diabetes and maximize cost-effectiveness approaches for payers.

D

iabetes is an important disease state causing significant morbidity and mortality throughout the United States and worldwide. The current obesity epidemic, together with the US aging population, is fueling the rapid increase in diabetes prevalence. A modeling study suggests that by 2020, 15% of adults will have diabetes, and 37% will have prediabetes compared with 12% and 28%, respectively, today.1 By 2050, approximately 15 new diabetes cases per 1000 people are expected annually. This will result in a diabetes prevalence of between 1 in 5 diagnosed adults and 1 in 3 undiagnosed adults.1 Estimates from the Centers for Disease Control and Prevention (CDC) suggest that as of 2007, 23.6 million adults and children in the United States had diabetes; this represented nearly 8% of the US population.2 In addition, 5.7 million individuals who have diabetes Ms Greenapple is President, Reimbursement Intelligence, LLC, Madison, NJ.

Vol 4, No 6

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September/October 2011

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Am Health Drug Benefits.

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remain undiagnosed.2 Currently, type 2 diabetes accounts for at least 95% of diabetes cases.3 Prediabetic patients with elevated blood glucose levels represent 57 million individuals who are at high risk for progressing to diabetes within 10 years.3

Diabetes Comorbidities Patients with type 2 diabetes are at increased risk for the development of cardiovascular disorders, including coronary artery disease (CAD) and stroke. The constellation of symptoms that includes insulin resistance and central obesity greatly increases the likelihood of emergence of additional comorbidities.4 Common comorbidities associated with diabetes include hypertension (Figure 1), hyperglycemia, and dyslipidemia.

Overall, interventions to improve these comorbidities individually result in concurrent improvements in other related clinical parameters. For example, when obese individuals lose weight, insulin resistance is typically diminished, improving blood glucose levels, blood

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KEY POINTS ➤

➤

➤

➤

➤

Patients with type 2 diabetes are at increased risk for cardiovascular disorders, including coronary artery disease, stroke, and peripheral vascular disease.

The costs for diabetic patients with complications are nearly 3-fold greater than for diabetic patients without complications.

The complications of diabetes can be prevented or delayed with appropriate glycemic control, disease management, and ongoing monitoring.

An approach that uses a combination of strategies across a variety of care and payer modalities may provide substantial improvements in patient outcomes and curb the excess costs.

Payers may need to reexamine how they approach the management of care for patients with diabetes.

Figure 1 Prevalence of Comorbidities: Diabetes and Cardiovascular Disease in Adults Aged 20-69 Years 20

Hypertension CAD CHF

16.7%

imately 2 to 4 times higher than adults without diabetes.

And the risk for stroke is 2 to 4 times greater in patients with diabetes compared with those without diabetes.

Macrovascular complications of diabetes include CAD, stroke, and peripheral vascular disease, which can result in ulcers, gangrene, and lower-extremity amputations. Diabetes macrovascular complications associated with larger blood vessels include CVD and stroke, which are responsible for 65% of all deaths in diabetes.5 Macrovascular complications representing small vascular injuries include diabetic retinopathy and peripheral nerve damage. Neuropathy, renal disease, and ocular damage are among the microvascular complications of diabetes. Diabetes is currently the leading cause of endstage renal disease.5 The complications of diabetes can be prevented or delayed with appropriate glycemic control and ongoing disease management and monitoring. The benefits of good glycemic control have a long-term impact on outcomes. For example, a reduction in hemoglobin (Hb) A1c of 1% diminishes the risk for microvascular complications of eye, kidney, and nerve damage by 40%.1 Each 10-mm Hg reduction in systolic BP reduces diabetesrelated complications by 12%, and correction of dyslipidemia may reduce the risk for cardiovascular complications by up to 50%.1

Prevalence, %

15 12% 10 7.4% 5.6% 4.7%

5 2.4%

1.5%

0.8%

0.1%

0 Type 1 diabetes

Type 2 diabetes

Nondiabetic patients

Patient population

CAD indicates coronary artery disease; CHF, chronic heart failure.

Reprinted with permission from Fitch K, et al. Value-based insurance designs for diabetes drug therapy: actuarial and implementation considerations. Milliman Client Report. December 1, 2008.

pressure (BP) typically decreases, and lipid parameters are improved.

Clinical Consequences Patients with diabetes are at great risk for serious and life-threatening complications.5 Adults with diabetes have cardiovascular disease (CVD)-related death rates approx-

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Economic Impact The costs associated with diabetes are staggering.

Data released by the CDC in 2007 showed that the total cost of diagnosed diabetes in the United States was $174 billion, which included $116 billion of direct medical costs and $58 billion of indirect costs (ie, disability, work loss, and premature death).2 An analysis by UnitedHealth Group indicated that the majority of patients with diabetes are covered by private insurance, but the prevalence of diabetes and prediabetes in Medicare and Medicaid populations is higher than among the privately insured; consequently, these programs carry a disproportionate responsibility for healthcare costs attributed to these conditions.1 This analysis included data from a sample of 10 million commercial health plan members, showing that the average annual costs incurred by a patient with diabetes in 2009 was $11,700 compared with annual costs of $4400 for a patient without diabetes.1 Furthermore, the average annual costs incurred by a diabetic patient with complications was $20,700, which is nearly 3 times that of a diabetic patient without complications ($7800).1 Another analysis demonstrated that even when controlling for specific comorbidities, including hypertension, congestive heart failure, and CAD, patients with diabetes require greater expenditures compared with

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nondiabetic patients with those conditions.6 Estimates from the Agency for Healthcare Research and Quality indicate that nearly 25% of hospital spending results from patients with diabetes.7 In addition, hospital admissions for persons with diabetes cost more than comparable admissions for patients without diabetes.1 The optimal management of diabetes requires control of the patientâ&#x20AC;&#x2122;s glucose levels, BP, and lipid levels.

However, a relatively low proportion of patients with diabetes actually achieve the treatment goals. Less than 50% of adults with diabetes aged <65 years demonstrate target HbA1c levels of <7%, as illustrated in Table 1.8 Adherence to antihyperglycemic drug therapy is relatively poor, which is an important reason for limited treatment success.6 A meta-analysis of adherence studies demonstrated a range of adherence between 36% and 93% in retrospective studies, and between 67% and 85% in prospective monitoring studies.9 Multiple studies have confirmed that poor adherence to drug therapy is associated with poor glycemic control; similarly, a strong correlation exists between good compliance and adherence to antihyperglycemic medication regimens and glycemic control. One issue that contributes to poor medication adherence is the burden of copayments.10 With increasing copayments for antihyperglycemic drugs, adherence to prescribed regimens decreases.

Overview of the Approach to Treatment Major medical associations have adopted treatment algorithms and guidelines for the management of patients with diabetes, including the American Diabetes Association, the European Association for the Study of Diabetes, American College of Endocrinology, and the American Association of Clinical Endocrinologists.11 Although there are differences and distinctions in their recommendations, overall treatment approaches include lifestyle modifications to improve diet, increased physical activity, and smoking cessation.

Virtually all patients with diabetes require pharmacologic therapy, however. In addition to achieving glycemic control with target HbA1c levels >7%, medical interventions aim to control BP, correct dyslipidemia, and facilitate weight reduction for patients who are obese or overweight.1 Metformin, a biguanide, is generally the first oral antidiabetic medication administered. Metformin is titrated to maximal effect over 1 to 2 months, with the goal of achieving a significant reduction in HbA1c. If metformin monotherapy does not achieve an HbA1c control level at or near 7%, additional drugs may be added.

Some oral drugs are formulated as combinations (typically with metformin) to enhance compliance with

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Table 1 Control Rates of Blood Glucose, Blood Pressure, and Cholesterol in Patients with Diabetes Control rate for patients aged <65 years

Control rate for patients aged â&#x2030;Ľ65 years

Blood glucose target HbA1c <7%

49%

62%

Systolic BP target <130 mm Hg

60%

33%

HDL-C target >40 mg/dL men, >50 mg/dL women

49%

56%

LDL-C target <100 mg/dL

39%

48%

BP indicates blood pressure; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Reprinted with permission from Fitch K, et al. Improved management can help reduce the economic burden of type 2 diabetes: a 20-year actuarial projection. Milliman Client Report.

April 28, 2010.

multiple-drug combinations. Frequent monitoring is necessary, and clinicians should aggressively modify medication regimens to achieve treatment goals.

Appropriate medication selection requires that physicians be cognizant of all of the potential effects of antidiabetic medications, beyond their effects on hyperglycemia. For example, the vast majority of patients with type 2 diabetes are overweight or obese, yet the use of many antihyperglycemic medications (ie, insulin, sulfonylureas) results in weight gain. Selection of agents that are weight neutral, or promote weight loss, can offer additional advantages to patients.

Other factors to consider include the effects of different medications on dyslipidemia and BP.5 The choice of agents may also depend on their effects on beta-cell function. It is estimated that by the time of diagnosis, patients with type 2 diabetes have lost at least 50% of their beta-cells.12 Preservation of remaining beta-cell function should be a therapeutic priority; weight loss is an important route to this goal. Different antihyperglycemic medications have variable effects on beta-cell function, which should figure in the clinical decision-making.12 For example, the thiazolidinediones promote weight gain, but the thiazolidinedione pioglitazone delays betacell decline. Agents that promote the release of insulin, including sulfonylureas and the glinides, appear to increase the rate of beta-cell failure. Agents that work

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via the incretin pathway, glucagon-like peptide (GLP)-1 analogs and dipeptidyl peptidase (DPP)-4 inhibitors, appear to preserve beta-cell function.12

Unmet Needs Current treatment approaches remain far from solving the problem of diabetes. This enormous unmet need has driven the development of many novel agents that incorporate innovative technologies and address different metabolic pathways.

At least 3 different classes of agents to stimulate the incretin pathway are being investigated12: • Small-molecule glucose-dependent insulinotropic receptor agonists (GPR119) are in clinical development by at least 3 different companies • Compounds to stimulate TGR5, which is expressed in enteroendocrine cells of the gut and augments GLP-1 release, are being investigated • Activators of fatty acid–binding receptors, which potentiate insulin secretion by the pancreas in response to fatty acids, are particularly interesting, because they do not seem to promote beta-cell decline.

Glucokinase activators increase pancreatic beta-cell sensitivity to glucose, thereby promoting insulin secretion and enhancing hepatic handling of glucose; they also promote beta-cell function and survival.12 At least 8 companies have glucokinase activators in preclinical or clinical development. Another class of agents under investigation, sodium-glucose transport inhibitors, promotes urinary excretion of glucose; at least 9 of these agents are the subjects of clinical investigation.

Several formulations of oral insulin are in development.12 Strategies to Improve Care and Control Costs Disease/Case Management Disease management programs have long been used to improve outcomes for patients with diabetes. These programs can encompass a wide range of interventions, including patient education, biometric monitoring, reminders for tests and examinations, review of care plans, and patient support programs, all with the goal of supporting treatment adherence.13 The Living Well care process, created by the Diabetes Workgroup of Intermountain Healthcare, includes stateof-the-art educational materials for physicians and patients, as well as expert advice to help clinicians with complex treatment decisions.14 The program also provides multidisciplinary coordination of diabetes care, enhancements to the electronic medical record (EMR), as well as data systems to allow healthcare providers to more readily track their performance.14 Highmark, a BlueCross BlueShield health plan in Pennsylvania, evaluated the cost-savings and return on

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investment (ROI) of its employee wellness programs, which included smoking cessation, guidance for nutrition and weight management, and stress management.15 Support was offered via online programs, individual coaching, and classes. Their analysis compared medical claims for participants in the wellness programs with risk-matched employees who did not participate in the wellness programs (N = 1892 for both groups). Although program expenses totaled $808,403, the savings generated from these programs over 4 years was $1,335,524, resulting in an ROI of $1.65 for every dollar spent on the wellness program.15 Affinia Group provided economic incentives for patients with diabetes to better manage their disease.

Participation in their program resulted in a substantial discount on annual insurance premiums, as well as extra reimbursement for annual healthcare costs and reductions in copays for drugs and provider visits.14 Ralston and colleagues implemented a novel webbased collaborative care program.16 After an initial consultation, participants used online counseling services and medical records were reviewed by a care manager.

After adjusting for age, sex, and baseline HbA1c, enrollment in this program for 12 months resulted in a significant reduction in HbA1c levels. After 1 year, 11% of patients in the usual-care group had HbA1c levels <7% compared with 33% of participants in the web-based intervention (P = .03).16 Another study examined the use of a diabetes management program in a Medicare Advantage population.13 To be included, these high-risk patients had to have had at least 1 emergency or urgent care visit or 1 hospital admission with a diabetes-related diagnosis in the 12 months before admission. Patients with CAD and diabetes were randomized to the intervention or usual-care group. Patients in the intervention group received educational materials at the beginning of the program and a quarterly newsletter on diabetes.13 A critical component of this disease management included periodic telephone calls from a nurse case manager, who called participants every 14 to 30 days for assessment and to provide coaching, education, and reminders about vaccinations, eye and foot examinations, and adherence to prescribed medications. Nurse managers also communicated regularly with patients’ physicians to support treatment plans.

This telephone-based intervention was very effective in decreasing diabetes-related inpatient admissions and all-cause medical costs (P ≤.05 vs usual-care group, for both comparisons). The annual all-cause medical costs per member decreased by $985 in the intervention group and increased by $4547 (P <.05) in the comparison group.

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Significant improvements (P <.001) were realized in all clinical measures assessed, including HbA1c, foot examinations, low-density lipoprotein cholesterol (LDLC) levels, and the presence of microalbuminuria.

Consistent, timely management via telephone by a nurse case manager effectively improved clinical parameters and resulted in cost-savings in patients from a Medicare Advantage population.

Pharmacist-Led Intervention Approximately 15 years ago, the Asheville Diabetes Care Project was begun.17,18 This innovative, community-wide disease management program utilized pharmacists to provide critical information and support to enhance outcomes in patients with diabetes in the Asheville, NC, area. The North Carolina Center for Pharmaceutical Care coordinated the project, which included pharmaceutical companies, universities, and hospital-based resources, physicians, and communitybased pharmacists. The city of Asheville was the employer and payer; patients included active and retired employees and their families.17,18 Once patients were identified, their physicians were notified, and a participating pharmacist was assigned to each patient. Pharmacists met with their designated patients for initial 60-minute counseling sessions and offered guidance and advice to help patients achieve their therapeutic goals: patients understood that their progress would be monitored, their physicians would be informed of their progress, and monthly follow-up visits with the pharmacist were planned. Pharmacists documented patient interactions according to a specified protocol and communicated regularly with referring physicians.19 This pharmacist-implemented disease management program offered financial benefits for all stakeholders as well as the potential for improved clinical results.19 Copays were waived if patients participated in the program with a trained pharmacist. Pharmacists were paid for their interactions with these patients, and the employer incurred lower overall healthcare costs as a result of improved clinical benefits resulting from enhanced diabetes management.19 The first clinical outcomes of the Asheville Project were reported after 14 months.20 At baseline, 33% of patients had HbA1c levels between 4.4% and 6.4%; after 14 months, 67% of patients enrolled demonstrated HbA1c levels within this range. The mean HbA1c of the group improved by 1.4 percentage points. Significant improvements from baseline were observed for highdensity lipoprotein cholesterol and LDL-C.20 The economic impact of the Asheville Project was evaluated by comparing insurance claims and prescription drug claims for the 12 months before and after the

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program initiation date. The total cost of inpatient and outpatient services declined by $20,246 during 12 months of this program.20 Although the number of patient–provider interactions increased, inpatient services decreased as outpatient services were increasingly used, leading to decreased costs. This improvement in expenditure includes fees paid to the pharmacists for their intervention, the initial cost of supplying patients with glucose monitors, and charges for the educational program to train participating pharmacists.

The Asheville Project utilized an innovative community-based disease management approach that included pharmacist–patient interactions to provide education and support. With more than 5 years of follow-up, clinical and economic improvements were clear.21 At each follow-up visit, increasing numbers of patients achieved HbA1c levels <7%, and more than 50% demonstrated improvements in dyslipidemia at every measurement.

Multivariate analyses revealed that the patients who benefited the most were the ones with the highest baseline HbA1c levels and the highest costs at baseline.

Expenditures, which had initially been concentrated on inpatient and outpatient physician services, were increasingly dedicated to prescription medications. Total mean direct medical costs decreased by between $1200 and $1872 per patient annually. One employer group noted that employees lost fewer days to sick time annually, resulting in annual increases in productivity of approximately $18,000.

Individuals enrolled in the Asheville Project were committed to participating in the program. The risk manager for Asheville reported that when individuals did not comply with they disease management program, they were notified that they would no longer receive free medications and healthcare services; that knowledge became “the greatest adherence tool we ever saw.”22 The program was subsequently expanded to cover other disease areas, including hypertension, dyslipidemia, and asthma; favorable clinical and economic results emerged for all of these conditions.23 The diabetes program was successfully expanded in 2009 to cover 30 employers in 10 cities. Economic analyses confirmed the benefits of the program: employers saved $1100 annually on patient healthcare costs on average, and employees typically saved $600.24 Another North Carolina company instituted a similar program, which covered about 150 individuals with diabetes. In 3 years, the program resulted in savings of approximately $5115 per patient.25

Physician Involvement As noted, diabetes and its associated conditions represent a complex constellation that requires proactive, thoughtful clinical intervention. Treatment often re-

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quires significant management support and education, and may optimally include medical nutrition therapy, smoking-cessation guidance, as well as other services. A recent web-based survey of 300 primary care physicians and endocrinologists revealed that most physicians feel they are underreimbursed for services they provide to patients with diabetes, resulting in less time spent with each patient.26 The consequence of this perceived limitation in time prevents physicians from providing comprehensive diabetes care.

Wellmark Blue Cross and Blue Shield, which covers >2 million individuals in Iowa and South Dakota, developed a program to enhance clinical services for patients with diabetes.27 Wellmark partnered with physicians to design all aspects of the program, including software selection to identify patients who did not meet clinical targets of optimal BP, lipid levels, and glycemic control.

Clinicians who achieved high levels of performance, those who utilized EMRs and electronic prescribing, received additional compensation. Overall, Wellmark found that physician-directed quality improvements resulted in better care for patients with diabetes and significant cost-savings. Currently, other payers are reviewing ways to follow the Wellmark model with the goal of achieving similar successful results.

The Physician Consortium for Performance Improvement (PCPI) is an interdisciplinary group convened by the American Medical Association that aims to improve patient health and safety by development and implementation of evidence-based clinical performance measures.28 The performance measures created focus on outcomes and group-related measures to generate composite information; they also incorporate best practices information and include results from testing projects, and ultimately support patient-centered, appropriate care. Diabetes and hypertension are 2 of the many conditions for which PCPI measure sets exist and are being continually updated and refined. Development of these measure sets is an important vehicle by which physicians can guide provision of coordinated care delivery systems to enhance patient outcomes and utilize economic resources most efficiently.

Value-Based Pricing/Risk-Sharing Value-based pricing, or risk-sharing, represents a novel approach to reimbursement based on patient outcomes.29 In the most common type of risk-sharing agreement, the manufacturer assumes the risk of the drug providing benefit to patients. Either the cost of the ineffective drug is refunded to the payer, or an equivalent amount of drug is provided to another patient at no cost. The net effect is that the payer is responsible to pay only for agents that result in improved health outcomes.

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Several modifications of this approach have been devised, although details in the literature are few. An antiobesity drug rimonabant was marketed in Sweden according to a finding that it could be cost-effective for patients whose body mass index (BMI) exceeded 35 kg/m2 or for those with a BMI >28 kg/m2 plus dyslipidemia or type 2 diabetes. A value-based pricing scheme was developed, but it was in effect only through the end of 2008, and no follow-up details are found in the literature.

Merck and CIGNA developed a novel agreement regarding the use of sitagliptin and a metformin and sitagliptin combination.29 Merck discounts the cost of these agents to CIGNA with documentation of improved blood glucose control, regardless of whether the improvement results from the use of sitagliptin, the metformin-sitagliptin combination, or other drugs.

With this arrangement, Merck actually makes less money per drug used as health outcomes improve, but by placing these products favorably among CIGNAâ&#x20AC;&#x2122;s options for diabetes treatment, increased use of these agents is expected.

An important limitation in understanding the impact of this type of risk-sharing is that, unlike results of controlled clinical trials that are generally widely published, reports of postmarketing outcomes-based approaches, typically based on private agreements between manufacturer and payers, are not often published or disseminated.

Value-Based Insurance Design Value-based insurance design (VBID) is an innovative approach to benefit planning to reduce long-term healthcare costs while improving health quality.5,10,30 It involves changing the cost structure for plan participants to promote the use of services or treatments that result in relatively high health benefits and to discourage use of interventions with no or limited health benefits.6 Briefly, VBID uses a so-called â&#x20AC;&#x153;clinically sensitive copay structure.â&#x20AC;?10 Patients with diabetes represent a potentially valuable population within which to study this approach, because previous work has demonstrated relatively poor adherence with antidiabetic drug therapy, and a consistent relationship showing diminished medication adherence with increasing copays.10 Poor adherence is associated with poor glycemic control. VBID for patients with diabetes aims to increase adherence and treatment compliance by decreasing drug copays.10 The Milliman Group performed a modeling experiment to assess 3 different VBID copay tier structures, comparing them with a standard structure in which the copay is $10 for generic drugs, $25 for preferred brands, and $40 for nonpreferred brands (Table 2).6 The options modeled included a plan with no copay for any medica-

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tion ($0/0/0), one in which there was the same copay regardless of preferred status ($10/10/10), and one that reflects the usual copay structure, although at markedly lower copays ($0/12.5/30).6 The analysis demonstrated that all these VBID plans increased medication adherence as well as costs to the payer. Increased payer costs result from lower copays required from patients with diabetes, as well as from filling of prescriptions by patients who previously were not obtaining their medications.6 The Milliman report did not further analyze models to predict the cost-savings that might result from improved glycemic control achieved with increased medication adherence after reduction of copays. Results of such modeling exercises would be very informative and could further guide rational program development to enhance outcomes and control costs.

Pitney Bowes implemented a limited VBID program for employees and beneficiaries with diabetes or vascular disease.30 Copays were eliminated for cholesterol-lowering statins, and copays were reduced for patients who were prescribed the antiplatelet agent clopidogrel for blood-clotting prevention. Results on drug adherence from the Pitney Bowes group were evaluated together with data from comparable patients covered by another plan without VBID.30 Eliminating copays for statins promoted stabilization of statin use and encouraged adherence; statin use continued the typical decline in use in the control group.

Adherence to statins was 2.8% higher by patients in the Pitney Bowes group than in the control group.

Adherence to clopidogrel was stabilized with copay reduction, with 4% higher adherence for Pitney Bowes patients compared with controls. Implementation of this VBID plan for statins and a clot-inhibiting drug resulted in modest improvements in medication adherence.30 Nair and colleagues reported on utilization and expenditures in a population of patients with diabetes from a healthcare industry employer.31 Expenditures and drug prescriptions filled were tracked for a 9-month baseline period and 2 full years after initiation of the program. A total 225 patients with diabetes were continuously enrolled (mean age, 49 years); 52% had dyslipidemia, and 68% had hypertension.31 The VBID plan introduced for this study had all diabetes drugs and testing supplies at tier 1; retail copay was $10 and mail-order copay was $20. Investigators found a mean increase of 9% for any diabetes-related prescription in year 1, with a smaller increase of 5.5% in year 2.

Medication adherence increased between 7% and 8% during year 1, but decreased slightly during the second year of the study. Pharmacy expenditures increased by nearly 50% in both years. Total medical expenditures for

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Table 2 Cost and Adherence Impact of 3 Benefit Designs for Patients with Type 2 Diabetes Plan Copay structure Generic/preferred brand/nonpreferred brand, $

Standard VBID1

VBID2

VBID3

10/25/40 0/12.5/30

0/0/0

10/10/10

Net copayment 60

79

102

80

PMPM, $

2.16

2.82

3.65

2.85

PMPM increment to base, $

NA

0.67

1.49

0.69

Patients adherent, %

49

60

69

57

Increment to base, %

0

22

41

16

Per patient per month, $

Virtual adherence

Copays are listed by tier 1/tier 2/tier 3. Model uses data on the actuarial impact of copays. Virtual population is based on a typical employee population.

NA indicates not applicable; PMPM, per member per month; VBID, value-based insurance design.

Reprinted with permission from Fitch K, et al. Value-based insurance designs for diabetes drug therapy: actuarial and implementation considerations. Milliman Client Report.

December 1, 2008.

diabetes-related services increased 16% in year 1 and 32% in year 2 from baseline, although these changes were not significant.31 Of note, emergency department visits decreased in year 1, although expenditures for office visits increased in both years. As shown in Figure 2, patients who adhered to drug therapy required far fewer emergency department visits overall.31 This analysis indicates that although implementation of VBID by reducing drug copays increases prescription medication adherence, other measures may be necessary to effect the changes that result in meaningful improvements in clinical outcomes. For example, these approaches may include patient and provider education and techniques to aid compliance with treatment, potential components to an integrated disease management program. Furthermore, economic gains resulting in improved adherence to diabetes treatment, with resultant benefits to clinical outcomes, may require a longer-term view.

Future Directions in Diabetes Interdisciplinary Cooperation, Engagement As healthcare-related costs in the United States

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Figure 2 Medication Adherence and Emergency Care Utilization

0.25

Nonadherent Adherent

0.23

Mean visits PMPY, N

0.20

0.15 0.11 0.10 0.06 0.05

0.05

0.04

0.03

0 Preperiod

Year 1

Year 2

Observation period

PMPY indicates per member per year.

Adapted with permission from Nair KV, et al. Am Health Drug Benefits. 2009;2:14-24.

have spiraled in an explosive fashion, many stakeholders have actively been seeking creative approaches to maximize the value of healthcare. A diverse array of strategies have been proposed, including consumer-driven health plans, wellness and prevention programs, pay-for-performance initiatives, and use of health information technology to collect, measure, and analyze data. Although economic incentives to patients, such as VBID, may increase adherence, such programs alone seem to provide only modest gains.

An approach that uses a combination of strategies designed to impact patients’ health-related behaviors across a variety of modalities may provide a route to substantial improvements both in health outcomes and, ultimately, in health-related expenditures. The Diabetes Ten Cities Challenge used an integrated disease management approach together with elimination of drug copays, educational initiatives, acceptance of evidence-based guidelines, and community-based pharmacist coaching.32 In a cohort of 573 patients with diabetes, this program demonstrated an average reduction of $1079 in annual total healthcare costs per patient, and mean HbA1c levels decreased from 7.5% to 7.1% (P = .002).32 Caterpillar’s employees with diabetes enrolled in a disease management program that included economic incentives (elimination of copays for medications for diabetes and associated conditions; reduction in annual insurance premiums with participation in health risk

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assessment); after 1 year, HbA1c levels declined markedly for many participants.10 A quality collaborative, the Institute for Clinical Systems Improvement, is sponsored by 6 health plans in Minnesota, including HealthPartners, which covers >1 million individuals.33 This group defined “optimal diabetes care” for its members; features include BP <130/80 mm Hg, LDL-C <100 mg/dL, HbA1c <7%, no tobacco use, and daily aspirin use for individuals aged 41 to 75 years. Minnesota Community Measurement operates a website that tracks patient progress and identifies clinics whose patients successfully achieve optimal diabetes care. Initially, <4% of patients achieved all 5 of these diabetes care goals, but after several years the statewide average indicated that 17.5% of patients with diabetes were receiving optimal care.33 In addition to publicly reporting clinical indicators of quality of care, HealthPartners worked with individual employers to provide annual health assessments, devise workplace wellness programs, and institute telephone-based counseling and support services. The innovative, multifaceted approach of HealthPartners provides just one example of creative programming that can be developed to aid in management and provide support to encourage beneficial health behaviors and improve diabetes treatment.

Potential Cost-Savings: Large-Scale Interventions Better disease control for patients with diabetes will go far toward improving morbidity and mortality and controlling disease-related expenditures. UnitedHealth Group identified 4 interventions that could ultimately result in a 10-year net savings of up to $250 billion and up to 10 million fewer individuals with prediabetes or diabetes.

Initiatives to promote weight loss in overweight and obese persons can reduce the incidence of prediabetes and diabetes; modeling studies indicate that a 5% weight loss by overweight or obese individuals could translate into $45 billion in projected health system cost-savings over a decade.1 Reversing prediabetes, preventing disease progression and the ultimate development of complications, is another important goal. Previous trials have shown that adherence to intensive lifestyle interventions can reduce the incidence of diabetes by 58% among prediabetic patients; this could diminish the prevalence of diabetes by 8% and result in cumulative health system cost-savings of up to $105 billion.1 Improving medical compliance by patients with diabetes can reduce complications and improve clinical outcomes, leading to an estimated cost-savings of $34 billion over 10 years. Intensive lifestyle interventions among patients with diabetes to control overweight and obesity

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will further facilitate clinical improvement and may contribute to an additional $88 billion in cost-savings.

Payersâ&#x20AC;&#x2122; Key Role in Improving Outcomes The diabetes population is a medically complex population that requires more aggressive case management and medical intervention. Many payers have implemented innovative approaches to improve health outcomes and per member per month costs for diabetes and at-risk populations. At the same time, payers are limited in how they can effectively engage noncompliant patients with diabetes to change their lifestyle and improve their overall medical care.

With the advent of EMRs and accountable care organizations, payers, physicians, and patients will likely have greater coordination of care, adherence to guidelines, and aligned incentives. Patients and their families will need ongoing case management and monitoring to prevent further progression of the disease and its associated complications. Physicians need the tools and incentives to continue to educate and monitor ongoing treatment planning. Future models must take the successes of prior initiatives and ensure that current and future highrisk patients are engaged into the healthcare system.

Payers in particular may need to reexamine how they approach care of patients with diabetes.34 The Diabetes Prevention and Control Alliance is a partnership between the CDC, the YMCA, UnitedHealth Group, and Walgreens that aims to reduce the risk of developing diabetes by encouraging lifestyle modifications. Their goals include identification of prediabetic individuals, contacting and screening them, and enrolling them in a program designed to support lifestyle changes. In addition, pharmacists are trained to provide support with regard to diabetes education, medication management, behavioral interventions, and monitoring for complications.

Conclusion To effect meaningful change, improve health outcomes, and maximize cost-effectiveness, novel programs to engage patients with diabetes should seek to combine educational initiatives; support for lifestyle modifications, including smoking cessation; encouragement of exercise programs; nutritional counseling; health awareness reminders to promote foot and eye examinations; and regular HbA1c, lipid, and BP monitoring, together with financial incentives to support patients behaviorally and economically. These wide-ranging interdisciplinary cooperative initiatives may result in improved glycemic control and a reduced risk of the long-term complications of diabetes with their attendant effects on morbidity and mortality.

Diabetes will continue to represent a major and growing source of morbidity, mortality, and spiraling healthcare costs. Novel strategies to prevent diabetes, slow the transition from prediabetes to diabetes, and delay disease progression to forestall the development of complications are necessary to improve health outcomes for the increasing numbers of patients affected by these conditions as well as to control related healthcare expenditures. It is clear that these efforts will need to be comprehensive and multidisciplinary, engaging patients, physicians, diabetes educators, nutritionists, care managers, and payers in complex cooperative endeavors. â&#x2013; Author Disclosure Statement Ms Greenapple reported no conflicts of interest.

References 1. UnitedHealth Center for Health Reform & Modernization. The united states of diabetes: challenges and opportunities in the decade ahead. Working paper 5, November 2010. www.unitedhealthgroup.com/hrm/UNH_WorkingPaper5.pdf.

Accessed September 1, 2011.

2. Centers for Disease Control and Prevention. National Diabetes Fact Sheet. 2007. www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed August 2, 2010.

3. National Diabetes Information Clearinghouse. Diabetes Prevention Program. http://diabetes.niddk.nih.gov/dm/pubs/preventionprogram/DPP.pdf. Accessed August 31, 2011.

4. Long AN, Dagogo-Jack S. Comorbidities of diabetes and hypertension: mechanism and approach to target organ protection. J Clin Hypertens (Greenwich). 2011;13:344-351.

5. American Diabetes Association. Complications of diabetes in the United States. http://schoolwalk.diabetes.org/swfd/swfd_mshs_attach.pdf. Accessed April 7, 2009.

6. Fitch K, Iwasaki K, Pyenson B. Value-based insurance designs for diabetes drug therapy: actuarial and implementation considerations. Milliman Client Report.

December 1, 2008. www.sph.umich.edu/vbidcenter/publications/pdfs/vbid-diabetesdrug-therapy-RR12-01-08.pdf. Accessed September 7, 2011.

7. Fraze T, Jiang J, Burgess J. Agency for Healthcare Research and Quality. Hospital stays for patients with diabetes, 2008. Statistical brief #93. August 2010. www. hcup-us. ahrq.gov/reports/statbriefs/sb93.pdf. Accessed September 7, 2011.

8. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among US adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care.

2004;27:17-20.

9. Cramer JA. A systemic review of adherence with medications for diabetes.

Diabetes Care. 2004;27:1218-1224.

10. Arevalo JD. Perspectives in value-based insurance design for patients with diabetes: assessment and application. Am Health Drug Benefits. 2011;4:27-33.

11. Nguyen Q, Nguyen L, Felicetta J. Evaluation and management of diabetes mellitus. Am Health Drug Benefits. 2008;1:39-48.

12. Aicher TD, Boyd SA, McVean M, Celeste A. Novel therapeutics and targets for the treatment of diabetes. Expert Rev Clin Pharmacol. 2010;3:209-229.

13. Rosenzweig JL, Taitel MS, Norman GK, et al. Diabetes disease management in Medicare Advantage reduces hospitalizations and costs. Am J Manag Care. 2010;16: e157-e162.

14. Aggressive diabetes management: evolving paradigms/innovative solutions.

Takeda slide set. www.thechroniccarecollaborative.com/Data/Sites/2/PDFFile/ AGGRESSIVE_DIABETES_MANAGEMENT_Evolving_Paradigms_Innovative_ Solutions_Virtual_Conference_Slides.pdf. Accessed September 7, 2011.

15. Naydeck BL,Pearson JA, Ozminkowski RJ, et al. The impact of Highmark employee wellness programs on 4-year healthcare costs. J Occup Environ Med. 2008; 50:146-156.

16. Ralston JD, Hirsch IB, Hoath J, et al. Web-based collaborative care for type 2 diabetes: a pilot randomized trial. Diabetes Care. 2009;32:234-239.

17. Kent S. The Asheville Project: walking the tightrope to better health. Pharmacy Times. 1998;suppl:9-10.

18. Spillers C. The Asheville Project: using existing resources to prepare pharmacists for an expanded role. Pharmacy Times. 1998;suppl:30-31.

19. Bunting B, Horton B. The Asheville Project: taking a fresh look at the pharmacy practice model. Pharmacy Times. 1998;suppl:11-18.

20. Cranor CW. Outcomes of the Asheville Diabetes Care Project. Pharmacy Times.

1998;suppl:19-25.

21. Cranor CW, Bunting BA, Christensen DB. The Asheville Project: long-term clinical and economic outcomes of a community pharmacy diabetes care program.

J Am Pharm Assoc (Wash). 2003;43:173-184.

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22. Kertsz L. Copay waiver programs cut health costs, improve productivity. Business Insurance. May 10, 2009. www.businessinsurance.com/article/20090510/ISSUE01/ 100027603#crit=kertesz. Accessed September 7, 2011.

23. Bunting BA, Smith BH, Sutherland SE. The Asheville Project: clinical and economic outcomes of a community-based long-term medication therapy management program for hypertension and dyslipidemia. J Am Pharm Assoc (2003). 2008;48:23-31.

24. Esola L. Asheville, NC, spawns a movement while improving the health of residents. Business Insurance. March 14, 2010. www.businessinsurance.com/article/ 20100314/ISSUE07/303149993&template=preprint. Accessed September 7, 2011.

25. Wojcik J. Employer sees clear results. Business Insurance. April 22, 2007. www.businessinsurance.com/article/20070422/ISSUE01/100021708&template= printart. Accessed September 7, 2011.

26. Pozniak A, Olinger L, Shier V. Physicians’ perceptions of reimbursement as a barrier to comprehensive diabetes care. Am Health Drug Benefits. 2010;3:31-40.

27. Diamond F. Empowered physicians are key to diabetes program’s success. Manag Care. 2009;January:44-46. www.managedcaremag.com/archives/0901/0901.planwatch. html. Accessed September 7, 2011.

28. Physician Consortium for Performance Improvement: ahead of the curve. www. ama-assn.org/resources/doc/cqi/pcpi-brochure.pdf. Accessed September 7, 2011.

29. Hunter CA, Glasspool J, Cohen RS, Keskinaslan. A literature review of risksharing agreements. J Korean Acad Managed Care. 2010;2:1-9.

30. Choudhry NK, Fischer MA, Avorn J, et al. At Pitney Bowes, value-based insurance design cut copayments and increased drug adherence. Health Aff (Millwood).

2010;29:1995-2001.

31. Nair KV, Miller K, Saseen J, et al. Prescription copay reduction program for diabetic employees: impact on medication compliance and healthcare costs and utilization. Am Health Drug Benefits. 2009;2:14-24.

32. Fera T, Bluml BM, Ellis WM. Diabetes Ten City Challenge: final economic and clinical results. J Am Pharm Assoc (2003). 2009;49:383-391.

33. Butcher L. Multifaceted diabetes program pays off for HealthPartners. Manag Care. 2009;18:36-40.

34. Kuznar W. Payers lead healthcare reform toward prevention of chronic disease.

Am Health Drug Benefits. 2010;3(suppl 5):S10. www.ahdbonline.com/sites/default/ files/AHDB0410_0.pdf. Accessed September 1, 2011.

STAKEHOLDER PERSPECTIVE We Must All Engage in the Diabetes Challenge: A Lifelong Journey, with No Silver Bullet MEDICAL/PHARMACY DIRECTORS: In her article, Ms Greenapple provided an extensive list of successful strategies to go into full battle with the evergrowing type 2 diabetes giant in an effort to produce better outcomes for patients with this disease. So, why is the rate of diabetes continuing to skyrocket? The medical literature is filled with many articles and volumes indicating that good glycemic control is key to diabetes management.

Recommendations from health plans regarding diabetes management start with suggesting to members to change their diet, increase their exercise, and for those who smoke, quit smoking. For the majority of individuals, however, these 3 functions likely represent the most difficult goals to accomplish successfully longterm, with or without diabetes.

After members unsuccessfully attempt these behavioral modifications, the next payer answer is to provide a plethora of pharmacotherapy options for providers to choose from for their patients. These, however, remain just that—a list of options. Payers must become more active in engaging providers to implement more structured diabetes management initiatives. Gone are the days of simply making antidiabetes drugs available at the preferred lowest branded copayment, thereby relieving the payer of any further involvement.

Payer reimbursement for a diabetes office visit and the cost differential of the prescribed drug is just a “paper exercise.” Have we become mere transactions?

Our healthcare delivery system deserves more: it hinges on the payer environment. If we are in this diabetes fight together, then we should demand payers to pro-

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vide the structured framework necessary to effectively manage diabetes. In this article, Ms Greenapple discusses many examples of innovative payers who took the initiative and developed novel diabetes management programs that led to better outcomes by decreasing hemoglobin (Hb) A1c, blood pressure, and lipid levels, as well as weight.

There is no silver bullet to diabetes management, and the onus does not fall entirely on the payer’s shoulders. An integrated approach is absolutely necessary: all stakeholders must step up and get engaged for successful management to become sustainable. Perhaps the introduction of accountable care organizations (ACOs) and ACO-like groups will motivate the healthcare community to implement more aggressive diabetes management interventions. Aggressive intervention in the prediabetes population puts a stake in the ground toward reversing the ever-increasing trend of diabetes prevalence in this country. Of course, the ultimate elements of successful diabetes management are patient commitment and accountability.

For health plans not already engaged, this is a grand opportunity to motivate their members, providers, and retail pharmacists to take charge and make a difference.

We need a healthier nation, and it starts with aligning all stakeholders. To paraphrase an old saying, the success of diabetes management in reducing weight, HbA1c levels, blood pressure, and cholesterol is a lifelong journey, not a destination.

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Charles E. Collins, Jr, MS, MBA Vice President, Client Strategy Fusion Medical Communications

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The Era of Personalized Medicine in Oncology: Novel Biomarkers Ushering in New Approaches to Cancer Therapy Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice, Samford University McWhorter School of Pharmacy, Birmingham, AL

I

t is next to impossible for a day to go by without thinking about the contributions of personalized medicine to the care of patients living with cancer.

Whether we are treating a newly diagnosed patient with HER2/neu-positive breast cancer using trastuzumab, or using erlotinib in the management of a patient with non–small-cell lung cancer (NSCLC) whose tumor harbors specific mutations in the epidermal growth factor receptor genes, individualizing therapy based on molecular biology and genetic testing has become commonplace in contemporary oncology practice.

Yet, as our knowledge of cancer biology continues to increase exponentially, we now find ourselves on the brink of where discovery and clinical practice collide, permanently changing the future of cancer medicine by altering the way we think not only about cancer therapy but also about cancer classification.

In August 2011, the US Food and Drug Administration (FDA) approved 3 novel targeted therapies for patients with cancer. Although the availability of new drugs is often enough to generate attention among healthcare providers and patients with cancer alike, what is unique, in this case, is the simultaneous approval of 2 of these new drugs—crizotinib (Xalkori) and vemurafenib (Zelboraf)—with companion molecular assays, representing a potential paradigm shift in the FDA’s approach to new, niche, biomarker-guided therapies.

The specificity of each of these drugs for discrete, and somewhat uncommon, molecular targets will undoubtedly change the way we approach the management of patients for which these new therapies may be indicated.

Crizotinib is a first-in-class oral anaplastic lymphoma kinase (ALK) inhibitor indicated for the management of locally advanced or metastatic NSCLC. Mutations or translocations within the ALK gene, which are found in only 3% to 5% of all NSCLCs, give rise to the overexpression of the fusion protein EML4-ALK, ultimately resulting in the constitutive activation of the Ras/MAP kinase pathway.

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When aberrantly activated, this signaling pathway is known to fuel cancer growth by promoting cell proliferation and survival.1 Before prescribing crizotinib therapy to a patient, providers must first ensure that the patient is ALK-positive by using the concurrently approved molecular assay known as the Vysis ALK Break-Apart FISH Probe Kit. This test uses fluorescence in situ hybridization technology to detect gene rearrangements within the 2p23 chromosome that indicate that a patient may derive benefit from treatment with crizotinib.

For the small percentage of patients with NSCLC and the appropriate ALK mutations, the efficacy of crizotinib demonstrated in clinical trials suggests that this drug may be a valuable addition to our arsenal of available treatment options. The FDA granted crizotinib accelerated approval after the completion of 2 early-phase studies that enrolled a total of 255 patients (94% had received previous treatment).2 A phase 1 study demonstrated a 57% overall response rate (complete plus partial responses) and a 72% progression-free survival (PFS) at 6 months.3 Results from the phase 2 PROFILE 1005 trial confirmed similar findings, with an objective response rate of 61% and median response duration of 48 weeks.3 Furthermore, crizotinib appears to be well tolerated, with vision disorders (occurring in 62% of patients), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%) representing the most common adverse events.4 In view of the poor prognosis of patients with metastatic melanoma and the relative lack of therapies offering improved survival outcomes, the approval of vemurafenib represents a significant achievement for the role of personalized medicine in this deadly disease state.

Mechanistically, vemurafenib is an inhibitor of the BRAF V600E mutation found in approximately 40% to 60% of all patients with cutaneous melanomas.

Much like the ALK mutations in NSCLC, these BRAF V600E mutations result in the activation of the MAP kinase pathway, thereby promoting tumor growth.

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However, it should be noted that vemurafenib has no activity in patients with the wild-type BRAF, so patients must be screened by using the companion cobas 4800 BRAF V600 Mutation Test, which was concurrently approved by the FDA. The phase 3 BRAF Inhibitor in Melanoma (BRIM) 3 trial compared vemurafenib with dacarbazine, a standard of care for patients with metastatic melanoma.5 With a primary end point of overall survival at 6 months, the BRIM 3 study demonstrated a significant improvement in favor of vemurafenib (84% vs 64% with dacarbazine). PFS was also more favorable with vemurafenib than with dacarbazine (5.3 months vs 1.6 months, respectively).5 Vemurafenib was well tolerated, with rash, arthralgia, and fatigue reported as the most common adverse events.5

Is it possible that the historic nomenclature of breast cancer, lung cancer, pancreatic cancer, and so on, has become an outdated system of thinking that will be toppled by a new system in which malignancies will be thought about, classified, and treated according to their biomarkers?

Undoubtedly, the availability of vemurafenib and ipilimumab (a CTLA-4 targeted monoclonal antibody approved by the FDA in March 2011) represents a major stride in our understanding of the molecular basis of stage IV melanoma, for which the median survival has historically been only 8 to 18 months.6 Brentuximab vedotin (Adcetris)—the third new drug approved in August—not only offers new hope to patients with Hodgkin lymphoma who have previously failed autologous stem-cell transplant (ASCT) therapy or who are not candidates for ASCT after failing previous Hodgkin lymphoma therapy, but it may also help to reignite a debate regarding a new way of classifying malignant diseases based on underlying molecular abnormalities rather than the traditionally used organ-based system of origin.

It has been well documented that CD30 is expressed on a subset of Reed-Sternberg cells found in Hodgkin lymphoma and anaplastic large-cell lymphomas (which is also an FDA-approved indication for brentuximab), some T-cell lymphomas, and some B-cell non-Hodgkin lymphomas. Brentuximab vedotin combines a CD30targeted monoclonal antibody with the antitubulin compound monomethyl auristatin E to form a potent novel drug capable of inducing apoptosis by inhibiting the cell cycle in the G2/M phase.7

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In the Hodgkin lymphoma study, the overall response rate was 73%, with an astounding 32% of patients achieving a complete response. These results are especially significant in view of the historically poor prognosis observed in patients with Hodgkin lymphoma who failed ASCT.8 A new clinical trial will attempt to screen for CD30 positivity among patients with metastatic solid tumors who are running out of treatment options. Patients confirmed as CD30-positive will be treated with brentuximab in the experimental setting to assess disease response.9 This idea of evaluating malignancies for commonly expressed molecular biomarkers and treating those patients with similar therapeutic approaches is not new.

In a 1999 article published in Science, Golub and colleagues attempted to challenge our thinking of oncology practice by suggesting just such a molecular classification system.10 With 32 targeted therapies currently approved by the FDA for patients with cancer, and with, arguably, hundreds more in various stages of development, is it possible that we have entered the era of molecular classification of cancer? Is it possible that the historic nomenclature of breast cancer, lung cancer, pancreatic cancer, and so on, has become an outdated system of thinking that will be toppled by a new system in which malignancies will be thought about, classified, and treated according to their biomarkers (eg, CD30, ALK, mTOR, KRAS)?

It is reasonable to believe that the onslaught of new knowledge of cancer biology and the development of targeted therapies has begun a revolution in cancer medicine that will ultimately result in a totally new way of thinking about cancer and usher in a new era of personalized cancer medicine. ■

References 1. Barreca A, Lasorsa E, Riera L, et al. Anaplastic lymphoma kinase in human cancer.

J Mol Endocrinol. 2011;47:R11-R23.

2. Leach B. FDA approves crizotinib for late-stage non-small cell lung cancer. August 26, 2011. www.onclive.com/web-exclusives/FDA-Approves-Crizotinib-for-Late-StageNon-Small-Cell-Lung-Cancer. Accessed September 30, 2011.

3. Kwak E, Bang YJ, Camidge D, et al. Anaplastic lymphoma kinase in non–smallcell lung cancer. N Engl J Med. 2010;363:1693-1703.

4. Pfizer. Xalkori—general safety and efficacy data in ALK-positive advanced NSCLC [Medical Letter]. September 29, 2011. Pfizer, New York, NY. 5. Chapman PB, Hauschild A, Robert C, et al, for the BRIM-3 Study Group.

Improved survival with vemurafenib in melanoma with BRAF V600e mutation.

N Engl J Med. 2011;364:2507-2516. Epub 2011 Jun 5.

6. Balch C, Gershenwald J, Soong S, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199-6206.

7. Younes A, Bartlett N, Leonard J, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363:1812-1821.

8. National Cancer Institute. FDA approval for brentuximab vedotin. August 19, 2011. www.cancer.gov/cancertopics/druginfo/fda-brentuximabvedotin. Accessed September 30, 2011.

9. Study presented at the US Oncology Community Oncology Research Forum; September 15-16, 2011; Dallas, TX. 10. Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286: 531-537.

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JOIN AHDB PEER REVIEW American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other healthcare experts who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal.

You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewersâ&#x20AC;&#x2122; names will be published online at the end of the year.

Please indicate at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted to AHDB.

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to) those listed below.

Please mark the categories that apply to your expertise: Administration/management Benefit design Disease management/state (eg, asthma, diabetes, heart disease, infectious diseases, pain management, etc) Drug therapy (including biologics, generics) Drug utilization Employers/health plans Finance/health economics Health information technology Health policy/reform Patient education/initiatives/quality-of-life issues Payer perspectives Pharmacoeconomics analyses Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits Reimbursement: Medicare/Medicaid, health insurance, prior authorization Research: methods, study design, data collection/analysis

To become a peer reviewer, please complete the form below and fax to: 732-992-1881 or e-mail to editorial@AHDBonline.com Your Information _______________________________________________________________________________________ First Name

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INDICATION EXALGO速 tablets are an extended release oral formulation of the opioid agonist hydromorphone hydrochloride that is indicated for once daily administration for the management of moderate to severe pain in opioid tolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time.

IMPORTANT RISK INFORMATION WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time.

Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/ hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer.

EXALGO is for use in opioid tolerant patients only.

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain.

EXALGO is not intended for use as an as-needed analgesic.

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone.

• EXALGO is also contraindicated in patients who: - need management of mild pain or pain not expected to persist - have significant impaired respiratory function including those with acute or severe bronchial asthma or hypercarbia.

- have or are suspected to have paralytic ileus - have narrowed or obstructed gastrointestinal tract including those from previous surgery or “blind loops” in the GI tract - have known hypersensitivity to any components including hydromorphone hydrochloride and sulfites.

• Avoid concurrent use of alcohol and EXALGO. Concurrent use of EXALGO with CNS depressants, including alcohol, increases risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. EXALGO may impair the ability to drive a car or operate machinery.

• Not intended in patients who have received MAO inhibitors within 14 days of starting EXALGO. • Use with caution and in reduced doses in older or debilitated patients, as well as patients with renal or hepatic insufficiency, Addison’s disease, delirium tremens, myxedema or hypothyroidism,

prostatic hypertrophy or urethral stricture, toxic psychosis. May aggravate convulsions in patients with convulsive disorders; may induce or aggravate seizures in some clinical settings. Consider use of an alternate analgesic in patients with severe renal impairment.

• Respiratory depression, which occurs more frequently in elderly or debilitated patients, is the chief hazard with EXALGO. • Serious adverse events could also include hypotensive effects, GI effects, cardiac arrest from overdose and precipitation of withdrawal. Most common adverse events (>10%) seen in clinical studies (N=2474) were: constipation (31%), nausea (28%), vomiting, somnolence, headache, asthenia and dizziness.

• Use EXALGO with extreme caution in patients susceptible to intracranial effects of CO2 retention.

• Do not abruptly discontinue EXALGO Please see brief summary of Full Prescribing Information, including boxed warning, on following pages.

COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and internationally registered trademarks of Covidien AG. EXALGO is a registered trademark of Mallinckrodt Inc. © 2011 Mallinckrodt Inc., a Covidien company. MK20036 May 2011 Printed in USA.

WHERE IS HER DAY HEADED WITHOUT A 24-HOUR PAIN MEDICATION? EXALGO® puts the power of hydromorphone into a once-daily dose, so your patients can worry less about their medicine wearing off.

To find out more, visit www.EXALGO.com.

®

BRIEF SUMMARY - Consult full prescribing information before use.

EXALGO® (hydromorphone HCl) Extended-Release Tablets WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression [see Drug Abuse and Dependence (9)].

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg of oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer [see Indications and Usage (1) and Dosage and Administration (2)].

EXALGO is for use in opioid tolerant patients only [see Indications and Usage (1) and Dosage and Administration (2)].

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions (5.1)].

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain [see Indications and Usage (1)].

EXALGO is not intended for use as an as-needed analgesic [see Indications and Usage (1)].

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5)].

CONTRAINDICATIONS Opioid Non-Tolerant Patients EXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant.

Impaired Pulmonary Function EXALGO is contraindicated in patients with significant respiratory depression, especially in the absence of resuscitative equipment or in unmonitored settings and in patients with acute or severe bronchial asthma or hypercarbia.

Paralytic Ileus EXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus.

Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI Tract EXALGO is contraindicated in patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have “blind loops” of the gastrointestinal tract or gastrointestinal obstruction.

Allergy or Hypersensitivity EXALGO is contraindicated in patients with known hypersensitivity to any of its components including the active agent, hydromorphone hydrochloride or known allergy to sulfite-containing medications [see Warnings and Precautions (5.8)].

WARNINGS AND PRECAUTIONS Information Essential for Safe Administration EXALGO tablets are to be swallowed whole, and are not to be broken, chewed, crushed, dissolved or injected. Taking broken, chewed, crushed, dissolved EXALGO or its contents leads to the rapid release and absorption of a potentially fatal dose of hydromorphone [see Boxed Warning].

EXALGO is for use only in opioid tolerant patients. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients who are not opioid tolerant [see Boxed Warning].

EXALGO tablets must be kept in a secure place out of the reach of children. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Misuse and Abuse EXALGO contains hydromorphone, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit.

This should be considered when prescribing or dispensing EXALGO in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion.

Breaking, crushing, chewing, or dissolving the contents of an EXALGO tablet results in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death [see Drug Abuse and Dependence (9)].

If attempts are made to extract the drug from the hard outer shell for purposes of parenteral abuse, the injection of tablet excipients may be toxic and may result in lethal complications.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Respiratory Depression Respiratory depression is the chief hazard of EXALGO. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids are given in conjunction with other agents that depress respiration.

Use EXALGO with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis or CNS depression. In these patients, even moderate therapeutic doses of hydromorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. In these patients, consider alternative non-opioid analgesics, and use EXALGO only under careful medical supervision at the lowest effective dose.

Interactions with Alcohol and Other CNS Depressants The concurrent use of EXALGO with other central nervous system (CNS) depressants, including but not limited to other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants. Avoid concurrent use of alcohol and EXALGO [see Clinical Pharmacology (12.3)].

Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the respiratory depressant effects of EXALGO and its potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, EXALGO can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Hypotensive Effect EXALGO may cause severe hypotension. There is added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines, general anesthetics, or other agents that compromise vasomotor tone.

Administer EXALGO with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Gastrointestinal Effects Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, do not administer EXALGO to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.

The administration of EXALGO may obscure the diagnosis or clinical course in patients with acute abdominal condition.

It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

Sulfites EXALGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

MAO Inhibitors EXALGO is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Special Risk Groups EXALGO should be administered with caution in elderly (≥ 65 years) and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease [see Use in Specific Populations (8)].

EXALGO should also be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addison’s disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis.

EXALGO may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Use in Pancreatic/Biliary Tract Disease EXALGO can cause an increase in biliary tract pressure as a result of spasm in the sphincter of Oddi. Caution should be exercised in the administration of EXALGO to patients with inflammatory or obstructive bowel disorders, acute pancreatitis secondary to biliary tract disease and in patients about to undergo biliary surgery.

Driving and Operating Machinery EXALGO may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. Also warn patients about the potential combined effects of EXALGO with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see Drug Interactions (7)].

Precipitation of Withdrawal Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, including EXALGO. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Do not abruptly discontinue EXALGO. Clinical conditions or medicinal products that cause a sudden and significant shortening of gastrointestinal transit time may result in decreased hydromorphone absorption with EXALGO and may potentially lead to withdrawal symptoms in patients with a physical dependence on opioids.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Respiratory Depression [see Warnings and Precautions (5.3)] • Head Injury and Increased Intracranial Pressure [see Warnings and Precautions (5.5)] • Hypotensive Effect [see Warnings and Precautions (5.6)] • Gastrointestinal Effects [see Warnings and Precautions (5.7)] • Cardiac Arrest [see Overdosage (10)] • Precipitation of Withdrawal [see Warnings and Precautions (5.13)]

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

EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year.

The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.

A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)]. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 1.

Table 1.

Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Preferred Term Open-Label Double-Blind Treatment Phase Titration Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Drug Withdrawal Syndrome 22 (5) 13 (10) 16 (12) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) Asthenia a 16 (4) 2 (1) 6 (4) Insomnia 13 (3) 7 (5) 5 (4) Diarrhea 13 (3) 5 (4) 9 (7) Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) 10 (2) 2 (1) 0 (0) Anorexia b Arthralgia 9 (2) 8 (6) 3 (2) Anxiety 9 (2) 0 (0) 4 (3) Abdominal Pain c 9 (2) 4 (3) 3 (2) Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) a b c

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain

The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 2.

Table 2.

Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N=2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) Asthenia a 272 (11) Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) Anorexia b 139 (6) Dry Mouth 121 (5) Abdominal Pain c 115 (5) Anxiety 95 (4) Back Pain 95 (4) Dyspepsia d 88 (4) Depression 81 (3) 76 (3) Dyspnea e Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) Chest Discomfort f 51 (2) a b c d e f

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and reported with dyspepsia Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

The following Adverse Reactions occurred in patients with an overall frequency of <2% and are listed in descending order within each System Organ Class: Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadism Eye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermia Infections and infestations: gastroenteritis, diverticulitis Injury, poisoning and procedural complications: contusion, overdose Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreased Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paraesthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggression Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension DRUG INTERACTIONS CNS Depressants The concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma could occur. When this combination is indicated, the dose of one or both agents should be reduced. The concomitant use of alcohol should be avoided [see Clinical Pharmacology (12.3)].

Monoamine Oxidase (MAO) Inhibitors MAO inhibitors may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids including EXALGO. EXALGO is not intended for patients taking MAO inhibitors or within 14 days of stopping such treatment.

Mixed Agonist/Antagonist Opioid Analgesics The concomitant use of EXALGO with morphine agonist/antagonists (buprenorphone, nalbuphine, pentazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended.

Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with EXALGO may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Cytochrome P450 Enzymes In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)].

Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day).

Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and <one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.

Nonteratogenic Effects In the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day).

Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Labor and Delivery EXALGO is not recommended for use in women during and immediately prior to labor and delivery. Administration of EXALGO to the mother shortly before delivery may result in some degree of respiratory depression in the neonate.

However, neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression.

Nursing Mothers Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk.

Pediatric Use The safety and effectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established.

Geriatric Use Elderly patients have been shown to be more sensitive to the adverse effects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose.

Neonatal Withdrawal Syndrome Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.

Hepatic Impairment In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0- ) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on a reduced dose and closely monitored during dose titration.

The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. Further increase in Cmax and AUC0- of hydromorphone in this group is expected, therefore, use an even more conservative starting dose [see Dosage and Administration (2.4)].

Renal Impairment Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on a reduced dose and closely monitored during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)].

DRUG ABUSE AND DEPENDENCE Controlled Substance EXALGO contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. EXALGO can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse.

Abuse All patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

“Drug-seeking” behavior is very common to addicts and drug abusers. Drugseeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts.

In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since EXALGO may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

EXALGO is intended for oral use only. Misuse or abuse by breaking, crushing, chewing, or dissolving EXALGO poses a hazard of overdose and death. This risk is increased with concurrent abuse of EXALGO with alcohol and other substances.

With intravenous abuse, the tablet excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Dependence Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)].

OVERDOSAGE Symptoms Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The extended release characteristics of EXALGO should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects.

Deaths due to overdose could occur with abuse and misuse of EXALGO. Due to the delayed mean apparent peak plasma level of EXALGO occurring at 16 hours following administration as well as the 11 hour mean elimination half-life of EXALGO, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 24 to 48 hours.

Treatment Give primary attention to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The pure opioid antagonists, such as naloxone and naltrexone are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of hydromorphone in EXALGO, the patient must be carefully monitored until spontaneous respiration is reliably re-established. EXALGO will continue to release and add to the hydromorphone load for up to 24 hours after administration and the management of an overdose should be monitored accordingly, at least 24 to 48 hours beyond the overdose.

Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including EXALGO, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

OROS is a registered trademark of ALZA Corporation.

EXALGO is a registered trademark of Mallinckrodt Inc. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and/or internationally registered trademarks of Covidien AG. © 2010 Mallinckrodt Inc., a Covidien company Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA Issued 11/2010

Mallinckrodt

V E G F

I N H I B I T I O N

THE PROPOSED EFFECTS OF

AVASTIN

®

VEGF

Avastin

VEGF Inhibition

The VEGF ligand is one of the first pro-angiogenic factors

and is present throughout the tumor life cycle1,2,3 Avastin directly binds VEGF to inhibit angiogenesis4,5

Avastin is designed to directly bind to VEGF extracellularly to prevent interaction

with VEGF receptors (VEGFR) on the surface of endothelial cells, thereby inhibiting its biologic activity5 Cessation of anti-VEGF treatment may diminish impact on tumors6,7,8 TO CONTACT YOUR ACCOUNT MANAGER FOR MORE INFORMATION ON AVASTIN VISIT:

genentechmm.com

Indications Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

The mechanism of action of anti-VEGF agents has been elucidated primarily in preclinical models. Its clinical significance is unknown.

Boxed WARNINGS and additional important safety information

Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation

Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention

Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade *3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (*1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation ()0.3%), arterial thromboembolic events (grade *3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Based on animal data, Avastin may cause fetal harm and may impair fertility. Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin. For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother Please see the following brief summary of full Prescribing Information, including Boxed Warnings, for additional important safety information.

References: 1. Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol. 2003;200:183-194. 2. Fontanini G, Vignati S, Boldrini L, et al. Clin Cancer Res. 1997;3:861-865. 3. Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. 4. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 5. Avastin Prescribing Information. Genentech, Inc. February 2011. 6. Bagri A, Berry L, Gunter B, et al. Clin Cancer Res. 2010;16:3887-3900 [and supplemental appendix]. 7. Baluk P, Hashizume H, McDonald DM. Curr Opin Genet Dev. 2005;15:102-111. 8. Inai T, Mancuso M, Hashizume H, et al. Am J Pathol. 2004;165:35-52.

©2011 Genentech Inc., So. San Francisco, CA AVA0000594601 09/11

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal,

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

appropriate medical therapy. [See Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: L Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

L Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

L Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

L Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

L Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

L Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

L Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

L Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

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

The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin.

[See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone.

In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone.

The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus-IFL plus Avastin as compared to patients receiving bolus-IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs.

13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN-α plus Avastin compared to the IFN-α plus placebo arm are presented in Table 4.

Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).]

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3-4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1.

Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI-CTC Grade 3-4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra-Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1 IFL + Placebo (n = 396) 74%

Arm 2 IFL + Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.

Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5-FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9 (Occuring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo) System Organ Class/ IFN-α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/ pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/ desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%).

Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.

Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).

Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Body as a Whole Asthenia Headache Pain Cardiovascular Hypertension Digestive Stomatitis Metabolic/Nutrition Weight loss Musculoskeletal Myalgia Respiratory Dyspnea Epistaxis Skin/Appendages Exfoliative dermatitis Urogenital Albuminuria

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

2%

24%

19%

25%

4%

9%

8%

14%

18% 1%

27% 16%

75%

84%

7%

22%

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal

a

IFN-α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

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

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions.

[See Nonclinical Toxicology (13.3).]

Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.

Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990

02/11 AVA0000306700 10127309 Initial U.S.Approval: February 2004 Code Revision Date: February 2011 Avastin® is a registered trademark of Genentech, Inc. ©2011 Genentech, Inc.

INDUSTRY TRENDS

Building Your Automated Bundled Payment for an Episode-of-Care Initiative Douglas Moeller, MD Medical Director, McKesson Health Solutions, Malvern, PA

P

ayers and providers are looking to “bundled payments” as the payment reform most likely to deliver cost-savings and drive positive outcomes. Bundled payment generally refers to a lump sum paid to providers for a predefined episode of care.

Several pilot projects are under way to test and refine this innovative payment model, initially focusing on a handful of surgical procedures but with an eye toward expanding to other services and chronic conditions. The intent is to reward value, not volume, by providing incentives to providers across settings to coordinate their efforts toward evidence-based care while reducing complications and duplicated services.

Projections have pointed to bundled payment as one of the more promising approaches for controlling healthcare spending, largely by reducing avoidable complications. A 2009 report from The Commonwealth Fund projected that bundling payments for acute care episodes could potentially reduce health expenditures in the United States by as much as $300 billion between 2010 and 2020.1 In the same year, an estimate from a team at RAND projected that one model of bundled payments for 6 chronic and 4 acute conditions could reduce the national health spending by 5.4% between 2010 and 2019.2 More than a decade earlier, in the early 1990s, the Centers for Medicare & Medicaid Services (CMS) initiated its experiment in bundling payments in Medicare for coronary bypass surgery, which showed savings of roughly 10%.3 The question is then, why is the use of bundled payments fairly limited today?

The Implementation Challenge As a physician participating in that early-1990s Medicare project, I saw firsthand the potential of bundled payments but also the challenges of implementation. Small projects have shown their worth with manual claims processing and reconciliation. However, a program large enough to deliver meaningful impact requires a supporting infrastructure to offset the administrative burden. Bringing a program to scale requires clinical and financial automation, which until recently was not available.

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The complexities of bundled payments create “substantial implementation challenges” and “the need for reliable software to automate bundled payment,” according to Robert E. Mechanic, of the Heller School for Social Policy and Management at Brandeis University, and Executive Director of the Health Industry Forum.4 Mr Mechanic calls for immediate investments “to develop administratively feasible, economically sustainable, scalable programs,” and describes ongoing development of software to “automatically convert feefor-service claims into episode-based payments—an extremely complex endeavor but one that could greatly reduce insurers’ administrative barriers.”4 Our experience has shown that technological innovations provide health plans with the flexibility to manage bundled claims even in the loosely organized networks of physicians and hospitals that characterize the majority of US healthcare delivery systems.

The 4 Key Areas for Technology Support Our experience in pilot projects with health plans and other payers has led us to define 4 areas of automation for a successful bundled payment program. At a minimum, technology must be able to support health plans (and subsequently providers) with these key activities: 1. Define a care episode and recognize the starting and stopping points (front-end). Defining included and excluded services is probably the single most important determinant of success. This requires payer–provider collaboration to itemize components for every step in the bundle (eg, clinical laboratory, imaging, anesthesia services). The beginning and end of a care episode must be defined and recognizable to the claims payment process (ideally during a care episode preauthorization or registration process), with a signal that a care episode is under way or will start at some future time.

The wide range of possibilities poses a challenge to many systems. Urgent procedures, such as cardiac catheterization for new chest pain, may have a minimum preintervention period, and the starting point may be the surgery itself. Elective surgeries, by contrast, will have a starting point (such as 30 days before a total

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knee replacement) and a trigger point (decision to initiate a care episode) sometime after the diagnosis, when the decision for surgery is made, and surgery may occur weeks later.

A follow-up period (such as 90 days after surgery) must also be defined. For chronic conditions, such as chronic heart failure, chronic obstructive pulmonary disease, or cancer, the episodes of care will typically be defined as a fixed time interval.

One challenge is to define the network of providers. Highly integrated delivery systems, notably Geisinger Health System and Kaiser Permanente HMO, have shown successful results for episode-based payments.

2. Resolving the care episode with accurate financial management (back-end). The claims submission process generally is used to track resources used in a bundled care episode, and a claims-processing system must be able to recognize excluded and included services and pay them according to the compensation model. Preventable complications must be clearly defined at the outset, so the stakeholders understand their risk. Once the episode is under way, electronic notifications from the health plan to providers can help in the financial management of bundling claims. Enhanced claims processing and management must be able to look across claim types to autoadjudicate contract terms.

3. Managing clinical care. This is the core of the bundled payment process and is essential to moving care toward best practices while using resources efficiently.

An ideal solution helps care coordination across multiple sites and integrates expert decision-support content.

The care episode definition that triggers financial management can also be used to generate provider alerts and reminders to drive care through appropriate pathways and keep the patient “on track.”

4. Providing analytics for action. Powerful analytics are essential to creating the information feedback loops that drive program refinement. Clinical and financial performance metrics must be able to identify variances from best practices in (or near) real time to trigger alerts that can help modify care, either for an individual patient while a care episode is under way, or for a provider overall.

Whether the bundled payment amount is tied to services used by a single patient or tied to average utilization, knowing what resources were used for each

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patient is important, because it can point to variations in care or utilization that signal opportunities for improvement. Shared information between payers and providers helps them to align their efforts to achieve a common goal.

Fast-Forward to Success Many organizations are closely watching current CMS projects, particularly its Acute Care Episode demonstration project that bundles Medicare Part A and Part B for orthopedic and cardiac inpatient surgical services at 5 sites.5 Results are not expected until 2013, but early positive reports include cost reductions, shared costsavings, and greater use of evidence-based medicine.4,6 Another program, announced this summer, invites providers to define and build episodes of care with 4 different models of bundled payments, selecting for themselves which episodes and services will be bundled.7 Organizations setting out on this path may feel stymied by the many choices they have to manage. One challenge is to define the network of providers. Highly integrated delivery systems, notably Geisinger Health System and Kaiser Permanente HMO, have shown successful results for episode-based payments. A pilot program through California’s Integrated Health Association is taking the model to a broader group of payers and providers and independent practice associations more typical of care delivery throughout the country.8 Payers also face a range of compensation options, including (1) a lump sum paid before or after the episode; (2) a reconciliation process that aggregates claims for all included services and pays based on a targeted goal; and (3) a modified fee-for-service payment at the start, before moving to a lump sum. One model may work well for an elective surgery, another may make more sense for a diagnostic procedure, and a hybrid may work best for a third type of care episode. Varied compensation models are viable if the payer’s technology for automating payments has the flexibility to adapt to varied compensation models.

For most health plans, bundled payments represent new territory. Many will need assistance—first, in determining which episodes, which regions, and which providers are most suited for collaboration. But plans need not wait to get started. The necessary technology and experience are currently available to help plans move ahead now in creating their own episode-ofcare programs.

To jump-start the first episode of care, packaged options of predefined bundles with industry-standard content are available now (or custom-made care episodes can be purchased). When the right workflow technology is then applied to manage the administrative

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burden, a bundled payment program can be on the fast track toward meaningful results. ■ Author Disclosure Statement Dr Moeller is an employee of McKesson Health Solutions, which provides software programs for bundled payments.

References 1. The Commonwealth Fund Commission on a High Performance Health System.

The Path to a High Performance U.S. Health System: A 2020 Vision and the Policies to Pave the Way. February 2009. www.commonwealthfund.org/~/media/Files/Publications/ Fund%20Report/2009/Feb/The%20Path%20to%20a%20High%20Performance% 20US%20Health%20System/1237_Commission_path_high_perform_US_hlt_sys _WEB_rev_03052009.pdf. Accessed September 7, 2011.

2. Hussey P, Eibner C, Ridgely MS, McGlynn EA. Controlling U.S. health care spending—separating promising from unpromising approaches. N Engl J Med. 2009;

INFORMATION Manuscripts submitted to American Health & Drug Benefits (AHDB) must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by AHDB. To be considered for publication, manuscripts must adhere to the format described in this document. All manuscripts are subject to peer review, and acceptance is based on that review. If accepted, authors will be notified of any recommended revisions. The revised manuscript should be resubmitted in its entirety, with all changes made.

Routine editorial changes will be made to conform to house style, following the AMA Manual of Style, 10th ed. (New York, NY: Oxford University Press; 2007). The edited manuscript is sent to the author for a final review and approval. Time from submission to publication is generally 3 to 5 months.

COPYRIGHT/DISCLOSURE Authors are required to sign a Copyright Transfer Form, assigning all copyrights to Engage Healthcare Communications, LLC, publisher of AHDB, as well as a Financial Disclosure Form, disclosing any financial interests or potential conflict of interest involving the materials discussed in the manuscript.

MANUSCRIPT FORMAT • Title page should have a proper title for the article

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361:2109-2111. Epub 2009 Nov 11.

3. Health Care Financing Administration. Medicare Participating Heart Bypass Center Demonstration. Extramural Research Report. September 1998. www.cms. gov/reports/ downloads/oregon2_1998_3.pdf. Accessed September 7, 2011.

4. Mechanic RE. Opportunities and challenges for episode-based payment. N Engl J Med. 2011;365:777-779. Epub 2011 Aug 24.

5. Centers for Medicare & Medicaid Services. Medicare News: CMS Announces Sites for a Demonstration to Encourage Greater Collaboration and Improve Quality Using Bundled Hospital Payments. January 6, 2009. www.cms.gov/DemoProjectsEval Rpts/downloads/ACEPressRelease.pdf. Accessed July 8, 2010.

6. Vesely R. An ACE in the deck? Bundled-payment demo shows returns for hospitals, physicians, patients. Modern Healthcare. February 7, 2011. www.modernhealth care.com/article/20110207/MAGAZINE/110209990#ixzz1XGbTKnjZ. Accessed September 7, 2011.

7. HealthCare.gov. Improving care coordination and lowering costs by bundling payments. www.healthcare.gov/news/factsheets/bundling08232011a.html. Accessed September 7, 2011.

8. Integrated Healthcare Association. Integrated Healthcare Association (IHA) launches episode of care payment project. April 26, 2010. www.iha.org/pdfs_docu ments/news_events/04_26_10_BundledEpisodePaymentPressRelease.pdf. Accessed September 20, 2011.

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and list the names, degrees, titles, and affiliations of all authors. Also list the contact information of the corresponding author Abstract: 150-200 words Double space the entire manuscript and number pages Cite all Tables and Figures in the text, but place the actual graphic elements at the end of the article; type all figure heads and captions in a Word format.

References: use 25-30 current, post-1990 references, cited in the text but listed at the end of the manuscript. Avoid automatic numbering or footnote/endnote features Length of article: 3000-3500 words, plus Tables and Figures Save all Figures or images (jpg, tiff) as individual files, at high resolution (300 dpi).

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in su 3 p rv ye M rev iva ar ul io l a ov tip us d er le ly van all M un ta ye tre ge lo a m te a d

If You Define Value as an Overall Survival Advantage:

In Previously Untreated Multiple Myeloma IMPORTANT IMPOR RTANT 3-YEAR 3-YEEAR UPDA UPDATEATETE- SUST SUSTAINED TAINED AINED BENEFIT VISTA* TA* OVERALL SURVIV SURVIVAL VAL ANALYSIS: LY VcMP† vs MP UPDATED UPD ATTED VIST A* O AL (OS) ANAL YSIS: VcMP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

90

% Pa Patients tients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP (n=344) MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

3

6

9

12

15

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21

24

27

30

33

36

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51

Months Kaplan-Meier estimate.

If You Define Value as Medication Cost:

VELCADE Warnings, Precautions, and Adverse Events

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

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

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

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone.

The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.

Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.

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

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

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

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency.

Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information.

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

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

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

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

MA 02139Company. Cambridge, MA 02139 Millennium Pharmaceuticals, Inc., Cambridge, The Takeda Oncology 10 Millennium Pharmaceuticals, Inc. Copyright ©2009, V-10-0204 10 All rights reserved.

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April 2011

DIABETES TYPE 2 PIPELINE

Drugs in Phase 3 Clinical Trials for Type 2 Diabetes

By Alice Goodman, Medical Writer

T

his article outlines some of the novel therapies recently approved by the US Food and Drug Administration (FDA) or are furthest along in clinical trials for type 2 diabetes.

Dipeptidyl Peptidase-4 Inhibitors Linagliptin belongs to the dipeptidyl peptidase (DPP)-4 inhibitors class that was recently approved by the FDA for type 2 diabetes and has the potential to replace sulfonylureas in the future. Linagliptin is not excreted renally, and therefore no dose adjustments are needed in patients with renal impairment. With sulfonylureas, patients need to be taught to self-measure blood glucose, which involves substantial costs; this is not necessary with linagliptin, which could result in cost-savings.

Alogliptin (Nesina) is another DPP-4 agent in latestage development. In 2008 alogliptin was submitted to the FDA, which requested additional cardiovascular (CV) safety information. A clinical trial is now underway examining the CV safety profile.

Glucagon-Like Peptide-1 Receptor Agonists Exenatide is being investigated as 2 new formulations—once weekly (Bydureon) and once monthly. A twice-daily formulation (Byetta) was approved by the FDA in 2005. Exenatide mimics the effect of incretins, such as glucagon-like peptide (GLP)-1 receptor agonists that increase the secretion of insulin from the pancreas, slow the absorption of glucose, and reduce the action of glucagon. GLP-1 agents also reduce appetite.

The 3-year data from DURATION-1 and 84-week data from DURATION-2 trials plus 3 additional studies demonstrated that the once-weekly formulation of exenatide achieved a significant 1.6% reduction from baseline in hemoglobin (Hb) A1c and weight (5.1 lb).

Cardiometabolic risk markers also improved, including systolic blood pressure (–2.1 mm Hg), total cholesterol (–9.9 mg/dL), low-density lipoprotein cholesterol (–7.0 mg/dL), and triglyceride levels (–12%). Bydureon was approved in the European Union in June 2011.

Lixisenatide (Lyxumia) achieved positive results in patients not achieving glycemic goal with oral therapies or basal insulin. In the GetGoal-X trial, once-daily lixisenatide achieved noninferiority results in HbA1c reduction versus twice-daily exenatide; both drugs were used as add-on to metformin in patients inadequately controlled with metformin.

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A second study, GetGoal-L Asia, showed that Asian patients with type 2 diabetes who were inadequately controlled with basal insulin with and without sulfonylurea were significantly improved with lixisenatide once daily versus placebo at week 24, as reflected by the improvement in HbA1c level, with a target of <6.5% or <7.0%.

Sodium-Glucose Cotransporter-2 Inhibitors Sodium-glucose cotransporter (SGLT)-2 inhibitors represent a promising new class of drugs for treatment of type 2 diabetes. These drugs work by inhibiting reabsorption of endogenously produced glucose in the proximal tubules of the kidney.

Results from a phase 3 trial showed that the investigational SGLT-2 inhibitor dapagliflozin added to metformin sustained reductions in HbA1c from 52 weeks to 104 weeks in adults with type 2 diabetes compared with glipizide (a frequently used sulfonylurea) plus metformin. Adverse events were similar in frequency between the 2 treatment arms. These results are from an extension phase of the original 52-week trial.

Weight reduction was sustained at 104 weeks, and hypoglycemic episodes were 10 times more frequent in patients treated with glipizide plus metformin than with dapagliflozin plus metformin (45.8% vs 4.2%, respectively). Genital and urinary tract infections were more frequent with dapagliflozin than with glipizide.

Canagliflozin is safe and generally well tolerated at doses up to 300 mg twice daily when added to stable doses of insulin in subjects with type 2 diabetes, based on a randomized, double-blind, placebo-controlled, parallel-group, multidose study. Canagliflozin reduced the renal threshold for glucose excretion, improved glycemic control, and was associated with weight loss.

A trend toward blood pressure reduction was observed, with no orthostatic symptoms.

Ultra-Long-Acting Insulin Degludec The activity of the investigational ultra-long-acting basal insulin degludec lasts for up to 40 hours and may be able to reduce the insulin dosing frequency. In two phase 3, 52-week trials, it reduced the rates of hypoglycemia compared with insulin glargine.

A late-breaking 26-week study presented at ADA 2011 showed that insulin degludec could be dosed at different times from day to day. ■

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ADA 2011 HIGHLIGHTS

Cutting-Edge Data Presented at ADA 2011 Highlight the Diabetes–Cardiovascular Disease Link

By Wayne Kuznar, Medical Writer

S

ome 13,000 healthcare professionals from around the world gathered in San Diego, CA, in June 2011 to attend the annual meeting of the American Diabetes Association. Cutting-edge research presented at the meeting included more than 2000 abstracts and 96 symposia, as well as 7 state-of-the-art lectures and 131 late-breaking posters, reflecting the growing urgency of the diabetes epidemic and the focus on improving patient care and clinical outcomes.

Presentations included the latest on new strategies in the management of type 2 diabetes, improving insulin treatment in type 1 and type 2 diabetes, the translation of research to improvement in patient outcomes, and trends in diabetes education and its impact on health outcomes—including data from the LOOK AHEAD trial, the first study to compare the effect of intensive diabetes education and usual care in the management of diabetes.

The complex interaction between diabetes and the cardiovascular (CV) system was featured prominently throughout the sessions, with the renewed focus of CV safety of medications to treat diabetes.

New data about several new and promising drugs for the treatment of type 2 diabetes—once-weekly exenatide, linagliptin, alogliptin, and the investigational sodium-glucose cotransporter 2 inhibitors—were abundant, as well as the investigational ultra-long-acting basal insulin known as insulin degludec, which has a duration of action of 40 hours that potentially could reduce the frequency of insulin dosing.

Progress on the artificial pancreas was the focus of several abstracts. The most recent stage is the development of fully automated, closed-loop devices in which all insulin calculations and delivery are done automatically, without direct intervention from patients or researchers.

New research into the ocular complications of common medications to treat type 2 diabetes were presented, as well as phase 3 data that showed that an antivascular endothelial growth factor could improve vision in patients with diabetes and macular edema.

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Much of the research today revolves around patients with type 2 diabetes, but the following new drugs are currently in late stages of development for type 1 diabetes.

The anti-CD3 drug teplizumab, which modulates Tcells, failed to show in a phase 3, double-blind, multinational study a significant improvement over placebo on reducing the hemoglobin A1c level to <6.5% for patients newly diagnosed with type 1 diabetes or reducing the amount of insulin needed to <0.5 U/kg of body weight per day. Nevertheless, 5% of those receiving teplizumab no longer needed insulin at the end of 1 year compared with zero of those who received placebo.

In a phase 2 study, those receiving teplizumab continued to show improved (a 77% decrease) beta-cell function, even 2 years after diagnosis, over an untreated group (a 45% decrease). In addition, at 24 months, the untreated group used 57% more insulin, on average, than the group that received teplizumab.

DiaPep277 is a potential vaccine for type 1 diabetes, with the goal of preventing beta-cell destruction. During the development of type 1 diabetes, an increase in a protein in the beta-cell called “heat shock” protein is thought to cause beta-cell destruction through activation of destructive T-cells. In a phase 2 study, the altered “heat shock” protein, given subcutaneously to 100 patients with type 1 diabetes, protected the beta-cells, replicating in humans the findings in laboratory mice.

The use of this vaccine also allowed beta-cells to continue to secrete insulin for up to 2 years after a type 1 diabetes diagnosis. The drug is now in phase 3 trials in which beta-cell function, insulin use, and glucose control are being monitored.

In a phase 2 randomized study, abatacept recipients had a 59% increased C-peptide level after 2 years compared with placebo. On average, abatacept preserved beta-cell function for an additional 9.6 months. ■

For complete meeting coverage and key presentations, visit www.AHDBonline.com.

www.AHDBonline.com

September/October 2011

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Vol 4, No 6

The Hedgehog Pathway:

PTCH

A critical factor in cancer development SMO

1 Following mutation in SMO or PTCH, SMO is translocated to the cell surface

2 Once at the cell surface, SMO activates the GLI family of transcription factors

GLI

3 Nucleus

GLIs travel to the nucleus to trigger tumor cell growth and proliferation

Nucleus

Mutations in the Hedgehog pathway are implicated in over 90% of basal cell carcinomas (BCCs)1 The Hedgehog pathway plays an important role in regulating cell growth and differentiation during normal human embryonic development but remains inactive in most adult tissues. Mutations in the Hedgehog pathway can occur and may lead to different types of cancer.2 Most notably, Hedgehog pathway mutations are known to occur in BCC, medulloblastoma, and BCC in Gorlin syndrome.3,4

Genentech is actively researching the potential of Hedgehog pathway inhibition and how it may fit into the therapeutic paradigms of various malignancies.

Key components of the Hedgehog pathway include Smoothened (SMO), which enables the signaling cascade, and Patched (PTCH), which normally suppresses the activity of SMO. In preclinical models, mutations in SMO or PTCH render the pathway constitutively active, triggering the activation of GLI transcription factors.

GLI, in turn, mediates the expression of genes involved in tumor cell growth, differentiation, and proliferation.1,5-7

For more information about the Hedgehog pathway and its components, please visit:

www.ResearchHedgehog.com

References: 1. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743-754. 2. Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009;30:303-312.

3. Unden AB, Holmberg E, Lundh-Rozell B, et al. Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation.

Cancer Res. 1996;56:4562-4565. 4. Pietsch T, Waha A, Koch A, et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 1997;57:2085-2088. 5. Stone DM, Hynes M, Armanini M, et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature. 1996;384:129-134. 6. Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates Hedgehog signaling at the primary cilium. Science. 2007;317:372-376. 7. Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 2000;100:423-434.

Demonstrating the Value of Innovation Š2011 Genentech, Inc., So. San Francisco, CA HED0000596500 09/11

A Member of the Roche Group