The May 2013 Digital Edition of Pharmacy Practice News

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The Pharmacist’s News Source

pharmacypracticenews.com

Vollume 40 • Number 5 • May 2013

Printer-friendly versions available online

in this issue UP FRONT

4

White-bagging column has some readers seeing red.

OPERATIONS & MGMT

10

When drugs become scarce, OhioHealth’s rapid response team answers the call.

CLINICAL

17

Preventing rare but deadly lithium toxicity, other clinical pearls.

TECHNOLOGY

24 29

A tale of two IV prep robots. A trio of high-tech pharmacy successes.

POLICY

36

FDA official: agency needs more weapons in fight against unsafe compounders.

EDUCATIONAL REVIEW

Pathogenesis Of a Hereditary Predisposition To Breast Cancer See insert after page 16.

Corporate Spotlight Medi-Dose/EPS see page 15

APP see page 39

FDA Inspections Taking a Toll On Compounders

A Dangerous Interplay: Rx Shortages and Med Errors D

barrage of inspections by FDA and state pharmacy board investigators has uncovered numerous safety violations at compounding pharmacies that supply hospitals and practitioners across the country with batch quantities of customized sterile solutions. Most of the investigators’ on-site reports have focused on incidents of failure to maintain optimal-quality conditions and procedures for safe sterile compounding, a reflection of lax adherence to U.S. Pharmacopeia Chapter <797> standards. But some inspections also have uncovered evidence of product contamination, and several recent highly publicized cases have led to large-scale product recalls. On April 17, for example, Balanced Solutions Compounding Pharmacy, of Lake Mary, Fla., initiated a total sterile products recall “due to concerns associated with quality control processes” that led to “a lack of sterility

uring two months starting in November 2010, more than 200 patients at seven hospitals in the MedStar Health system in the Maryland and Washington, D.C., region received double their prescribed concentration of potassium acetate. In response to a shortage of the usual stock dose of the drug (2 mEq/mL), MedStar acted to fill the gap by procuring vials containing a 4-mEq/mL solution. The wrong concentration was entered into the An image of a TPN room IV compounder software, with drug error investigators. which then identified the new vials as containing the lower dose, and the drug was administered to patients receiving total parenteral nutrition. No patients experienced injuries or medical abnormalities, which is one reason why the mistake went undetected for so long. That the error occurred is disturbing, but unfortunately no longer surprising in a time when medication errors are rampant. Yet something does set this event apart other than its scope and duration—the fact that MedStar chose to shine a light on the event and allow

see COMPOUNDERS, page 34

see INTERPLAY, Y page 8

A

•

Help Wanted, Onc Pharmacist? Getting the OK Los Angeles—Does your hospital need a new oncology pharmacist? At the annual meeting of the Hematology/Oncology Pharmacy Association, attendees were given ammunition— such as the potential for millions of dollars in annual savings and revenue—they can use to convince administration of the benefits that accrue when such a specialist is added to the patient-care team.

•

see HELP WANTED, page 20

•

Goading and Gaming Can Help Increase Medication Adherence San Diego—The staggering $317 billion that medication nonadherence costs our health care system each year can be chipped away at if pharmacists encourage proper medication use, an expert told attendees of the Academy of Managed Care Pharmacy’s (AMCP) 25th Annual Meeting and Expo. “None of the medicines we develop, none of our efforts to make sure these medicines are accessible to patients, none of the guidelines we create, none of these matter if we don’t actually get the medicine into a patient’s body,” said Yelena Yankovskaya,

PharmD, a fellow in managed markets at Mayes College of Healthcare Business and Policy at the University of the Sciences, in Philadelphia. “As pharmacists, I think we have a great opportunity to save lots of money both for our patients and ourselves if we improve adherence.” The financial toll of nonadherence is striking: $317 billion in health care expenditures are attributable to preventable disease-related complications, Dr. Yankovskaya said, referring to data from Express

New Product

Special Report

•

see ADHERENCE, page 22

Fresenius Kabi USA introduces new Heparin Labels

Understanding Key Differences Between Biosimilars and Small Molecule Generics

See page 23.

See insert after page 24.

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Up Front 3

Pharmacy Practice News • May 2013

Capsules

Adherence in CAD a Cost-Effective Strategy

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MAY 2013

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. A Million-Dollar Strategy for Managing Acid Suppression in the ICU 2. Anticoagulation Experts Argue a Bloody Debate 3. In Ranking of Superbugs, Klebsiella Takes the Lead 4. The Tricky Business of Treating Massive Hemorrhage 5. Pharmacy IT Strategies Can Prevent Errors and Help Streamline Operations Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘We have been hampered in our ability to protect the

American people [from unsafe compounders] because of ambiguities regarding FDA’s enforcement authority….’ —Margaret A. Hamburg, MD

See article, page 36

etter medication adherence can improve outcomes and reduce costs of care for patients with coronary artery disease (CAD), according to a systematic literature review. The study, a collaboration between CVS Caremark and Brigham and Women’s Hospital, in Boston, showed that improved adherence potentially could save up to $868 per patient annually. The results of the partnership appear in The American Journal of Medicine (2013;126: 357.e7-357.e27, doi: 10.1016/j.amjmed.2012.09.004). Lead investigator Asaf Bitton, MD, MPH, an instructor in medicine at Brigham and Women’s and Harvard Medical School, also in Boston, and his team conducted a systematic review of 45 years of literature on the association between better medication adherence and CAD outcomes and costs. After reviewing 2,636 articles published between 1966 and 2011, the team analyzed 25 studies in greater detail that met their inclusion criteria related to adherence and CAD outcomes. The analysis showed a strong and consistent association between patients who had the highest medication adherence and improved CAD outcomes, including decreased mortality. Additionally, in the studies that measured costs, high adherence rates were associated with 17% lower costs per year. The studies used a variety of measures to define high versus low adherence. These measures included medication possession ratio (MPR), where an MPR greater than 80% was defined as high adherence and an MPR less than 80% was defined as low adherence; proportion of days covered (PDC), where a PDC greater than 80% was considered high adherence and a PDC less than 80% was considered low adherence; direct pill counts; and patient questionnaires. “CAD and cardiovascular disease in general has an annual health care cost of about $475 billion. Our analysis showed that adherence not only improved health outcomes, it also … reduced total annual CAD costs consistently from $294 to $896 per patient,” Dr. Bitton told Pharmacy Practice News. Pharmacy involvement plays a major role in getting patients to be more compliant with their medication, he added. “I practice in a patient-centered medical home here at Brigham and Women’s. We are one of the new team-based models of primary care and because we find that adherence is so important in determining the outcomes that our patients have, we have a full-time outpatient pharmacist in our clinic who works with patients on adherence, helps manage and do medication reconciliation, and guides those patients who have many different medications. We find it immensely helpful to have [such] pharmacist expertise and input on our team.” Troyen A. Brennan, MD, MPH, the chief medical officer at CVS Caremark, noted that the company has been working with Brigham and Women’s Hospital to research pharmacy claims data in order to better understand patient behavior, particularly patient adherence. Dr. Brennan said the study is “significant because it broadens the discussion … about ways that we can best serve patients and meet their needs while reducing spending within the health care system.” The results, he added, “[offer] evidence that medication adherence strategies and interventions for CAD patients may be one way to [achieve those two goals].” —Fran Lowry

EDITORIAL BOARD

ART/PRODUCTION STAFF

ADMINISTRATION

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

Frank Tagarello, Senior Art Director/Managing / Director, r MAX Graphics

Ernest R. Anderson Jr., MS, RPh, Brockton, MA

Volume 40 • Number 5 • May 2013 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

INTERNAL MEDICINE

EDITORIAL STAFF

David S. Craig, PharmD, BCPS, Tampa, FL

Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP, Des Moines, IA

David Bronstein, Editorial Director davidb@mcmahonmed.com

Robert L. Barkin, MBA, PharmD, Chicago, IL

NUCLEAR PHARMACY

BIOTECHNOLOGY Jeffrey Norenberg, PharmD, Albuquerque, NM

Indu Lew, PharmD, Livingston, NJ

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

CARDIOLOGY

ONCOLOGY

C. Michael White, PharmD, Storrs, s CT

Robert T. Dorr, PhD, RPh, Tucson, AZ

Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Contributing Editors

CNS/PSYCHIATRY

Robert Ignoffo, PharmD, San Francisco, CA

James Prudden, Group Editorial Director

Charles F. Caley, PharmD, Storrs, CT

Philip E. Johnson, MS, RPh, FASHP, Tampa, FL

Robin B. Weisberg, Manager, r Editorial Services

Cindy O’Bryant, PharmD, Aurora, CO

Elizabeth Zhong, Associate Copy Chief

Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, Texas Larry Ereshefsky, PharmD, San Antonio, TX COMPLEMENTARY AND ALTERNATIVE MEDICINE

Ali McBride, PharmD, MS, BCPS, St. Louis, MO

Cathy Rosenbaum, PharmD, Cincinnati, OH

Sara S. Kim, PharmD, BCOP, New York, NY

CRITICAL CARE

PEDIATRICS

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

SALES David Kaplan, Group Publication Director dkaplan@mcmahonmed.com

James O’Neill, Senior Systems Manager Dan Radebaugh, Director of Production and Technical Operations Marty Barbieri, Production Manager Brandy Wilson, Circulation Coordinator

McMAHON PUBLISHING Raymond E. McMahon, Publisher and CEO, Managing Partner Van Velle, President, Partner Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

MCMAHON PUBLISHING MCMAHONMED.COM Sales, Production and Editorial Offices: 545 West 45th Street, 8th Floor, New York, NY 10036. Telephone: (212) 957-5300. Corporate Office: 83 Peaceable Street, Redding CT 06896

David P. Nicolau, PharmD, Hartford, CT

TECHNOLOGY

Robert P. Rapp, PharmD, Lexington, KY

Thomas Van Hassel, RPh, Yuma, AZ

Alina Dasgupta, Junior Sales Associate, e Classified Advertising adasgupta@mcmahonmed.com

Copyright © 2013 McMahon Publishing, New York, NY 10036. All rights reserved. Pharmacy Practice News (ISSN 0886-988x) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Send address changes to Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036.

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tion pay payable able to Pharmacy Practice News to McMahon PubPub lishing, 545 West 45th St., 8th Floor, New York, NY 10036. Please allow 8 to 12 weeks for delivery of the first issue. Individual issues are $7.00 (U.S.) or $10.00 (outside U.S.). McMahon Publishing is a 41-year-old, first-generation, family-owned publishing company dedicated to providing medical professionals with essential, up-to-date news. As

the second largest publisher of medical newspapers, newspapers McMahon produces Anesthesiology News, Clinical Oncology News, Gastroenterology & Endoscopy News, General Surgery News, Infectious Disease Special Edition, Pain Medicine News, Pharmacy Practice News. Rheumatology Practice News and Specialty Pharmacy Continuum.

INFECTIOUS DISEASES

REIMBURSEMENT

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH Peggy McKinnon, PharmD, Lexington, M MA

Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

A family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers and several annual or semiannual Special Editions.

Matt Spoto, Senior Account Manager mspoto@mcmahonmed.com David Nathanson, Account Manager dnathanson@mcmahonmed.com

4 Up Front

Pharmacy Practice News • May 2013

Your Letters

Some Seeing Red Over White-Bagging Article Bonnie Kirschenbaum’s “Reimbursement Matters� column, “Stop Whining About White Bagging� (Pharmacy Practice News, March 2013, page 36) triggered many readers to respond online. What follows is a selection of the comments, along with a response from Ms. Kirschenbaum.

Prefers Buy-and-Bill

36 Policy

I

’m not sold. This practice of white-bagging adds extra steps, introduces billing errors and is time-consuming for the clinics, patients, specialty pharmacies and infusion pharmacies/centers. Drugs show up late, aren’t sent at all or are sent to the wrong locations. I agree that there are steps that could be taken to improve the process, but the second it’s embraced is the second that payers push even harder. We’re a large health system and payers will let their patients see our physicians, clinics and nurses, and be hospitalized (and rehospitalized) here, and even get their outpatient scripts filled by us, but they want to send us a $10K vial for us to infuse? Doesn’t make sense. Employee plans and payers nationwide should support the buy-and-bill method ‌ or just go buy their own hospitals, clinics and infusion centers. —pschw...

Reimbursement Calculus Doesn’t Add Up

W

hat Ms. Kirschenbaum fails to point out is that ASP [average sales price] +6% is more than being reimbursed $0 for a drug the pharmacy does not buy and bill. Are we only entitled to administration fees? By your own admission, CMS [Centers for Medicare & Medicaid Services] does not include procurement or storage costs in the administration fee. It is much less costly for me to pay a technician for his or her time to order 10 vials of product X from our normal supply channel than to call five different specialty pharmacies to order two vials of product X for each of those five patients. In addition, why am I under an obligation to examine infrastructure and correct weaknesses for the benefit solely of the specialty

Pharmacy Practice News • March 2013

Reimbursement Matters

It’s Time To Stop Whining About White Bagging P

atient assistance programs (PAPs) and white bagging share many characteristics. Why, then, are attitudes toward these drug acquisition and distribution programs so different? After all, both practices have several attributes in common. In both cases, for example, a distributor, manufacturer or specialty pharmacy sends the drugs to the pharmacy at no cost. Actually, we could add a third category to this as well: nominally or zero-priced drugs such as alemtuzumab (Campath, Genzyme) for leukemia patients. The prin-

First, let’s define some terms in a bit more depth. As noted, white bagging is the practice of having patient-specific medications or supplies delivered directly to the practice setting. That setting may be an outpatient infusion center, a physician’s office or a hospital, but the common link is that the drug is intended for use by a specific patient. As the medications may be prepaid or complimentary, no billing for these products/supplies transpires. However, billing for the clinic visit where the drugs are administered and for the drug administration itself still

pharmacy supplier? After the NECC [New England Compounding Center] fiasco, am I to visit every specialty pharmacy that supplies my patients to ensure they are following proper procedures for procurement and storage of these injectables? It’s no longer a far-fetched liability if I fail to do that, and at some later date that specialty pharmacy is found to be deficient. Furthermore, outpatient pharmacy does not have sufficient refrigerated storage for segregating white-bag drugs in a patientspecific manner. So am I to undergo the expense of buying another refrigerator and maintain an extra tracking system to order refills so that insurance company Y can pay less money to supply product X? Why don’t these payers negotiate directly with the hospitals to pay a similar reimbursement as they pay to a specialty pharmacy? We accept drugs on behalf of PAP [patient assistance programs] as part of our mission to serve those less fortunate. Limiting it to those patients keeps the administrative costs of managing the refilling of those meds to a minimum. If we open the floodgates to all white bagging, it becomes very time-consuming. Please do not underestimate the time and expense it takes the final

Advocating Outsourcing Not a Good Idea To the Editor:

I

feel compelled to comment on the article titled “In Operating Room, a Switch to Prefilled Syringes Pays Off� (Pharmacy Practice News, March 2013, page 1). I find it irresponsible of your newspaper to publish this article, which basically condoned the practice of using a compounding pharmacy to mass-produce syringes for use in a hospital. Although the article does not address the issue, having worked in hospitals for 30 years, I can guarantee you that the hospital is not sending individual prescriptions for specific patients for each compounded syringe of succinylcholine, vecuronium etc. Therefore, the compounding pharmacy is providing products that it is not licensed to distribute AND the hospital is liable for purchasing such products from a provider who is not licensed to provide the medications under those circumstances. I believe that a huge number of pharmacy directors still do not understand the liability they are taking on when they are purchasing syringes for the operating room, or for PCA [patient-controlled anesthesia], or any of the myriad other products that compounders are making and continue to ship. I understand that for some drugs there are shortages, and hospitals have resorted to using compounders because they have to get the drug for their patients and the compounders have bought up all the supply. However, that is not the case in this “study�/article. Yes, it is an improvement in care for the anesthesiologists to have prefilled syringes and the hospital certainly demonstrated that they saved lots of money. But at what cost? I recognize that there is a sidebar accompanying the article containing a disclaimer about the potential downsides and safety risks related to outsourcing, and the article mentions that the hospital is trying to make as much drug product as possible on its own. However, with PPN publishing this article without addressing the fact that [those purchases are] illegal, more naive pharmacy directors are going to jump on the bandwagon and keep the process going as opposed to addressing the need to ramp up their internal compounding capabilities. —Dan Ross, PharmD, D Ross Consulting, Glendale, Calif.

codes that are used to bill for drug administration. Some are specific to the type of drug administered, with more complex administrations receiving considerably higher reimbursement. Both private payers and Medicare reimburse for drug administration using these codes. Thus it’s important to look at the CPT definition of drug administration. It includes the following exact wording, according to CMS: use of local anesthesia; starting the IV; access to IV, catheter or port; routine tubing, syringe and supplies; prepara-

“Reimbursement Matters� is a tool for maintaining your health system’s fiscal health. Please email the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP

bundled payment. Drugs costing less than $80 per day and being bundled

dispensing pharmacy to wait on hold with the specialty pharmacies and manage the logistics of obtaining these meds for each patient from a completely different supplier. —robbi...

Ms. Kirschenbaum replies:

T

hanks to all of you who took the time to express your opinions about the March 2013 PPN article on white bagging. Interestingly, the comments fell into two categories: those who saw the benefit of a “patientcentricâ€? model and could envision incorporating (or already had) white bagging into their workflow and those who took a very strong “pharmacy-centricâ€? approach and would continue to prevent white bagging at their facilities. As I read through the posts, there also were a few comments about the inequity of reimbursement in general as well as Medicare issues that were not tied to white bagging. So, just to clarify‌. White bagging has come about as a result of tussling over the control of both Medicare Part D and now some Part B drug spend within private insurance plans. It does not apply to Medicare or Medicaid patients

unless they are being managed by a private payer’s plan (e.g., perhaps a Medicare Advantage plan). Medicare’s reimbursement of OPPS [Outpatient Prospective Payment System] Part B drugs is set at 106% of ASP [average sales price], less the sequestration cut of 1.6% to 1.7%, depending on how calculations are handled. Both the pharmacy and the medical professions are dismayed at this reimbursement level and how those values are calculated, but this is an entirely separate issue from white bagging. As far as some of the specific concerns raised, I’d like to respond to one particularly important point—the idea of negotiating directly with payers for specialty pharmacy contract pricing. My fear is that some hospitals taking that approach may be overreaching. To get those favorable prices, a facility has to deliver on several challenging fronts, including ensuring compliance with REMS [Risk Evaluation and Mitigation Strategies], data reporting, adherence monitoring, etc. It can be done, but it may be a hard build. Moreover, negotiating directly with the manufacturer for contract pricing may not even be possible if the company has entered a closed, exclusive relationship with distributors and/or specialty pharmacy providers. Certainly, there’s lots of valid debate on all of this. But what’s not to be denied is the incredible growth of specialty pharmacy and attendant white bagging that it will continue to bring to your hospital. According to Pembroke Consulting, by 2016 seven of the top 10 best-selling drugs (by revenue) will be distributed and, to varying degrees, managed through the specialty pharmacy channel, versus three in 2010. Although many of these drugs will be oral formulations, several will be injectables and thus continue to fall into the white-bagging category. So fighting this trend without any consideration for extracting some economic benefit from it (e.g., by smartly submitting for administration fees) seems ill-advised— especially given the real risk that you’ll lose access to these patients if you don’t assume a more proactive, realistic strategy.

Rachel Stratman, PharmD, lead author of the study, replies:

T

ypical anesthesia practice in relation to drug preparation in the OR often does not comply with USP Chapter <797>, JC [Joint Commission] and CDC [Centers for Disease Control and Prevention] guidelines related to drug preparation, labeling and expiration dating. This medication practice compromises patient safety in the operating room on a daily basis. Through this study, I advocate for institutions to adopt the Anesthesia Patient Safety Foundation’s recommendations of standardization and provision of pharmacy-prepared products in the most ready-to-use form possible ((APSF Newsletter 2010;25:1-20). The article describes the impact of deploying a system that incorporates standardization and pharmacy-prepared products in the intraoperative environment to improve medication management and safety by reducing the use of provider-prepared medications. While both pharmacy insourcing and outsourcing played a key role in the success of this project, the intent of this article is not to promote pharmacy outsourcing. If outsourcing pharmaceutical services is chosen, due diligence must be taken to research the compounding practices of the outsource company and to become familiar with federal and respective state laws and licensure requirements. Indiscriminate use of outsourcing compounding pharmacies is not advisable, as there are significant differences between the companies in terms of safe manufacturing practices. Any hospital pharmacy considering outsourcing should follow the ASHP Guidelines on Outsourcing Pharmaceutical Services ((Am J Health Syst Pharm 2010;67:757-765), validate a company’s legal status in the respective state, obtain copies of state and FDA licensure and re-validate licensure status as necessary. Also note that the cost of outsourced syringes is higher per unit than the cost of provider-prepared doses and thus represent a material cost increase to the institution, even after accounting for decreased drug waste.

What’s Your View on Outsourcing? Email the editor: davidb@mcmahonmed.com

TRANEXAMIC ACID INJECTION t "1 3BUFE UP $ZLMPLBQSPO¥Ħ t -BUFY 'SFF t 1SFTFSWBUJWF 'SFF NDC 0517

Strength

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0960-10

1000 mg/10 mL

10 mL

10

(100 mg/mL)

Single Dose Vial

1 Cyklokapron® is a registered trademark of Pfizer Health AB

Customer Service

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IMPORTANT SAFETY INFORMATION Tranexamic acid injection is ccon ontr trai aind ndic icat ated ed:: 1. In patients wiith acq cqu uireed de defe fect ctiv ivee co colo lorr vi visi s on, since this prohibits measuring one endpoint that should be followed as a measure of toxicity. 2. In patients witth suba barach hno noid id h hem emor orrh rhag age. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid injection in such patients. 3. In patients wiith aact ctiv ivee in intr trav avas ascu cula larr cl clot otti ting n . 4. In patients with th hyperseens nsit itivvit ityy to traane nexamic acid or any of the ingredients. Focal areas of retinal degeneration have developed in cats, dogs and rats following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times the recommended usual human dose) from 6 days to 1 year. The incidence of such lesions has varied from 25% to 100% of animals treated and was dose-related. At lower doses some lesions have appeared to be reversible. Limited data in cats and rabbits showed retinal changes in some animals with doses as low as 126 mg/kg/day (only about 3 times the recommended human dose) administered for several days to two weeks. No retinal changes have been reported or noted in eye examinations in patients treated with tranexamic acid for weeks to months in clinical trials. However, visual abnormalities, often poorly characterized, represent the most frequently reported postmarketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, color vision, eye-ground and visual fields, is advised, before commencing and at regular intervals during the course of treatment. Tranexamic acid should be discontinued if changes in examination results are found. Convulsions have been reported in association with tranexamic acid treatment. The dose of tranexamic acid injection should be reduced in patients with renal insufficiency because of the risk of accumulation. Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with tranexamic acid. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid injection. Central retinal artery and central retinal vein obstruction have been reported. Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis. Tranexamic acid injection should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Patients with disseminated intravascular coagulation (DIC), who require treatment with tranexamic acid, must be under strict supervision of a physician experienced in treating this disorder. Tranexamic acid may cause dizziness and therefore may influence the ability to drive or use machines. Pregnancy Category B: Reproduction studies performed in mice, rats, and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. There are no adequate and well-controlled studies in pregnant women. However tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid. To avoid this response, the solution should not be injected more rapidly than 1 mL per minute. Worldwide Postmarketing Reports: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined.

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TRANEXAMIC ACID INJECTION

Rx Only

DRUG DESCRIPTION Tranexamic acid is an antifibrinolytic agent. Each mL of the sterile solution for intravenous injection contains Tranexamic Acid 100 mg and Water for Injection to 1 mL. INDICATIONS Tranexamic acid injection is indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. CONTRAINDICATIONS Tranexamic acid injection is contraindicated in patients with acquired defective color vision, since this prohibits measuring one endpoint that should be followed as a measure of toxicity (see WARNINGS); in patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid injection in such patients; in patients with active intravascular clotting; and in patients with hypersensitivity to tranexamic acid or any of its ingredients. WARNINGS Focal areas of retinal degeneration have developed in cats, dogs and rats following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times the recommended usual human dose) from 6 days to 1 year. The incidence of such lesions has varied from 25% to 100% of animals treated and was dose-related. At lower doses, some lesions have appeared to be reversible. Limited data in cats and rabbits showed retinal changes in some animals with doses as low as 126 mg/kg/day (only about 3 times the recommended human dose) administered for several days to two weeks. No retinal changes have been reported or noted in eye examinations in patients treated with tranexamic acid for weeks to months in clinical trials. However, visual abnormalities, often poorly characterized, represent the most frequently reported postmarketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, color vision, eye-ground and visual fields, is advised, before commencing and at regular intervals during the course of treatment. Tranexamic acid should be discontinued if changes in examination results are found. Convulsions have been reported in association with tranexamic acid treatment. PRECAUTIONS General: The dose of tranexamic acid injection should be reduced in patients with renal insufficiency because of the risk of accumulation. Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with tranexamic acid injection. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid injection. In addition, cases of central retinal artery and central retinal vein obstruction have been reported. Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis. Tranexamic acid injection should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Patients with disseminated intravascular coagulation (DIC), who require treatment with tranexamic acid injection, must be under strict supervision of a physician experienced in treating this disorder. Tranexamic acid may cause dizziness and therefore may influence the ability to drive or use machines. DRUG INTERACTIONS No studies of interactions between tranexamic acid and other drugs have been conducted. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY An increased incidence of leukemia in male mice receiving tranexamic acid in food at a concentration of 4.8% (equivalent to doses as high as 5 g/kg/day) may have been related to treatment. Female mice were not included in this experiment. Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic/neoplastic changes in the liver. No mutagenic activity has been demonstrated in several in vitroo and in vivo test systems. There are no clinical or nonclinical data to assess the effects of tranexamic acid on fertility.

Pregnancy (Category B) Reproduction studies performed in mice, rats, and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. There are no adequate and well-controlled studies in pregnant women. However, tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery (See above under Pregnancy) Nursing Mothers: Tranexamic acid is present in the mother’s milk at a concentration of about a hundredth of the corresponding serum levels. Caution should be exercised when tranexamic acid injection is administered to a nursing woman. Pediatric Use: The drug has had limited use in pediatric patients, principally in connection with tooth extraction. The limited data suggest that dosing instructions for adults can be used for pediatric patients needing tranexamic acid injection therapy. Geriatric Use: Clinical studies of tranexamic acid injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid. To avoid this response, the solution should not be injected more rapidly than 1 mL per minute. Worldwide Postmarketing Reports: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined. OVERDOSAGE Cases of overdosage of tranexamic acid injection have been reported. Based on these reports, symptoms of overdosage may be gastrointestinal, e.g., nausea, vomiting, diarrhea; hypotensive, e.g., orthostatic symptoms; thromboembolic, e.g., arterial, venous, embolic; visual impairment; convulsions, mental status changes; myoclonus, and rash. DOSAGE AND ADMINISTRATION Immediately before tooth extraction in patients with hemophilia, administer 10 mg per kg body weight of tranexamic acid injection intravenously together with replacement therapy (see PRECAUTIONS). Following tooth extraction, intravenous therapy, at a dose of 10 mg per kg body weight three to four times daily, may be used for 2 to 8 days. For dosing in patients with moderate to severe impaired renal function, see Full Prescribing Information. For intravenous infusion, tranexamic acid injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions and Dextran solutions. The mixture should be prepared the same day the solution is to be used. Heparin may be added to tranexamic acid injection. Tranexamic acid injection should NOT be mixed with blood. The drug is a synthetic amino acid, and should NOT be mixed with solutions containing penicillin. HOW SUPPLIED Tranexamic Acid Injection, 100 mg/mL, is a clear, colorless solution STORAGE Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Discard unused portion. AR117 Iss. Date 9/2011

Operations & Management 7

Pharmacy Practice News • May 2013

Medication Safety

Survey: Drug Shortages May Weaken Cancer Care hortages of cancer drugs continue to take a toll on patient care, increasing drug errors and costs, and leading in some cases to the purchase of short-supply products from “gray-market” suppliers, according to results of a new survey of oncology practitioners. “We were expecting oncology drug shortages to be very common and we showed that, but I’m not sure I expected the extent of patient impact that we saw—93% of respondents reported a delay in chemotherapy administration or change to a different treatment,” said lead researcher James Hoffman, PharmD, MS, BCPS, a medication outcomes and safety officer in pharmaceutical sciences at St. Jude Children’s Research Hospital, in Memphis, Tenn. “Further, I was impressed that 16% of respondents reported an adverse patient outcome such as disease progression or an increase in adverse drug events.” Dr. Hoffman said that although other investigators have looked at shortages of single-agent cancer medications, his research team’s study ((Am J Health Syst Pharm 2013;70:609-617) is the first to focus on a wider range of chemotherapy regimens. “Cancer shortages are difficult in that there are few [alternative agents available],” commented Erin Fox, PharmD, the director of the drug information service at the University of Utah Hospitals & Clinics in Salt Lake City, who was not involved with the study. “This [research] is important because it demonstrates the broad impact and overall concern for future outcomes.” The survey was distributed to 1,672 members of the Hematology/Oncology Pharmacy Association (HOPA). The Institute for Safe Medication Practices also distributed the survey, by various methods, to an undetermined number of recipients through the Association of Community Cancer Centers and the American Society of Clinical Oncology. Of the 243 survey respondents, the majority represented community hospitals (41%) and academic medical centers (39%), and 97% were pharmacists. Ninety-three percent reported delays in chemotherapy administration or changes in treatment regimens related to drug shortages. Fluorouracil, leucovorin, liposomal doxorubicin and paclitaxel were most frequently reported as being in short supply. Sixteen percent of those surveyed said therapy modifications caused nearmiss medication errors, and 6% said the shortages had caused one or more medication errors. Wrong-drug errors, incorrect dosing conversions and the use of the wrong concentration of medication collectively accounted for 74% of near-

miss errors. The majority of wrong-drug errors involved shortages of liposomal doxorubicin, and the majority of incorrect dosing conversions involved leucovorin shortages. Cytarabine shortages were the cause of the majority of wrongconcentration errors. Near-miss errors included incorrectly converting IV etoposide doses to equivalent amounts of oral etoposide or etoposide phosphate, ordering liposomal doxorubicin in place of doxorubicin, mixing multiple concentrations of cytarabine, and incorrectly converting a prescribed dose of leucovorin to an equivalent dose of levoleucovorin. One institution linked a patient’s death to incorrect medication dosing of epirubicin, which replaced daunorubicin during a shortage. At 34% of the surveyed institutions, the shortages added at least 1,000 hours of additional labor annually, which correlates to approximately 20 hours per week. Despite this increased workload, only 4% of respondents reported that their institution had hired additional personnel. “Hospitals and pharmacies would definitely welcome [additional] resources to manage shortages; it’s time that is being taken away from other tasks that add much more value to patient care,” Dr. Hoffman said. “For example, inventory and purchasing [pharmacists] could be spending time looking for opportunities to save the hospital money and improving purchasing practices. Clinical folks could be writing another guideline or doing another performance improvement project. Dealing with shortages takes time away from direct patient care.” The survey also revealed that drug shortages disrupted clinical trials at 44% of institutions, mainly by preventing patients from being enrolled (67%) or delaying patient enrollment (44%). Eighty-five percent of survey respondents reported that the treatment modifications increased costs, and 10% said they had difficulties getting reimbursed because of drug substitutions. Nearly one-third (28%) of survey participants admitted to purchasing products from the gray market, with 14% paying at least 100% over fair market value.

Gray-Market Purchasing Deemed a Risky Strategy In a presentation at the recent annual HOPA meeting, Moe Schwartz, PharmD, BCOP, the senior director of clinical content and services at McKesson Specialty Health, said uncertain medication integrity and inflated costs are problems with the gray market. Questions arise about the production source, product handling throughout the life of the drug, storage

100

93 85

Incidence, %

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80

60 44 40

34 28 16

20

6 0 Delays in Increased chemotherapy drug costs

Clinical trials At least Short-supply Near-miss disrupted 1,000 hours of drugs medication labor added purchased errors annually from gray reported market

Medication errors occurred

Figure. Negative effects of ongoing drug shortages. ‘This isn’t a problem easily fixed; these shortages are due [in large part] to manufacturing issues, and they are taking a long time to resolve.’ —Erin Fox, PharmD conditions, accuracy of the expiration date, manipulation of the drug product, and whether the product is in fact counterfeit. The World Health Organization estimates that 10% of pharmaceuticals in the world are fakes, but this number is significantly lower in the United States, in part because the lion’s share of medications are bought from legitimate channels such as community pharmacies and mail order. (More than 50% of medications purchased from illegal Internet sites, in contrast, are counterfeit, according to the organization). Despite the low overall incidence of counterfeiting in this country, it remains a vexing problem, Dr. Schwartz stressed. And it only promises to worsen, given the rapid rise in drug shortages, which have tripled in the past five years in the United States and in many countries around the world, she noted. The shortages clearly are taking their toll. Dr. Schwartz said a recent survey of 1,322 directors of pharmacy who were members of the American Society of Health-System Pharmacists estimated labor costs associated with managing drug shortages in the United States to be $216 million annually (Am ( J Health Syst Pharm 2011;68:1811-1819). In this survey, respondents said the shortages increased work burden by 97%, increased costs by 93% and increased perceived frustration directed at pharmacy by 82%. Eighty percent of those surveyed thought shortages changed practice and 55% felt they compromised patient care. Those survey results follow on the heels of a study published in The New England Journal of Medicine that also underscored the clinical price to pay when crucial drugs become scarce. The

researchers documented a 13% drop in two-year event-free survival rates when pediatric patients with Hodgkin lymphoma were given cyclophosphamide in place of mechlorethamine because of a prolonged shortage of the latter agent ((N Engl J Med d 2012;367:2461-2463; Pharmacy Practice News, February 2013, page 1). Dr. Fox said she is not surprised by the HOPA/ISMP survey statistics. “The numbers, unfortunately, aren’t a shock,” she said, “but I hope they will help people understand that drug shortages are a widespread problem.” The challenge, Dr. Fox noted, is that “this isn’t a problem easily fixed; these shortages are due [in large part] to manufacturing issues, and they are taking a long time to resolve.” She noted for example that supplies of electrolytes, common salts such as calcium and phosphate, and trace elements such as zinc continue to be in chronic short supply, creating “severe difficulties for clinicians and patients.” For Dr. Hoffman, a bill passed by the FDA in 2012 offers hope that at least some shortages may be checked before they get out of hand. In 2012, new federal legislation gave the agency additional tools to prevent and ease the shortages, including requiring manufacturers to report anticipated supply problems of key medications. But more work is ahead, he stressed: “While the FDA and others have worked diligently to address continuing shortages, additional action is needed to address this problem.” —Kate O’Rourke Drs. Fox, Hoffman and Schwartz have no relevant financial conflicts of interest.

8 Operations & Management

Pharmacy Practice News • May 2013

Medication Safety

INTERPLAY continued from page 1

non-MedStar colleagues to observe its failings, its investigation and the changes it implemented to increase medication safety. “We knew this error could happen anywhere because the compounding device we used is common and the problems with drug shortages are everywhere,” said Bonnie Levin, PharmD, MBA, the corporate assistant vice president of pharmacy services at MedStar Health. “We didn’t want this happening at another hospital; we want others to learn about the approach we took to identify and fix the problem and prevent it from happening again.” The incident was central to a session at the 2012 American Society of HealthSystem Pharmacists (ASHP) Midyear Clinical Meeting (MCM) that explored the link between drug shortages and medication errors and how hospitals can mitigate their negative impact. In addition to Dr. Levin, the speakers at the MCM session included Michael R. Cohen, RPh, MS, ScD, the president of the Institute for Safe Medication Practices (ISMP), and Terry Fairbanks, MD, MS, FACEP, an associate professor of emergency medicine at Georgetown University, in Washington, D.C., and director of the National Center for Human Factors Engineering in Healthcare (NCHFEH), a division of MedStar Health.

Rapid Response Team “This is a rare situation where an entire health system allowed its staff to step forward and teach others what they went through,” Dr. Cohen told Pharmacy Practice News. “I’m sure it was embarrassing to go public with this event and I hope they get credit for stepping up like this.” Dr. Cohen and other ISMP representatives, along with Dr. Fairbanks and other consultants from the NCHFEH were part of a response team summoned by MedStar within a day or two after the error was discovered. They worked closely with hospital clinicians and administrators to determine the cause of the error, examine IV compounding policies and procedures, and offer recommendations to decrease the risk for future errors. The ISMP reviewed every step of the IV admixture process, from drug procurement, labeling and packaging, to communication issues, staffing competency and education. Among their findings: • Pharmacy staff focused on the ingredient name and the volume of the container, but not the concentration. Additionally, a high level of trust among the staff led to expectations that mistakes would occur at an unre-

A two-fold f ld dosing d error off potassium acetate given to more than 200 patients in the MedStar Health system was attributed to several factors, including confusion over the switch to a 4 mEq/mL dose after the usual 2 mEq/ mL product was not available (left); the fact that such a change in drug concentration is uncommon and challenging to detect (vs. a change in manufacturer or volume); and a failure to place non-formulary concentrations on a designated non-formulary drug shelf (right).

‘We knew this error could happen anywhere because the compounding device we used is common and the problems with drug shortages are everywhere.’ —Bonnie Levin, PharmD, MBA alistically low level, which can lead to cursory checks of drug and patient information. • Buyers did not routinely inform the pharmacy supervisor when alternate products were purchased. • The purchased strength was not contained on log sheets and an assumption was made that 2 mEq/mL was received. • Most items stored in the drug room are high-alert medications; therefore, labeling them as such does not provide any additional safety benefit. • There was no standardized process that incorporated a printed checklist to validate that whatever changes are made to the databases are correct. Communication lapses played a prominent role. For instance, Dr. Cohen and his ISMP colleagues found that staff members were not always aware of the reasons for changing processes within the IV admixture service, and that a systematic approach to communication about shortages and product changes with staff was lacking. “Communication always turns out to be a major issue when the ISMP conducts consultations,” Dr. Cohen said. “Everything from the way orders are communicated by computers, the way drugs are listed on a screen, look-alike drug names, handwriting problems, abbreviations, verbal orders, telephone orders, the way we speak with one another—all that falls under communication. In this case, the health system’s purchasing department knew it was buying the higher concentration because that’s all they could obtain, but that information never reached the people who make the adjustments in the automated compounder system.” Dr. Cohen urged health systems to use the ISMP’s “Ten Key Elements” of the medication-use system when evalu-

ating pharmacy processes (http://www. ismp.org/faq.asp#Question_3). “The Ten Key Elements offers a template for designing an interlocking system of safety checks and balances that is very helpful when alternative drugs are brought in,” Dr. Cohen said. “Hospitals will want to know what it has to teach the medical and nursing staffs about a drug in order to monitor it because it’s different. Do we need to adjust equipment because the concentration is different, for instance? Do we need to collect additional patient information that allows safer use of the substitute? What about differences in how to store the drug and the nomenclature we use? All these things come into play when using alternative therapies.”

‘Inattentional Blindness’ To Blame Dr. Cohen also discussed the role of “inattentional blindness” in medication errors (http://www.visualexpert.com/ Resources/inattentionalblindness. html). The phenomenon occurs when someone performing a task fails to see what should have been plainly visible. Later, the individual cannot explain the lapse. Inattentional blindness certainly played a part in the MedStar incident, because clinicians repeatedly looked at the stock drug vial but did not register the new drug concentration on the label, Dr. Cohen said. Inattentional blindness has been the culprit in many errors documented by the ISMP, such as when a nurse pulled a vial of heparin from an automated dispensing cabinet, read the label, prepared the medication and administered it intravenously to an infant, despite the heparin concentration being 1,000 times greater than prescribed. The child died. In another event, a pharmacist entered a prescription for methotrexate into the

pharmacy computer daily. A dose warning appeared on the screen, which the pharmacist read and bypassed, leading to a fatal overdose. According to a 2009 ISMP Medication Safety Alert, “In many cases, people involved in the errors have been labeled as careless and negligent. But these types of accidents are common—even with intelligent, vigilant and attentive people. The cause is usually rooted in inattentional blindness, a condition all people periodically exhibit” (http://www.ismp.org/newsletters/ acutecare/articles/20090226.asp). Dr. Fairbanks identified root causes of the MedStar incident from the vantage point of safety engineering. He found, for example, that the staff exhibited decreased sensitivity to changes after long-term drug shortages; to facilitate bar-code scanning, vials at the compounding station were hung upside down with labels turned away from the operator; and nonformulary drug concentrations were stored on formulary drug shelves. He also noted that a change in a drug’s concentration is a rare and, therefore, unexpected event—one that individuals are unlikely to detect unless forewarned. Among his group’s recommended corrective actions were measures to restrict access to the IV compounder database; define a formulary list in the drug purchasing system (purchasing outside of which required the buyer to involve the pharmacist); procedural review and revision; staff retraining and re-education; and promoting a culture of continual feedback among staff. More broadly, he emphasized that the success of medication safety hinges on designing systems that compensate for inevitable human error—a tenet that is central to human factors engineering. “The key to designing safe systems is to design them around human performance

Operations & Management 9

Pharmacy Practice News • May 2013

Medication Safety and failings,” he said. “You can’t teach humans to not make mistakes; they’re an underlying fact of life, so we design systems to mitigate for inevitable errors.”

Lessons From Other Industries For decades, human factors engineering has been a fixture in high-risk, highconsequence fields like aviation, nuclear power and the military. Only recently has it begun to rise within health care, Dr. Fairbanks said. “Health care has not become any safer since the 1999 Institute of Medicine report, To Err is Human, probably because we continue to take the misguided approach that if there’s a human error involved in an adverse event we can prevent it from happening again by telling other clinicians not to make that same mistake, or by disciplining or punishing the person who made the mistake.” A far more realistic and effective strategy, he noted, is to approach safety breaches with the attitude that if it happened once it will happen again, then take steps to make sure that when the error is repeated it won’t affect the patient. “It’s striking to me, coming from a background as a safety engineer who then went into health care, that these concepts are so foreign in medicine,” Dr. Fairbanks said. To make the case that safety improvements need to be targeted toward systems and not individuals, Dr. Fairbanks, a licensed pilot, noted that an average of four communications errors occur between pilots and air traffic controllers every hour on every commercial airliner. “Yet we hardly ever crash a plane anymore” because aviation safety adjusts for human imperfection, he noted. But changing the entrenched way of thinking about safety will take some time. “It’s hard to change the culture in health care, where we really want to blame someone and punish them when something goes wrong,” Dr. Fairbanks said. “If our answer to patient safety is to stop humans—even those who are very well trained—from making mistakes, we’re going to fail.” The inertia within health care can be overcome by health system leadership and changes implemented hospital-wide or systemwide, he added.

purposefully ignoring policies can still result in disciplinary action. “If the leadership changes the way they approach safety, then front-line people will change their approach as well,” Dr. Fairbanks said. “It’s a huge change of culture and it allows people to be more comfortable talking about their errors, which allows for learning and mitigation of those errors. It alters the entire tone of discussion and the environment. Even more importantly, it helps the people on the front line to recognize that they can mitigate errors

in the future.” It was the intersection of Just Culture and transparency within MedStar that empowered the people involved in the incident to openly discuss errors and system shortcomings with managers without fearing unfair repercussions, according to Dr. Fairbanks. “Our hospital isn’t different from any other, and this could happen anywhere,” he said. “We didn’t injure a patient, but someone else could injure a patient, so we have a duty to report it and talk about it.”

Another reason that human factors are so important in health care, noted Medstar Health’s Dr. Levin, is because “we have cobbled together over the years a collection of different technologies that don’t integrate with each other very well. At each point, there is an opportunity for a human intervention, and, therefore, an error. Human factors looks at the whole picture and tries to understand all of it, identify where the weak points are and strengthen them.” —Steve Frandzel

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10 Operations & Management

Pharmacy Practice News • May 2013

Supply Chain

OhioHealth Uses Team Approach To Tame Drug Shortage

B

efore a shortage of potassium phosphate products hit the OhioHealth health system in March 2011, the eight member hospitals had been “acting in silos” to manage scarcities. However, things changed after they realized they only had a two-week supply of potassium phosphate and an indefinite shortage resolution date ahead of them. As Lorrie Burns, PharmD, one of OhioHealth’s medication safety pharmacists, explained during a recent Institute for Safe Medication Practices (ISMP) webinar, the health system quickly moved to a collaborative and proactive approach. “We didn’t know how long the shortage would last, so we developed a systemwide Shortage Response Team to meet weekly,” Dr. Burns recalled. The team, which is now part of OhioHealth’s drug shortage management strategy, includes pharmacy procurement coordinators, registered dietitians, clinical pharmacists and pharmacy managers. “Our initial goal was to preserve phosphate products for neonatal TPN [total parenteral nutrition] and adults requiring custom TPN,” she said. To achieve that goal, the team developed a potassium phosphate conservation strategy. The strategy specified that, when appropriate, patients not in these two priority groups should be switched from IV to oral potassium phosphate for phosphate replenishment. For nonpriority patients requiring TPN, they recommended using a premixed TPN solution containing phosphate when appropriate. A health-system team of registered dietitians and pharmacists created an order set for substituting the premixed TPN products. “Another very important thing we did was to have a smaller hospital transition

the preparation of neonatal TPN to a larger hospital in the system so that we didn’t have two sites opening phosphate vials every day and potentially throwing away product,” Dr. Burns said. Dr. Burns and her colleagues quickly disseminated details of the potassium phosphate shortage and the newly developed conservation strategy. “It was very important that physicians and particularly front-line nurses be aware of what was happening and felt comfortable with the conservation strategy,” Dr. Burns said, noting the centralized communication approach also saved staff time and effort. The strategy proved a success, she said, and “we had our changes in place within nine business days and were able to conserve our potassium phosphate stock until it was again made available.”

Team, which is charged with directing our conservation efforts,” she said. An individual hospital might volunteer to take the lead in developing a conservation strategy because it has the staff resources to do so or if it is particularly affected by the specific shortage, Dr. Besco noted. Building a conservation strategy begins with a look at each hospital’s internal product purchase history to get a snapshot of usage patterns.

Lessons Learned

If the usage patterns suggest inventory is likely to last until the predicted shortage resolution date, the team keeps an eye on stock. If the findings indicate supply may be depleted before the shortage resolution date, the team conducts a more detailed “deeper dive,” looking at the product’s use patterns, which indications it is most often prescribed for, whether order sets are used and who the most frequent prescribers are. The deeper dive helps identify which substitutions can be made, whether and when drug administration routes can be switched, how supply can be centralized and what patient groups should be prioritized to receive the drug. The individual conservation steps can be triggered sequentially when stock drops below prespecified inventory thresholds. And the finalized conservation protocol is shared across the entire OhioHealth system, but discretion as to when to implement the protocol is left up to individual sites based on their own patterns of use and existing inventory. “It’s a challenge to carve out resources to perform the deeper dive,” Dr. Besco admitted, “but we’ve found students and

In addition to teaching the importance of working collaboratively, the potassium phosphate shortage highlighted the need for vigilant drug shortage monitoring as a way to head off crisis situations, Kelly Besco, PharmD, medication safety coordinator for OhioHealth Pharmacy Services, in Dublin, Ohio, told webinar attendees. “Tracking wholesaler stock and our own internal inventory of shortage drugs allows us to be a bit more proactive so that we aren’t waiting until our supply reaches a critical state or until we aren’t able to obtain any product.” Dr. Besco said the conservation process typically begins when wholesaler supply of a shortage drug is noted to be trending down. “Once we identify a current or predicted national and wholesaler shortage, we report it to our health-system Shortage Response

‘The lessons learned from implementing [this] strategy with one product will help make it easier when another product is identified on shortage.’ —Allen J. Vaida, PharmD

pharmacy residents are very helpful in conducting these reviews.”

ISMP’s Take At first glance, the OhioHealth approach might seem too involved for some institutions to emulate, said Allen Vaida, PharmD, ISMP’s executive vice president. However, “as you continue this approach with repeated shortages with even a small shortage management

‘Once we identify a current or predicted national and wholesaler shortage, we report it to our healthsystem Shortage Response Team, which is charged with directing our conservation efforts.’ —Kelly Besco, PharmD team, what may seem resource intensive becomes less so,” he said. Moreover, “the lessons learned from implementing the strategy with one product will help make it easier when another product is identified on shortage.” To ensure success, he stressed, “the team should be given the backing to implement the change that may be needed in the organization, whether it be a health system or an individual hospital.” —David Wild Drs. Burns, Besco and Vaida reported no relevant financial conflicts of interest.

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12 Ops & Management

Pharmacy Practice News • May 2013

Reimbursement Matters

Time To Take Leadership With Billing and Data Transmission

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Find New or Revised Breakpoints and QC Ranges M100-S23 Vol. 33, No. 1 Replaces M100-S22 Vol. 31 No. 1

M100-S23 Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement

This document provides updated tables for the Clinical and Laboratory Standards Institute antimicrobial susceptibility testing standards M02-A11, M07-A9, and M11-A8.

M100-S23 | Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement This document provides updated tables for CLSI AST standards M02-A11, M07-A9, and M11-A8.

A standard for global application developed through the Clinical and Laboratory Standards Institute consensus process.

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Pharmacy billing remains the portal for pharmacy costs to feed into the overall system. If this is a weak link, shore it up. If every single item used is not accounted for through the charging mechanism, this needs to be fixed quickly. Defensible pricing, charge capturing and ongoing charge master management tools should leap to the forefront on your “to do” list. With the pharmacy budget having such high visibility, anything that can be done to lead to an improvement in data integrity, streamlining of business processes and enhancing internal controls in financial reporting is essential. Ask yourself this: “Is our department a contributor to old, incomplete data being used for new calculations that will fund my future budget requests?” If so, then it’s time to do something about it—quickly! Granted, how the system works and what all the terms mean can be puzzling and frustrating when you’re new to this game. I hope these FAQs help. Q: What is an FI or MAC? A: The United States is divided into several geographical regions, each assigned to a fiscal intermediary (FI) or Medicare administrative contractor (MAC). The MAC receives billings from hospital and outpatient clinics and submits them to the Centers for Medicare & Medicaid Services (CMS) for payment. Knowing who your MAC is and what peculiarities may affect your region is important. MACs determine if all program requirements for coverage are met (e.g., that it is reasonable and necessary to treat the beneficiary’s condition and whether it’s excluded from payment). Q: What are billing codes and why are they important? A: Coding is the language with which

“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health. Please email the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP

to describe what procedure was done and what product was used. It’s the operational link between coverage and payment. However, any payer at any time can look at what was done and on the merits of that information decide that they are not going to pay for it. Here are a few additional codes and definitions to keep in mind: • International Classification of Diseases Ninth Revision (ICD-9) codes are used by hospitals to designate disease types; ICD-10 codes will replace these by October 2014. • Current Procedural Terminology (CPT) codes are descriptive and identifying terms for reporting medical services, procedures and lab tests that provide a uniform language to describe medical, surgical and diagnostic services. They are created by the American Medical Association and its specialty organizations and may include payment for all the products used during the procedure. • Healthcare Common Procedural Coding System (HCPCS) codes describe products and may or may not be reimbursed. The fact that a drug, device, procedure, or service has a HCPCS code and a payment rate under the Outpatient Prospective Payment System (OPPS) does not imply coverage by Medicare but indicates only how the product, procedure or service may be paid if covered by the program. Most HCPCS codes are listed generically, but beware, there are several brand-specific ones as well (www.cms. gov/medhcpcsgeninfo). Also note that Diagnosis-Related Groups (DRGs) apply to inpatients and Ambulatory Payment Classifications (APCs) apply to outpatients; both only apply to Medicare billing. And remember that DRG and APC methodology often is used as a template for other insurance reimbursement. Q: Do I really have to bill for all products even if they’re not going to be reimbursed? A: Yes, this is a Medicare requirement. Most facilities with outpatient services were shocked when the Health Care Financing Administration, the predecessor of CMS, implemented APCs several years ago, especially when the reality set in concerning which products were

Operations & Management 13

Pharmacy Practice News • May 2013

Reimbursement Matters being reimbursed and their corresponding rates of payment. The response from health care providers to the low rates of payment was: How could this have happened? As I think we’ve made clear by now, their own negligence in failing to pay strict attention to the pharmacy billing system and to the use of appropriate codes and descriptions (as well as the charge itself ) was partly responsible. Facilities neglecting to bill for pharmaceutical products at all because it was “too complicated for too little return” further contributed to the problem. Their patients and their product use were averaged into the calculations—but at a zero dollar price. This is a huge issue at this very moment as rates for bundled and global payments are being determined. Q: Should I bother to collect copays? A: Yes! But first, a definition: The copay, for the uninitiated, is the amount that the patient is expected to pay out of pocket or through a secondary insurance carrier. CMS reimburses 80% and the beneficiary is expected to contribute 20%. Billing for and collecting copays is critical to a hospital’s financial solvency. For example, a $10 million CMS “drug spend” means $8 million coming from CMS and $2 million coming from copays. Can you afford not to bother collecting $2 million in copays? How much therapeutic intervention would you have to do to guarantee $2 million in savings? Copays from insurance companies usually are tiered and may range up to 40% for specialty pharmaceuticals. Q: What are billing units and why are they important to reimbursement? A: Several years ago, CMS implemented the concept of billing units rather than vial sizes when structuring reimbursement. Medicaid also uses billing units, although they are not necessarily the same ones used by Medicare. Although there has been ample discussion of these changes in the pharmacy literature, implementation of the concept continues to plague pharmacy directors and those involved with managing all the pieces of the pharmacy computer and automated dispensing systems. The billing unit tables are not static and require vigilance to ensure that the correct billing units are matched to the correct billing codes (HCPCS codes) in the pharmacy charge description master (CDM). National Drug Code (NDC) changes provide an additional complication. Failure to do so will result in significant over- or undercharging and resulting complications on audit. How does one ensure proper handling of billing units? It’s simple arithmetic. The goal is to be able to convert dispensable quantities either from automated dispensing cabinets or the pharmacy IV room into a HCPCS billable quantity. Some facilities have built and maintain conversion tables either by going through the pharmacy system if it supports this function, by using

a lookup table with conversion logic in the translator outbound to the financial system or by building a multiplier/divisor table on the back end of the financial system. This multiplier table takes the number of units sent from the transaction and multiplies it by the appropriate factor without affecting the price. Your action step? Accept that there is ongoing maintenance with the CDM, HCPCS codes and NDC changes. Develop a strategy for handling these in concert with your charge capture team. Q: What are ASP drug pricing files?

A: CMS reimburses based on the average sales price (ASP). CMS publishes a quarterly updated ASP drug-pricing file in three formats. It is available at CMS. gov and provides links to the actual listing of reimbursable Part B drugs and the amounts that will be reimbursed as well as a reminder of the billing units for each drug code. Also included are NDCs and the total billing units in each vial per NDC. Not surprisingly, reimbursement for some drugs increases yet decreases for others. There are a number of competitive market fac-

tors at work—multiple manufacturers, alternative therapies, new products, recent generic entrants or market shifts to lower-priced products, as well as the weighting given to the package sizes sold. Also, remember that ASP is calculated based on sales data from the manufacturer, not from the distributor. Q: Where do I get information? A: CMS; its website may be your new best friend. Stay informed with cms.hhs. gov/mailinglists. Sign up at cms.hhs.gov/ medlearn/matters. Good luck!

What’s all the hoopla? (ACETAZOLAMIDE from SAGENT)

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16 Clinical

Pharmacy Practice News • May 2013

Practice Pearls

Weight-Based Heparin Dosing Hits aPTT Target Ifeanyi Egbunike-Chukwuma, PharmD Clinical Coordinator Maryland General Hospital

Joseph Norbet Ngwa Nforbi, PharmD Candidate University of Maryland School of Pharmacy

Kevin A. Schnupp, PharmD, MBA Director of Pharmacy Maryland General Hospital Baltimore, Maryland

U

nfractionated heparin (UFH) remains an important parenteral anticoagulant for the treatment of several thrombotic disorders. Studies have demonstrated improved patient outcomes when targeted therapeutic ranges of activated partial thromboplastin time (aPTT) are achieved within 24 hours of therapy initiation.1,2 These therapeutic ranges are best achieved when weight-based heparin protocols (WBHP) are used.3,4 A WBHP was first introduced in our institution in 2008, with one dosing nomogram for all indications and a target aPTT range of 50 to 80 seconds. A medication use evaluation (MUE) conducted in 2009 revealed that therapeutic aPTTs were achieved in only 57% of patients within the first 24 hours of therapy; there was poor physician and nursing compliance with the dosing protocol, primarily due to their lack of familiarity with the WBHP and/ or their awareness of their role in dosing and monitoring these patients. In 2012, we revised and implemented a protocol that emphasized a multidisciplinary collaboration between prescribers, nurses, and pharmacists. The components of our WBHP protocol include the following: • 2 dosing nomograms, a low-dose nomogram for patients with acute coronary syndrome (ACS), with an aPTT target range of 50 to 70 seconds (printed on green paper), and a highdose nomogram for patients with other indications, including venous thromboembolism and atrial fibrillation or flutter, with an aPTT target range of 54 to 83 seconds (printed on pink paper); • a physician order form; • a color-coded heparin dosage calculation form (housed in the pharmacy); and • a color-coded weight-based heparin floor sheet (housed in the nursing station) (Figure 1). Before implementation of the revised protocol, extensive physician, nursing, and pharmacy education was conducted

Figure 1. Components of the weight-based heparin protocol. ACS, acute coronary syndrome; AF, atrial fibrillation; aPTT, activated partial thromboplastin time; DVT, deep vein thrombosis; PE, pulmonary embolism

and an online WBHP training course was developed for annual recertification of nurses and training of new nurses.

appropriate dosage adjustments are made and AEs are monitored.

Weight-Based Heparin Dosing Program

We conducted a post-implementation MUE to determine pharmacist and nursing compliance with the weightbased protocol and to determine the rate at which our patients achieve therapeutic aPTT targets using our current WBHP. We obtained a computergenerated list of all patients prescribed UFH 25,000 units/500 mL from Feb. 1, 2012 to May 31, 2012 and conducted a comprehensive review of the patient’s electronic medical records. Patients were excluded from the study if they received the heparin infusion for less than 24 hours, or if their heparin infusions were prescribed by vascular surgeons with targeted therapeutic ranges outside those recommended by our protocol. Pharmacy compliance with the protocol was determined by evaluating

The prescriber initiates the process by using the WBHP order form and defining the indication for therapy. The pharmacist calculates the initial loading dose and maintenance dose based on the patient’s weight using the appropriate color-coded form. For obese patients, a dosing weight (DWT) is calculated using the following formula: ideal body weight (IBW) plus 0.4 times (difference between the actual body weight [ABW] and the IBW). When the patient’s DWT falls between 2 points, for example 70 and 75 kg, the pharmacist will round down to the closest 5 kg. The pharmacist is responsible for verifying that baseline laboratory tests have been ordered before entering the heparin order into the computer. Our pharmacy uses a standard heparin concentration of 25,000 units/500 mL in a 5% dextrose solution (D5W). The protocol requires that 2 nurses verify the pharmacist calculation and the infusion pump setting before initiating the heparin infusion. The nurse also is responsible for verifying the availability of baseline laboratory tests before starting the infusion, and for obtaining the aPTT 6 to 8 hours after any bolus dose or dosage adjustments, and daily once the aPTT is in therapeutic range. The nurse modifies the patient’s heparin doses and infusion rates based on the aPTT, then documents any signs and symptoms of bleeding and other adverse events (AEs) on the appropriate color-coded heparin flow sheet. On a daily basis, the pharmacist reviews the patient’s laboratory values and consults with the nurse to ensure

Post-Implementation Evaluation

the accuracy of the pharmacy calculation of the bolus and maintenance infusion doses and their use of the appropriate nomogram form, based on the prescriber’s indicated patient diagnosis. Nursing compliance with the protocol was determined based on the nurse’s ability to adhere to the correctly calculated heparin dose; obtain all aPTT levels between 6 and 8 hours following any bolus or dosage adjustments; make appropriate dosage adjustments based on aPTT levels; and document on the dosing form that 2 nurses reviewed and signed off on dosage calculations and adjustments. Data collected include the following: age, gender, height, ABW, calculated IBW and DWT, pharmacy bolus and maintenance doses calculated and administered, and baseline laboratory tests, including complete blood counts, aPTT, and serum creatinine. The aPTT values were evaluated at 3 time points within 24 hours after therapy initiation.

Table 1. Pharmacy and Nursing Compliance To the Weight-Based Heparin Protocol Provider

Compliance Measure

N

Percent

Pharmacy

Use of correct color-coded dosing nomogram

88/88

100

Availability of baseline laboratory tests

88/88

100

Correct bolus and maintenance dose calculation

87/88

98.9

2 nurses review pharmacy dosing calculation

88/88

100

Nursing adherence to calculated doses

88/88

Nursing

aPTT obtained within 6-8 h post bolus or dosage adjustments

116/176

73.9

Daily aPTT after therapeutic target is achieved

42/88

47.7

Appropriate dosage adjustments made and documented in response to aPTT value

81/88

92

aPTT, activated partial thromboplastin time a

100 a

176 aPTT levels were available.

Clinical 17

Pharmacy Practice News • May 2013

Practice Pearls

Three Pearls of Enhanced Pharmacy Care Las Vegas—When no standards exist for managing the medication needs of obese patients who have undergone gastric bypass, which profession is uniquely equipped to ensure drug safety? Who has the skills to recognize the early signs of potentially lethal lithium-induced neurotoxicity? And who is well placed to prevent lipodystrophy caused by high-dose insulin? In each case, healthsystem pharmacists are meeting the clinical challenges head-on and illustrating their value to the patient-care team. They shared their successes during a Clinical Pearls Session at the 2012 Midyear Clinical Meeting of the American Society of Health-System Pharmacists.

Don’t Bypass Pharmacists for Medication Management After Roux-en-Y Procedure

P

harmacists can play an integral role in enhancing medication management in patients undergoing Roux-en-Y gastric bypass procedures, according to Tennessee pharmacist Robert A. Lucas, PharmD, BCPS. “There may be a lack of ownership in monitoring medications in this growing group of patients,” which opens the

100

Therapeutic

door for pharmacists to play a larger role and improve care, said Dr. Lucas, a clinical pharmacist and residency coordinator, at Blount Memorial, in Maryville, Tenn. The American Society for Metabolic & Bariatric Surgery has some standards for vitamins and minerals but no general standards for medications, he pointed out.

Subtherapeutic

Supratherapeutic 85.6

81.8

Percentage

80

76.9

60 53.4 43.2

40

35.2 28.4

20

21.6 18.2

20.4 15.9 12.2 2.3

2.6

2.2

0 1st aPTT

2nd aPTT

3rd aPTT

Obese

Nonobese

Figure 2. Distribution of patients’ aPTT values in therapeutic range. aPTT, activated partial thromboplastin time

The first aPTT was measured 6 to 8 hours after therapy initiation, the second aPTT was measured 6 to 8 hours after dosage adjustment (if applicable), and the third 6 to 8 hours after the dosage adjustment aPTT (if applicable). Additionally, we documented the availability of daily aPTT after therapeutic level was achieved and recorded any AEs from heparin therapy.

Findings Eighty-eight patients met the inclusion criteria for this study. Sixteen patients received heparin for ACS; 72 patients were treated for pulmonary embolism, deep venous thrombosis, or atrial fibrillation or flutter. The mean age of the patients in the study was 63.1 years, mean ABW was 87.3 kg, mean height was 73

inches, and mean DWT was 73.3 kg. Forty-nine (55.7%) of the patients were obese, and required calculation of their heparin DWT. Mean serum creatinine of the patients was 2.6 mg/dL (range, 0.48-9.9). The mean loading dose given to the patients was 5,400 units (range, 3,000-10,000 units) and mean maintenance infusion was 1,100 units per hour (range, 500-2,250 units/hour). The mean number of days of heparin therapy was 4.4 days (range, 2-16 days). Pharmacy and nursing compliance with the WBHP is outlined in Table 1. The pharmacist used the appropriate color-coded nomogram based on the prescriber’s indicated diagnosis 100% of the time, and accurately calculated the loading and maintenance dose 98.9% of the time. One patient received a slightly

The lack of standards presents continuity of care opportunities for pharmacists. There are several medicationrelated considerations before surgery, during hospitalization and after discharge, Dr. Lucas said. Before surgery, he noted, pharmacists should work with clinicians to make any medication changes well in advance of the procedure; assess and correct any metabolic deficiencies; and counsel patients about their medications. Dur-

higher dose than indicated because the patient’s weight was between 2 reference points and the pharmacist rounded up the weight. Nursing compliance with the protocol was as follows: 2 nurses acknowledged review of the pharmacist calculation by signing the dosing form 73.9% of the time; aPTT was obtained appropriately within 6 to 8 hours post bolus or dosage adjustment 66% of the time, and daily aPTT was obtained in only 47.8% of the patients once the patient achieved therapeutic aPTT. However, nurses adjusted doses appropriately based on the nomogram in response to aPTT levels 92% of the time. Seventy-two (81.8%) of our patients achieved therapeutic aPTT within 24 hours (Figure 2). Thirty-one (35.2%) achieved therapeutic aPTT within 6 to 8 hours after initiation of therapy, another 16 (18.2%) achieved therapeutic aPTT following one dosage adjustment, and another 25 (28.4%) achieved therapeutic aPTT following a second dosage adjustment. Our protocol called for calculation of a DWT; hence, we evaluated how well obese and nonobese patients attained aPPT target within 24 hours of initiation of therapy. Obese patients achieved therapeutic aPTT within 24 hours of initiation of therapy at a higher rate than nonobese patients (85.7% vs. 76.9%; Figure 2). Few patients experienced AEs. One patient experienced a minor nosebleed. This patient was on warfarin therapy; however, his aPTT was 31.4 seconds and his international normalized ratio was 1.23. Heparin was not discontinued in this patient. One patient experienced a significant 25% drop in hematocrit (40.2% to 30.3%) and a 6.3 g/dL drop in

ing hospitalization, pharmacists can review patients’ home medications and assist with proper application of protocols and standing order sets. After discharge, health-system pharmacists should liaise with community/ambulatory pharmacists to facilitate the transition of care. Beyond these general opportunities for pharmacists, Dr. Lucas pointed out specific opportunities for health-system pharmacists involved in the care of bariatric surgery patients. He said pharmacists must consider the absorption, distribution, metabolism and excretion of medications because these can be altered after the bypass (Figure). A specific area he said to consider is that certain medications will need to be changed to crushable formulations (eg, crush pills larger than a pencil eraser) to prevent adverse drug

•

see ENHANCED CARE, page 18

hemoglobin (16.8 to 10.5 g/dL), which led to discontinuation of therapy.

Conclusion Approximately 82% of our patients achieved therapeutic aPTT within 24 hours. Two areas of improvement identified nurses obtaining aPTT levels within 6 to 8 hours of each dosage adjustment and daily once the patient attains therapeutic aPTT. This problem was addressed in 2 ways: targeted nursing education and an expanded pharmacist role in daily monitoring of patients on WBHP. Because our institution has a pharmacy-managed anticoagulation program, a clinical pharmacist reviews all patients on WBHP and contacts the patient’s nurse to order an aPTT if it has not already been done. In February 2013, an audit of nursing compliance with aPTT draws revealed a 100% compliance with availability of daily aPTT once a patient had achieved therapeutic aPTT.

References 1. Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. Relation between the time to achieve the lower limit of the aPTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med. 1997;157:2562-2568. 2. Hirsch J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):141s-159s. 3. Schaefer DC, Hufnagle J, Williams, L. Rapid heparin anticoagulation: use of a weightbased nomogram. Am Fam Physician. 1996;54(8):2517-2521. 4. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with “standard care” nomogram. A randomized controlled trial. Ann Intern Med. 1993;119(9):874-881.

18 Clinical

Pharmacy Practice News • May 2013

Practice Pearls

ENHANCED CARE continued from page 17

reactions and possibly even mortality due to inadequate absorption of sustained-release medications. On the other hand, he said, pharmacists should keep a list of medications that cannot be crushed and share that list with patients. Another factor to consider is that the pH of the new pouch is higher and less acidic than normal, and that the absorptive surface of the gastrointestinal tract is now decreased, so extended-release, sustained-release and long-acting formulations may not be fully absorbed. Intestinal transit time also is decreased, causing incomplete absorption of coated or sustained-release medications. Because oral contraceptives may not be fully absorbed, Dr. Lucas cautioned that alternative birth control options might need to be considered.

Figure. ABSCORBED Acronym for Remembering Potential Medication Issues in Bariatric Surgery Patients

Absorptive surface decreased Birth control may be affected Site of absorption must be considered

Crush list should be compiled Other formulations may be required

Recheck levels of narrow index drugs

Bioavailability issues need to be considered

Electronic medical records should be flagged

Delayed-release medications must be changed

Pharmacists also should be aware of possible adverse effects with narrow therapeutic index drugs such as digoxin, carbamazepine and warfarin, according to Dr. Lucas. Additionally, drugs with low bioavailability may have even lower bioavailability. Dumping syndrome—characterized by a rapid peak and high absorption of medication, followed by a drop-off— may occur as well. This mainly occurs after ingestion of liquids that contain high concentrations of sweetener/sugars, which can lead to increases and drops in blood sugars as well as loose stools and the “dumping” of intestinal contents, he said. Avoiding liquid medications can help minimize the problem, Dr. Lucas noted. Another role for pharmacists treating bariatric

surgery patients is to flag patient’s medical records to apprise health care workers of these issues during any future admissions. Dr. Lucas reported no relevant financial conflicts of interest.

Sustained Lithium Toxicity: A Rare But Risky Phenomenon

P

harmacists can help prevent a rare but dangerous lithium-related neurotoxicity syndrome, according to a psychiatric clinical pharmacist from Mayo Clinic, in Rochester, Minn. A syndrome of irreversible lithiumeffectuated neurotoxicity (SILENT), characterized by persistent neurologic sequelae, can develop after resolution of acute lithium toxicity, according to Jonathan G. Leung, PharmD, BCPS, BCPP. Dr. Leung noted that the symptoms—cerebellar dysfunction, extrapyramidal symptoms and dementia symptoms—may persist for at least months and in many cases may improve but not completely resolve. Although this “is a rare phenomenon,” the repercussions are significant, so it is important to be aware of it and “keep lithium in the normal therapeutic range,” he cautioned. “It’s important to recognize the risk factors,” Dr. Leung said. These include elevated serum concentration of lithium. In a review of 79 likely SILENT cases, the serum concentrations averaged 2.29 ± 1.67 mEq/L, compared with the usual therapeutic range of 0.6 to 1.2 mEq/L (Clin Neuropharmacol 2005;28:38-49; Am J Pharm Ed 2005;69:88). Additionally, chronic exposure to even therapeutic serum concentrations also has been associated with the syndrome, Dr. Leung said. Coadministration with certain other medications also can put patients at increased risk because of drug interactions. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, nonsteroidal anti-inflammatory agents (with possible exceptions of aspirin and sulindac) and thiazide diuretics can increase lithium concentrations and should be avoided in patients taking lithium, he said. There also is some, albeit limited, evidence that non-dihydropyridine calcium channel blockers and some antipsychotic agents may enhance the neurotoxic potential of lithium (Clin Pharmacokinet 1995;29:172-191). Another potential risk factor is a preexisting neurologic disorder or fever, he said. Underscoring the potential irreversibility of the syndrome, Dr. Leung described the case of a 53-year-old

man with a history of bipolar disorder, who had been treated with lithium and also given lisinopril. The patient developed severe lithium toxicity requiring hospitalization and dialysis. Dr. Leung reported that the patient did not return to his previous baseline mental status, experiencing short- and long-term memory problems with ataxia, dysarthria and resting tremor subsequent to the lithium toxicity. These symptoms of SILENT still were present at four months’ follow-up. Dr. Leung said that pharmacists can play an important role in monitoring the safe and effective use of lithium. Opportunities for pharmacist intervention include serum monitoring and dosage adjustments and eliminating or minimizing drug–drug interactions. Dr. Leung reported no relevant financial conflicts of interest.

U-500 Helps Prevent Lipodystrophy Caused By High-Dose Insulin

U

-500 insulin is a viable option in patients who require high daily doses of insulin to forestall the development of lipodystrophy, according to Mississippi clinical pharmacist Matthew Strum, PharmD, BCACP, CDE.

said Dr. Strum, when patients require more than 200 units of U-100 of insulin per day and are faced with the side effect of lipodystrophy—divots that develop in the fat layer of the skin after repeated injections of insulin. “This is very disconcerting to the patient,” Dr. Strum said, and “they typically will then stop the insulin and get worse glucose control.” The onset of action of U-500 insulin is similar to that of U-100 insulin, according to Dr. Strum, but the duration of action is prolonged due to the delayed rate of absorption secondary to the higher concentration. Syringe selection can be a challenge with the higher concentration because “currently, there is no syringe calibrated for U-500 insulin.” Dr. Strum noted that TB volumetric syringes could be used if a volume calculation is done, but these are not always available and “there is a lack of reimbursement.” He said at his facilities, they use the U-100 syringe for the U-500 concentration and instruct patients to draw to a certain mark on the U-100 syringe. There are several different nomograms available for dosing U-500 insulin, Dr. Strum noted. He said he generally follows the dosing schedule shown in the Table. Beyond the benefit of less risk for lipodystrophy because of the decreased

Table. Dosing of U-500 Insulin TDD, Units/d

Injection Frequency/Delivery Schedule

Dose as a Percentage of TDD

200-299

2 injections/d (8 a.m., 8 p.m.)

a.m., 60; p.m., 40

3 injections/d (8 a.m., 12 p.m., 8 p.m.)

40/30/30, 45/35/20 or 40/40/20

Insulin pump: 1 unit = 0.01 mL; 0.01 mL of U-500 = 5 units

3 or 4 mealtime boluses

3 injections/d (8 a.m., 12 p.m., 8 p.m.)

40/30/30, 45/35/20 or 40/40/20

4 injections/d (8 a.m., 12 p.m., 5 p.m., 10 p.m.)

30/30/30/10

Insulin pump: 1 unit = 0.01 mL; 0.01 mL of U-500 = 5 units

3 or 4 mealtime boluses

4 injections/d (8 a.m., 12 p.m., 5 p.m., 10 p.m.); do not inject >2 mL in any one site

30/30/30/10

300-599

≥600

TDD, total daily dose

“A lot of people get scared of U-500. But it’s just a concentration issue. It’s simple math when you go from a U-100 [100 units/mL] to a U-500 [500 units/ mL] concentration,” said Dr. Strum, a clinical professor at the University of Mississippi School of Pharmacy and a clinical pharmacist at Oxford Endocrinology Consultants, who manages nearly 80 patients at any given time on the U-500 insulin therapy. The higher concentration is needed,

volume needed with U-500 insulin, “on a per-unit basis, U-500 insulin is actually less expensive” than U-100, Dr. Strum said. There are additional cost savings due to decreased need for needles, syringes and other supplies. Dr. Strum is a certified insulin pump trainer for Medtronic and Insulet Corporation.

—Sarah Tilyou

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To contact an Abelcet representative call 1-800-447-0169 Select option 1 and enter x572 or visit www.sigmatau.com/products/abelcet_rx.asp

20

Hem/Onc Pharmacy

Pharmacy Practice News • May 2013

In Focus

HELP WANTED continued from page 1

“Pharmacists are not cheap,” said Robert Mancini, PharmD, BCOP, an oncology pharmacist and a postgraduate year 2 oncology residency director at St. Luke’s Mountain States Tumor Institute, in Boise, Idaho. “So we need to prove—and often the burden falls on us—that they save more money than they cost.” As an example, he pointed to a recent study in which investigators conducted a retrospective review of clinical pharma-

cist interventions at a community oncology clinic over a two-year period ((J Oncol Pharm Pract 2011;17:426-432). The study focused on two areas: drug-related interventions, such as those involving adverse events, medication reconciliation and drug dosing (dose rounding, dose modifications etc.), and consultative interventions, such as patient education, patient visits and drug information. “What they found was that one pharmacist was able to [achieve] chemotherapy cost savings of $210,000 per year. Most of that cost savings came from preventing drug

waste, reducing doses when indicated and rounding to vial sizes,” Dr. Mancini said. As further evidence, Dr. Mancini cited a study showing that chemotherapy-related dose rounding at one hospital reduced waste by 42% over a three-month period, which resulted in savings of $24,434 ((J Oncol Pharm Practt 2011;17:246-251). At another hospital, a chemotherapyinduced nausea and vomiting algorithm, developed with the help of a pharmacist, saved $205,000 in the first year of use ((Am J Health Syst Pharm 1995;52:18791885). A study evaluating a pharmacist-

managed oral chemotherapy program showed that it increased retained scripts from 25% to 85% ((J Hematol Oncol Pharm 2012;2:42-46). The program reduced the non-fulfillment rate due to cost to 1%, reduced medication write-offs to less than 1%, and although its operating costs were $230,000 annually, it increased revenue by $2.4 million annually. “If you have the ability to better manage medications, you have the ability to bring in more money,” Dr. Mancini said. He noted that the high price of many cancer medications meant that a slight increase in prescriptions due to pharmacist interventions could mean a dramatic jump in revenue from drug reimbursement.

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In another study, a community hospital demonstrated the success of an interdisciplinary team at decreasing errors and improving efficiency. One of the key members of the team was a pharmacist who helped with the creation of order forms, collaborative practice agreements and protocol implementation. The team was able to reduce medication errors by 45%. Additionally, waste prevention produced an annual cost savings of $120,000 in the first five years of the endeavor ((Am J Health Syst Pharm 2011;88:1741-1747). A pharmacy-driven medication therapy management (MTM) initiative at The University of Texas MD Anderson Cancer Center in Houston is a prime example of pharmacy increasing revenue. In a threemonth period, 239 MTM visits were completed. Pharmacists spent a median of 20 minutes of face-to-face time and 18 minutes for documentation per visit. To date, no claims for MTM have been rejected, and reimbursement rates range from 47% to 79% depending on insurance provider ((J Am Pharm Assoc 2012;52:170174). The MTM practitioners used billing codes 99605 to 99607 to bill Medicare and negotiated rates with private payers. Dr. Mancini pointed out that a pharmacy or pharmacist must have a national provider identification number, and Medicare does not allow pharmacists to bill on the same day as a provider visit. A report from the Lewin Group shows that pharmacists must charge approximately $2 to $3 per minute to make an MTM program profitable and $1 to $2 to break even (The Lewin Report, May 17, 2005). This report also provides recommendations on how to implement MTM services.

$8 Million in Revenue From Oral Chemotherapy Pharmacists also can increase revenue by helping with prior authorizations, Risk Evaluation and Mitigation Strategies (REMS) paperwork, protocol management, inventory management and accreditation standards. REMS paperwork involved in dispensing drugs such

Hem/Onc Pharmacy 21

Pharmacy Practice News • May 2013

In Focus as lenalidomide (Revlimid, Celgene) can be burdensome, Dr. Mancini said, and pharmacists can help manage the REMS workload to free up physician time. “If physicians can see more patients, then we are going to bring more money into the institution,” he said. With oral agents flooding the market, creating an oral chemotherapy dispensing program can be very lucrative. According to Dr. Mancini, 52 oral agents are on the market for a cancer indication—seven of them were approved in 2012. Pharmacists interested in launching an oral chemotherapy program at their institution should use residents to perform a pilot for proof of concept. In the pilot that helped launch the program at St. Luke’s, residents demonstrated that the program only needed 82 prescriptions per year to break even because the hospital is a 340B institution, a status that affects the finances of running a program. St. Luke’s is generating $8 million in gross revenue each year through its oral chemotherapy program. Residents creating a pilot should determine factors such as how many pharmacists would be needed for a program, how many patients at the institution are receiving oral cancer medications and how many prescriptions would be referred to an in-house pharmacy. Dr. Mancini pointed out that although some insurers mandate the use of a mail-order pharmacy, they often are willing to negotiate when they see what a hospital pharmacy can offer. “A lot of time, all you have to do is start those conversations with the payer and you can get on the contract,” he said. Douglas Smith, PharmD, BCOP, an associate professor in the Department of Pharmacy Practice at Shenandoah University School of Pharmacy, in Winchester, Va., was involved in the previously mentioned study measuring the effect of clinical pharmacist interventions at the John Marsh Cancer Center, in Hagerstown, Md. He said the top three ways that pharmacists can generate money are “dose rounding and inven-

‘If you have the ability to better manage medications, you have the ability to bring in more money.’

—Robert Mancini, PharmD, BCOP

tory management, assuring appropriate use of antiemetics and growth factors (this would include recommending their use in appropriate cases), and taking an active role in the non-formulary drug review process and working with providers to ensure evidence-based/guidelinesdriven treatment.”

1

Whether it is to launch an oral chemotherapy program or add a pharmacist to enhance existing services or research, the best ally for arguing for a new pharmacy staff position is a physician. “If you can convince [physicians] of your benefit, you are going to get the administration convinced,” said Dr. Mancini, who noted

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that doctors can act as a bug buzzing in the ear of administrators. “That is how St. Luke’s recently justified an additional research pharmacist position. Our new medical director for research said, ‘I want a pharmacist’ and, guess what, we are getting a pharmacist.”

A PROVEN RECORD OF RESPONSE. APP® and are trademarks of Fresenius Kabi USA, LLC. ©2013, Fresenius Kabi USA, LLC. All Rights Reserved. 0512-APPF-05-01/13

22 Clinical

Pharmacy Practice News • May 2013

Patient Care

ADHERENCE continued from page 1

Scripts’ 2011 Drug Trend Report. A lack of symptoms is one predictor of nonadherence, but complex treatment regimens, a lack of confidence in the treatment or the care provider, the presence of mental illness and high treatment cost also are associated with poor adherence, Dr. Yankovskaya said. “By using what we already know about an individual from electronic health records and claims data, we can inter-

ment is important.” Furthermore, she added, “a letter-mailing intervention may seem resource-intensive, but it is not as expensive as setting up a case management team.” Another way of addressing cost barriers is to work with insurers to create a “value-based insurance design,” Dr. Yankovskaya said. This might include reducing or completely waiving a patient’s copay or lowering the cost of preventative physician visits, she explained. In one study including more than 35,000 patients with diabetes,

waiving copays increased adherence rates by approximately 6% ((Health Aff 2008;27:103-112).

Who Knew Adherence Could Be Fun? Dr. Yankovskaya pointed to a novel adherence intervention—aimed at reducing the number of accidentally missed doses—that strikes a lighter note. “Gamification uses game elements and game design techniques to make adherence into something fun,” she explained.

Although most attendees had not heard of the term “gamification,” an informal poll at the AMCP session revealed that many in the audience were enrolled in a reward points program, which is a gamification strategy used by companies to encourage purchases and brand loyalty. According to Dr. Yankovskaya, a gamification strategy like a rewards program can lure customers into “going out of their way to do certain things that they might not otherwise do.” Health care stakeholders are only

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“Gamification” can be used to promote medication adherence. An example is the free iPhone application, Mango Health, which rewards patients with gift cards and moves the user through various levels depending on how adherent they are to their medication schedule.

vene proactively,” Dr. Yankovskaya said. “Tailored interventions using a predictive model that takes variables into account can address particular problems that can lead to nonadherence.”

Tailoring Interventions To Reduce Cost Barriers When cost is a barrier, for example, pharmacists can mail patients a “loss aversion letter,” outlining the financial costs of nonadherence, Dr. Yankovskaya said. She pointed to a study conducted by Express Scripts that showed that mailing such a letter increased adherence by 8.8%, compared with a 7% improvement when no letter was sent out. “This may be a modest increase but it is still an increase,” Dr. Yankovskaya said. “Considering the costs of nonadherence, any improve-

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Clinical 23

Pharmacy Practice News • May 2013

Patient Care starting to apply gamification to tackle nonadherence, but Dr. Yankovskaya said that she believes it could prove effective in increasing adherence, particularly in the growing population of younger patients with chronic diseases. One example of gamification used to address nonadherence is the free iPhone application Mango Health, which Dr. Yankovskaya encouraged pharmacists to use with their patients. The application rewards patients with gift cards that can be redeemed at popular stores and also moves patients

‘Considering the cost of nonadherence, [even a 1.8%] improvement is important.’ —Yelena Yankovskaya, PharmD through different “levels,” depending on how adherent they are to their medication schedule. The app also includes a drug reference library, which patients can use to educate themselves about drug-related adverse events and drug interactions. “I can assure you you’ll be hear-

ing more about this approach,” Dr. Yankovskaya predicted, noting that pharmacists can learn more about gamification through a free online course at www.coursera.org. Eric Wee, PharmD, a postgraduate year 1 managed care pharmacy resident at CVS Caremark in Irving, Texas,

has a particular interest in medication adherence and he said that he believes technology-based tools like Mango Health “can definitely play a big role in increasing adherence in the near future. The main issue with nonadherence is that patients simply forget to take their medication,” Dr. Wee told Pharmacy Practice News. “Therefore, the best way to address the issue of nonadherence is to remind the patient to take their medication at the right time. From pill bottles that glow, vibrate, ring or beep, to iPhone apps that remind patients to take their medication, to the concept of gamification, I think technology can address the issue of nonadherence in an effective manner.” The toolbox of adherence-promoting interventions means pharmacists can choose one or more approaches that are most appropriate for an individual patient, Dr. Yankovskaya concluded. “Different strategies are effective for different patients. There is no single solution. There might be something that works best for one patient, but not another.” —David Wild Drs. Yankovskaya and Wee reported no relevant financial conflicts of interest.

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Teva Introduces Generic Oxymorphone Tablets

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© 2013 CareFusion Corporation or one of its subsidiaries. All rights reserved. CareFusion and the CareFusion logo are trademarks or registered trademarks of CareFusion Corporation or one of its subsidiaries. VA1964

eva Pharmaceuticals announced that it has introduced Oxymorphone Hydrochloride Tablets, CII. The product is ABrated and bioequivalent to Opana Tablets (Endo Pharmaceuticals), according to TEVA. Oxymorphone HCl Tablets are available in 5-mg and 10-mg strengths, in bottles of 100. For more information, visit www.teva.com

24 Technology

Pharmacy Practice News • May 2013

Automation

A Tale of Two IV Robots RIVA, i.v.STATION help hospitals automate infusion preparation, reduce need for potentially risky outsourcing Las Vegas—Renewed awareness of the risks inherent in IV drug compounding—most recently underscored by the ongoing fallout of the meningitis compounding crisis—was probably behind the steady traffic at the Intelligent Hospital Systems (IHS) booth at the 2012 American Society for Health-System Pharmacists Midyear Clinical Meeting in December, where visitors watched RIVA, the company’s fully automated IV compounding robot, methodically go through its paces. According to Bill Shields, IHS global vice president of marketing and sales, the contamination debacle prodded hospitals that had already been considering the system to accelerate their decisionmaking processes. “We’ve been talking to these hospitals for a long time,” Mr. Shields said. “Many have been saying

‘yes, we want to get this, but not immediately.’ Now they’re taking another hard look at compounding automation.” One of the driving design considerations for RIVA was minimizing human factors in the compounding equation. Designers viewed in-hospital compounding as a manufacturing process where safety breaches, production bottlenecks and errors arise from inescapable human foibles. With the robot, operators load stock drug vials, diluent bags and empty syringes and IV bags; set the production parameters; start the machine; and then collect the finished and labeled admixture bags or syringes from output chutes. “Other than taking the dust caps off the vials when you load them, there’s almost no touching of the medication containers before the robot goes

‘Our intent for [the i.v.STATION] robot was not large batch processing or pediatric preparations but rather to minimize reliance on outsourced products and the associated price premiums.’ —Kim Mason, PharmD

to work,” said Kevin Jones, PharmD, MBA, the director of pharmacy at Primary Children’s Medical Center, in Salt Lake City, which began using the RIVA robot in early 2009. “Once the racks are filled up, we can turn it loose for three to five hours.” The unit operates 18 to 22 hours daily, during which it can fill 400 to 500 syringes. About half of the 900,000 IV doses prepared by the hospital pharmacy annually come out of the robot, which can be programmed to produce batches of the same drug and dose or individualized, patient-specific doses. According to IHS, preparing 350 syringes with RIVA requires three hours of a technician’s time. All of the manipulations occur inside the robot’s aseptic environment. Accuracy checks include weighing drug vials before and after use, weighing syringes before and after filling, comparing a photo of drug labels with file photos, and bar-code scanning. The machine rejects preparations that fail any of those tests. Pulsed ultraviolet light bombards vial access points for sanitization. According to Dr. Jones, periodic testing for contaminants, which began shortly after RIVA’s installation, has yet to return a single positive culture. RIVA’s current price tag is $1.35 million, plus an annual maintenance fee of $130,000, according to IHS. That means the hospitals need solid assurance that the capital expenditure will pay off—and pay back. (RIVA’s cost has risen about 25% since its 2007 introduction, an increase commensurate with added features and functionality, according to Mr. Shields.) Dr. Jones’ foremost financial justification for the robot to administrators was the potential to reduce losses related to drug waste. “There’s lots of wasted medications at a pediatric hospital because we prepare so many customized, weightbased doses that cannot be redirected to other patients,” he explained. Dr. Jones estimated that monthly waste-related losses have dropped from $120,000 to $45,000. “Theoretically, you could do that without a robot, but this way we also eliminate worries about contamination and errors.” The hospital, he added, recouped the purchase price in about three years. One recurring error prior to the RIVA installation was narcotics overdoses, which occurred when technicians stocked automatic dispensing cabinets in pediatric areas with adult doses. The error reached the patient, Dr. Jones noted, but the mistake was caught early, reversing agents were quickly administered and no lasting patient harm occurred. The robot has eliminated those types of dispensing

errors and similar mistakes, Dr. Jones said. “We also have a rule that vancomycin bags used to draw syringes must be made by the robot, because we’ve had errors in the past where they were not made correctly or when the drug was omitted from the bag.” The robot also has relieved some pressure caused by drug shortages. For example, when vendors ran out of 25% prefilled dextrose syringes (kept in crash carts for cardiac emergencies), RIVA made them.

The First RIVA Installation Site Children’s Hospital of Orange County, Orange, Calif., attained similarly noteworthy savings after installing RIVA in 2007 (and becoming the first installation site), according to Rita Jew, PharmD, FASHP, the executive director of pharmacy. Because of its newfound ability to produce drug batches more frequently—and, therefore, closer to when they are actually needed—the pharmacy narrowed the time gap between drug order and delivery to patient floors and prepared fewer syringes after prescriber orders were discontinued or changed or patients were moved. “Wastage of IV drugs dropped by one-third,” Dr. Jew said. When colleagues at another hospital attempted the same tactic via manual compounding, they needed additional staffing. Moreover, per-dose costs fell in conjunction with decreased reliance on external compounders. And even at the volume of in-house IV compounding, Dr. Jew reduced the number of pharmacy technicians in the compounding pharmacy, yet hired more clinical pharmacists and increased direct patient care activities. Overall, the savings and added efficiencies translated to a threeyear return on investment. Before the robot, the reported error rate for IV medications from the hospital’s compounding pharmacy was slightly below 1%. The post-installation rate is zero. To be certain, the pharmacy still conducts random checks of 10% of patient-specific medication batches. “Introducing this big robot really worried people at the beginning,” Dr. Jew said. “At first, people were quick to criticize it. Now if RIVA is down, they feel the pain.” Both pharmacists report that RIVA does break down, although infrequently. Usually the periods of downtime last an hour or two, Dr. Jones said, adding that only twice in four years has the robot crashed for longer than a day. Dr. Jew said downtime with the robot was relatively common in the months after

Technology 25

Pharmacy Practice News • May 2013

Automation installation and often involved software glitches. Failures are now rare—perhaps once a quarter—and typically are caused by worn parts, she said. “It is important to note that Drs. Jones’ and Jew’s RIVA systems were considered our beta installations,” Mr. Shields said. “That would explain the downtime they experienced in the beginning. Those specific issues were resolved several years ago through our system upgrades.” RIVA is a big machine, requiring about 180 square feet of floor space. Because hospital sterile compounding rooms are often tight to begin with, accommodating such bulk can be a formidable challenge. Dr. Jones said he had to partition his small clean room to allow ongoing manual compounding. “The resulting work area was very cramped, but the installation was completed ahead of schedule, which helped remedy the situation,” he said. Afterward, the change in pharmacy workflow created “some anxiety,” but overall the conversion went smoothly.

Another Robotic Solution A more recent entrant to the robotic compounding arena, i.v.STATION, from Health Robotics, which launched in 2011, concedes capacity and more staff attention in favor of smaller size and lower price: Its physical footprint covers nine square feet, and the machine needs 20 square feet for operation and maintenance. The system is listed at $350,000 (plus a $50,000 annual service contract) and performs essentially the same functions as RIVA, according to Health Robotics. Both machines, according to their respective manufacturers, can compound and dilute liquids and reconstitute powders. Both are ISO Class 5 air-controlled environments that meet United States Pharmacopeia (USP) Chapter <797> standards for compounding sterile preparations, and both are compatible with many, although not all, stock vials and solution bags. The i.v.STATION handles only nonhazardous chemicals, Health Robotics explained, but when augmented with a chemotherapy module that requires a bit of additional floor space, it becomes the i.v.STATION ONCO for preparing oncology drugs. Although some internal process variations distinguish the two systems, “the intended final products are identical,” said Gaspar DeViedma, the executive vice president of Health Robotics and its chief designer. The i.v.STATION holds 42 empty syringes and can fill 40 syringes (or 50 bags) per hour, including the time required to reload the machine, which holds 25 empty IV bags. Mr. DeViedma added that bags can be loaded while the machine is running. RIVA holds up to 450 syringes, with outputs of up to 50 syringes or 25 bags hourly, IHS noted. “In my opinion as a designer, I felt that the added pharmacy real estate

needed to accommodate a much longer production queue was not a good tradeoff,” Mr. DeViedma said. “Both systems still produce just one syringe or IV bag at a time.” He explained that the i.v.STATION fits syringes with tamperresistant Luer-Lok caps, which accounts for the somewhat slower production rate. RIVA uses standard caps. Health Robotics has taken a modular approach by tying various smaller components together through a central control hub, which allows users to coordinate the operation of multiple units and position them at remote locations. The University of Tennessee Medical Center purchased the i.v.STATION because it provided “exactly what the medical center was looking for,” according to the center’s pharmacy director, Kim Mason, PharmD. “After thorough research, we realized that i.v.STATION was best suited for our specific needs,” she said. “Our intent for this robot was not large batch processing or pediatric preparations but rather to minimize reliance on outsourced products and the associated price premiums.” The robot is awaiting installation. Robotics technology has “dramatically changed how we do IV compounding in our facility,” said Bill Churchill, MS, RPh, the chief of service in the Department of Pharmacy at Brigham and Women’s Hospital, in Boston, which leases a pair of i.v.STATIONs, as well as four i.v.SOFT Assist semi-automated compounding stations. “I was looking for a complete system with workflow software to control all the components that could interact with our pharmacy system,” Mr. Churchill said. “That has allowed me to scale my operation appropriately—in other words, build it as large or small as I want. I also needed components that could fit into our rather small clean room and be positioned remotely.” He estimated that the work done by the robots equals the output of two full-time technicians working around the clock. Having multiple robots creates flexibility, too: While one prepares large batches, the other can work on patient-specific doses, for example. And if one crashes, the other can be ramped up to fill the gap. As with any mechanical device, crashes are inevitable. “Very early on, there were some mechanical and software problems that had to be addressed,” Mr. Churchill said. “Over time, the i.v.STATION support for both the software and the hardware dramatically improved, and so has reliability and performance.” The two i.v.STATIONs yield 7,000 to 8,000 doses monthly—well below their limits. Behind the deficit are shortages or sporadic supplies of key drug stocks, such as fentanyl, hydromorphone and midazolam, Mr. Churchill explained. “We want to make those on the robot, but we still have to rely on outsourcing.”

‘Introducing this big [RIVA] robot really worried people at the beginning. At first, people were quick to criticize it. Now if RIVA is down, they feel the pain.’

—Rita Jew, PharmD

He noted that the robot still has some limitations with regard to the vial sizes it can handle, but he said that he anticipates that as the robotic compounding field advances, those and other technological limitations will fall away. When that happens—and national drug shortage issues move toward resolution—he anticipates a dramatic ramp-up in robotic IV production. Mr. Churchill also plans to add several more robots to his stable. Dr. Jones acknowledges the value and flexibility of multiple smaller robots, particularly when space is at a premium. But after a good deal of consideration (he’s still shopping for a second robot dedicated to chemotherapy), he said he still favors longer uninterrupted production runs and less human–machine interaction. “To me, the biggest advantage of RIVA is that you can load so much into it and let the machine run for hours,” Dr. Jones said. “That means there’s less human touching of the machine and materials and a lower risk for drug contamination. If you’re configured with central distribution, as we are, it’s no advantage to have two or three of the smaller robots compared to one big one.” Dr. Jones is also leery of putting robots on nursing units, which, although convenient, raises concerns about fungal and bacterial contamination risks, in his view. Whether one of the robotic compounding models represented by these two machines gains the upper hand, one thing is certain: The old ways are fading. “We are at the dawn of a new age of technology and this is just the first generation of sterile IV compounding robots,” Mr. Churchill said. “They’ve

met my expectation and do exactly as advertised. But I expect in the next several years they will change substantially, with more functionality, more features and more capabilities. I see nothing but growth for IV robotics. One of the key decisions pharmacy leaders face is whether to buy the technology now while it’s still developing, or lease it until the technology matures.” —Steve Frandzel

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26 Technology

Pharmacy Practice News • May 2013

Automation

A Cost-Effective Option for Compounding H

ospital pharmacies face a stiff challenge as the fallout over the recent meningitis outbreak caused by tainted compounding continues: As scores of other vendors shut their doors because they failed FDA inspections, how does a hospital ensure the adequate flow of crucial admixtures? One solution is to bring more of the sterile compounding workload back into the hospital. But this strategy has its own risks and challenges, including ensuring United States Pharmacopeia (USP) <Chapter 797> compliance, adjusting staffing and workflow, and building expensive new clean rooms and buying other high-ticket equipment and technologies. Another roadblock: steering clear of the regulatory minefield surrounding beyond-use dating (BUD). “We all learned from the New England Compounding Center’s situation not to max out beyond-use dates,” said Bernadette Ellegard, RPh, MBA, principal at Ellegard Pharmacy Consulting, LLC, in Kent, Conn. “Hospital pharmacies should take control of batch sizes, make what’s needed for periods of time and not extend use dates as far as possible. Also, account for time out of refrigeration during delivery.” Such a strategy makes sense, given the increased regulatory scrutiny of compounding that already has been brought to bear. The New York State Board of Pharmacy, for example, has ended batch outsourcing. An established but newly enforced requirement for true patientspecific prescriptions aims to end the practice of pharmacies supplying fake names to outsource centers as placeholders to get product in advance, and later sending in actual patient names, according to Ms. Ellegard. Moreover, the New York board wants the FDA to inspect manufacturers before they can operate in the state, she noted. For resource-strapped hospitals that decide to meet at least some of the resulting compounding gap by doing the mixing in-house, help is at hand. Ms. Ellegard noted that it is possible to bring in relatively affordable technologies such as semi-automated compounding devices that can be used safely within an ISO Class 5 hood, making it easier for directors to balance patient needs with limited budgets. Such a strategy can help a hospital maintain a viable mix of batch and patient-specific in-house and outsource preparations, she noted. Ms. Ellegard said she has worked with semi-automated compounding technology for a decade in posts as an assistant director for sterile products and repackaging at Mount Sinai Medical Center,

mulary with [Grifols’] Mix Manager software, we consistently produce the same sterile product from one clinician to the next. The technology’s simplicity has streamlined order entry and decreased risk of calculation errors.” The Gri-Fill System meets the USP sterility standard with a 0.22-micron filter pre-attached to a proprietary polyvinyl chloride bag. According to Grifols, it “maintains sterility through media fill validation under worst-case conditions, with over 3,150 prepared doses with no microbiological growth.” The company states that there is “95% confidence the contamination rate is no greater than 0.095%.” For items prepared aseptically with the filter, the probability is one in 1,000 of a nonsterile item “making it through the validated sterilization process.”

Match Extended-Use Dates To Usage Forecasts

The Gri-Fill System 3.0 Compounder in use at a clean room at Sentara Virginia Beach General Hospital, in Virginia.

‘We all learned from the New England Compounding Center’s situation not to max out beyond-use dates.’ —Bernadette Ellegard, RPh, MBA New York City, and until 2012 as a Cardinal Health–contracted pharmacy director at Sharon Hospital, in Sharon, Conn.

Focus on Sterility, Not Production Speed The more prepared solutions that a pharmacy has on hand with BUD, the more stable its supply and the better it can schedule to maximize workflow. This is necessary with the GriFill System 3.0 Compounder (Grifols), for instance, because its deliberate filling processes to ensure sterility take at least a couple of minutes per bag. The 282-bed Sentara Virginia Beach General Hospital, in Virginia, uses the compounder during evenings when the clean

room is less hectic. This scheduling also enables technicians to perform required cleaning or do other simple tasks to be productive; they set up each bag and do other tasks while the semi-automated compounder works, explained Rich Grasmick, RPh, the pharmacy manager. Similarly, Healix ambulatory infusion centers, in Sugar Land, Texas, have “improved staff efficiency by allowing our clinicians to perform other duties while the product is being compounded,” said Brenda Parker, RN, the vice president of nursing. Healix, which has used Gri-Fill technology since 2010, now has 15 of the compounders in different sites and plans to add 30 more in the next 18 months. “Using our anti-infective for-

The Gri-Fill system tests each bag for sterility integrity, indicates immediately if it passes (for BUD) or fails (for shortterm use only), and prints a label to be affixed to each bag. Safe usage dates for compounded solutions depend on the inherent stability of the medications and the containers used, as well as the sterility levels achieved during preparation, Ms. Ellegard explained. Although the system is established for up to a 60-day BUD (in normal room temperature or refrigerated), individual pharmacies may elect not to maximize the shelf life of their products and use the added BUD to enhance the rotation of batch-prepared doses, Ms. Ellegard noted. “Doses stored on shelves maximizing the BUD is passé, and will be frowned upon by inspectors,” she stressed. By comparison, the USP Chapter <797> standard is 30 hours in normal room temperature and nine days refrigerated for medium-risk preparations. Longer dates help pharmacies match supply to usage forecasts. During her hospital tenure, Ms. Ellegard has used Gri-Fill technology across many drug classes such as electrolytes, antibiotics, oncology and controlled substances—about 30 to 40 different medication combinations in all. The Mount Sinai Medical Center pharmacy used it to pool electrolytes from as many as a half-dozen source containers for total parenteral nutrition, to serve an average of 70 adults and 20 neonates daily. “Each bag we pooled was guaranteed sterile,” she said. “This practice enabled us to use one supply container per electrolyte, with the possibility of one change on a busy day … rather than changing a source bag 10 or more times

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see COST-EFFECTIVE, page 28

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For more information on the BD Simplist product line, visit www.bdsimplist.com NOW AVAILABLE in Diphenhydramine Hydrochloride Injection, USP 50 mg/mL (NDC 76045-102-10) Order from your drug wholesaler today. INDICATIONS Diphenhydramine Hydrochloride Injection, USP is effective in adults and pediatric patients, other than premature infants and neonates, when diphenhydramine hydrochloride in the oral form is impractical. For amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated. For active treatment of motion sickness and for use in parkinsonism, when oral therapy is impossible or contraindicated in the elderly who are unable to tolerate more potent agents, mild cases of parkinsonism in other age groups and in other cases of parkinsonism in combination with centrally acting anticholinergic agents. IMPORTANT SAFETY INFORMATION Diphenhydramine hydrochloride is contraindicated in neonates, premature infants and as antihistamine therapy in nursing mothers and as a local anesthetic and when a patient is hypersensitive to other antihistamines of similar chemical structure. Considerable caution should be used in patients with narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy or bladder-neck obstruction. Local necrosis has been associated with the use of subcutaneous or intradermal use of the drug. It has an atropine-like action and, therefore should be used with caution in patients with a history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease or hypertension and in patients with lower respiratory disease including asthma. It has additive effects with alcohol and other CNS depressants. MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. The most frequent adverse reactions are: Nervous System: sedation, sleepiness, dizziness, disturbed coordination; GI System: epigastric distress; and Respiratory System: thickening of bronchial secretions. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see Brief Summary for additional Important Safety Information on following page.

1. Data on File, BD Rx. 2. Potter P, Perry A, Stockert P, Hall A. Vial & Syringe Injection Steps. Basic Nursing. 7th ed. (St. Louis, MO: Mosby, 2010), 442-447. 3. Diphenhydramine Hydrochloride Injection, USP Prescribing Information. Franklin Lakes, NJ: BD Rx Inc.; 12/2012. BD, BD Rx Logo and BD Simplist are trademarks of Becton, Dickinson and Company. ©2013 BD. BDRx0057a

BD Rx Inc. 1 Becton Drive Franklin Lakes, NJ 07417 www.bdrxinc.com

28 Technology DIPHENHYDRAMINE HYDROCHLORIDE INJECTION, USP Rx Only

Pharmacy Practice News • May 2013

Automation

This is a Brief Summary of the full prescribing information about Diphenhydramine Hydrochloride Injection, USP. INDICATIONS AND USAGE Diphenhydramine hydrochloride in the injectable form is effective in adults and pediatric patients, other than premature infants and neonates, for the following conditions when diphenhydramine hydrochloride in the oral form is impractical. Antihistaminic: For amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated. Motion Sickness: For active treatment of motion sickness. Antiparkinsonism: For use in parkinsonism, when oral therapy is impossible or contraindicated as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups and in other cases of parkinsonism in combination with centrally acting anticholinergic agents. CONTRAINDICATIONS Use in Neonates or Premature Infants: This drug should nott be used in neonates or premature infants. Use in Nursing Mothers: Because of the higher risk of antihistamines for infants generally, and for neonates and prematures in particular, antihistamine therapy is contraindicated in nursing mothers. Use as a Local Anesthetic: Because of the risk of local necrosis, this drug should not be used as a local anesthetic. Antihistamines are also contraindicated in the following conditions: Hypersensitivity to diphenhydramine hydrochloride and other antihistamines of similar chemical structure. WARNINGS Antihistamines should be used with considerable caution in patients with narrowangle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy or bladder-neck obstruction. Local necrosis has been associated with the use of subcutaneous or intradermal use of intravenous diphenhydramine. Use in Pediatric Patients: In pediatric patients, especially, antihistamines in overdosage may cause hallucinations, convulsions or death. As in adults, antihistamines may diminish mental alertness in pediatric patients. In the young pediatric patient, particularly, they may produce excitation. Use in the Elderly (approximately 60 years or older): Antihistamines are more likely to cause dizziness, sedation and hypotension in elderly patients. PRECAUTIONS General: Diphenhydramine hydrochloride has an atropine-like action and, therefore should be used with caution in patients with a history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease or hypertension. Use with caution in patients with lower respiratory disease including asthma. Information for Patients: Patients taking diphenhydramine hydrochloride should be advised that this drug may cause drowsiness and has an additive effect with alcohol. Patients should be warned about engaging in activities requiring mental alertness such as driving a car or operating appliances, machinery, etc. Drug Interactions: Diphenhydramine hydrochloride has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc).

COST-EFFECTIVE MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to determine mutagenic and carcinogenic potential have not been performed. Pregnancy: Pregnancy Category B: Reproduction studies have been performed in rats and rabbits at doses up to 5 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to diphenhydramine hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pediatric Use: Diphenhydramine should not be used in neonates and premature infants (see CONTRAINDICATIONS). Diphenhydramine may diminish mental alertness, or in the young pediatric patient, cause excitation. Overdosage may cause hallucinations, convulsions or death (see WARNINGS and OVERDOSAGE). See also DOSAGE AND ADMINISTRATION section.

ADVERSE REACTIONS The most frequent adverse reactions are underscored: 1. General: Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive perspiration, chills, dryness of mouth, nose and throat. 2. Cardiovascular System: Hypotension, headache, palpitations, tachycardia, extrasystoles. 3. Hematologic System: Hemolytic anemia, thrombocytopenia, agranulocytosis. 4. Nervous System: Sedation,, sleepiness, p , dizziness,, disturbed coordination, fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, paresthesia, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, neuritis, convulsions. pg distress, anorexia, 5. GI System: Epigastric nausea, vomiting, diarrhea, constipation. 6. GU System: Urinary frequency, difficult urination, urinary retention, early menses. 7. Respiratory System: Thickeningg of bronchial secretions, tightness of chest or throat and wheezing, nasal stuffiness. OVERDOSAGE Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. Stimulation is particularly likely in pediatric patients. Atropine-like signs and symptoms; dry mouth; fixed, dilated pupils; flushing and gastrointestinal symptoms may also occur. Stimulants should not be used. Vasopressors may be used to treat hypotension. For more information concerning this drug or to report an adverse event please call BD Rx Inc., at 1-866-943-8534. For the full prescribing information, visit www. BDRxInc.com Rev 12/12

BD Simplist™ BD, BD Rx Logo and BD Simplist are trademarks of Becton, Dickinson and Company. © 2013 BD BDRx0054

BD Rx Inc. Franklin Lakes, NJ 07417

continued from page 26

daily. We greatly lessened the chance of introducing contamination.”

Drug Shortage a Factor At the 73-bed Sharon Hospital, the pharmacy regularly replaced ambulance drivers’ kits. These included dextrose 50% solution (D50) for stat use in diabetes patients with hypoglycemia. During a drug shortage that lasted about two months, the pharmacy used Gri-Fill to compound the D50 from D70 and sterile water they had on hand to supply 100% of its needs—not only for the kits, but also for hospital code carts. “That was a big save; we helped about 25 patients with that,” Ms. Ellegard said.In her experience, a fentanyl epidural solution in normal saline that passes the integrity test could be used safely for 30 days at normal room temperature, and so could bupivacaine 0.125% solution in normal saline. Sentara uses Gri-Fill two to three times monthly to batch the sedative midazolam for intensive care trauma patients and fentanyl/bupivacaine bags for postoperative pain management; the preparations can be used safely because of the BUD, so more frequent scheduling isn’t necessary, Mr. Grasmick said. “We always keep most IV technicians trained on the Gri-

Fill as an advantage.” If not for Gri-Fill, technicians would need to replenish the preparations every few days. Sentara compounds another 70% inhouse, up to 150 to 200 compounds daily. These are patient-specific bags that are used quickly. It outsources the rest to PharMEDium, which picked up the slack from Ameridose and, like many large-scale pharmacy compounders, has undergone federal and state inspections in recent months. Mr. Grasmick said he is concerned that his facility may reach a point where, due to increased regulatory oversight of compounders, their sterile compounding needs from outsourcers may not be fully met. In such a scenario, he said, “we may have to choose between compounding in-house to USP <797> standards or using Gri-Fill; we may choose the latter.” According to Grifols, the Gri-Fill system costs about $32,000, and four- and five-year leases are available. Part of its worth is in less medication waste: Products don’t expire as fast because they’re sterile, and technicians don’t have to manually test samples for sterility and then discard the samples. Ms. Ellegard pointed out that “those costs add up with narcotics and oncology products.” —Al Heller

Web Exclusive: Why Pharmacists Blog www.pharmacypracticenews.com

Technology 29

Pharmacy Practice News • May 2013

A Trio of Pharmacy Technology Successes Las Vegas—Three very different problems in patient care—the overuse of growth factors in chemotherapy, medication mishaps caused by drug cabinet stocking errors and a lack of quick access to key data during clinical rounds—have a shared solution: the innovative use of pharmacy technology, according to poster presentations at the American Society of Health-System Pharmacists’ (ASHP) Midyear Clinical Meeting.

A Better System For Stocking ADCs Each month, the pharmacy at Baystate Medical Center, a 653-bed tertiary care facility in Springfield, Mass., dispenses about 800,000 IV and oral medication doses. In late 2008, the hospital instituted medication and patient ID bar-code scanning at the bedside, and the number of medication errors that reached patients decreased dramatically, according to Erin Taylor, PharmD, the assistant director of inpatient pharmacy services at Baystate. “But we noticed that although actual errors decreased, the number of near misses rose considerably—that is, incidents when the nurse discovered the mistake before administering the drug.” The reason: Pharmacy technicians some-

dispensed to six per million. Based on those results, Dr. Taylor noted, “we know our patients are safer than they were before we established this procedure.” Mark Heelon, PharmD, Baystate’s medication safety coordinator, emphasized the role pharmacy technicians played in the quality improvement initiative. “What really helped this program to be successful was that the technicians were strongly vested in the outcomes and wanted to make it work,” he said. “They were involved in much of the decision making as we developed the program. We told them, ‘We have a problem, we know we can do better and we need your expertise and devotion to patient safety to devise strategies to reduce these errors,’ and they came through.”

Growth Factor and Hodgkin Lymphoma Granulocyte colony-stimulating factor (G-CSF) is commonly used to maintain dose intensity and avoid treatment delays in patients who develop neutropenia caused by ABVD (adriamycin, bleomycin, vincristine and doxorubicin) chemotherapy. But a growing body of research has documented that the multidrug regimen

can be safely administered without the routine use of G-CSF. Given the growth factor’s high cost and propensity for potentiating bleomycinassociated lung toxicity, pharmacists at Kaiser Permanente Northwest, in Portland, Ore., knew they needed a method for reducing G-CSF use, particularly in patients with Hodgkin lymphoma (HL). Their solution: embedding therapeutic messaging about the proper indications for G-CSF into its electronic medical record (EMR). “We noticed that we were using a good deal of G-CSF in our Hodgkin’s disease population that received ABVD, even though [National Comprehensive

‘Many hospitals have focused on the use of bar-code technology at the point of care. The … technology can and should be integrated into other parts of the medication use process.’ —Karl Gumpper, RPh, BCPS, FASHP

times stocked the wrong drug or the wrong strength into the automatic dispensing cabinet (ADC) drawers located on the patient care floors. “Nurses were catching the errors, so you could say the system worked,” Dr. Taylor said. “But as a department, we saw an opportunity to add another safety barrier to further decrease the chances of the wrong medicines reaching patients.” In October 2010, the pharmacy instituted a protocol that stipulated scanning of all medications when they were loaded into the ADC. The goal was to attain a 90% scan rate among the technicians as they stocked the cabinets. At first, ADC scans were completed only 30% of the time, but the rate jumped to 90% after only four months, and now averages 93%, according to Dr. Taylor. As a result, near misses caught during bedside bar-code scanning by nurses dropped by 70%. In terms of absolute numbers, she added, dispensing errors went from 20 events per million doses

Commentary

K

arl Gumpper, RPh, BCPS, FASHP, the director of ASHP’s Section of Pharmacy Informatics & Technology, offered his views on the three quality improvement initiatives detailed in the poster presentations. Scanning medications before ADC stocking. “This research shows the next steps in the progression of bar-code technology within the pharmacy,” Mr. Gumpper said. “Many hospitals have focused on the use of bar-code technology at the point of care. The … technology can and should be integrated into other parts of the medication-use process. This work shows that there is a gain in patient safety when combined with the use of automated dispensing cabinets.” The ASHP’s Statement on Bar-Code Verification During Inventory, Preparation, and Dispensing of Medications “encourages hospital and health-system pharmacies to incorporate bar-code scanning into inventory management, dose preparation and packaging, and dispensing of medications” (http://www.ashp.org/DocLibrary/ BestPractices/AutoITStBCVerif.aspx). Therapeutic messaging on G-CSF. “This a good example of how clinical decision support can work to change physician practice and potentially improve patient care and outcomes,” Mr. Gumpper said. “The presentation of laboratory values in the decision-making process is much more effective than alerts alone. There may also be less alert fatigue with therapeutic messaging.” iPads and clinical rounding. “There are emerging studies using tablet devices by physicians for patient care, so it is encouraging to see the same type of uptake by pharmacy,” he said. “The need to have ready access to patient health information and drug information resources will allow us to meet the goals of the Pharmacy Practice Model Initiative” (http://www.ashp.org/PPMI). —S.F.

Cancer Network] guidelines clearly suggest it isn’t recommended,” said Jasen Knudsen, PharmD, BCPS, BCOP, an oncology/hematology pharmacist at Kaiser. “We wanted to align ourselves with the most current treatment guidelines without compromising care.” The embedded messages pop up on the computer screen as prescribers move through the drug-ordering process and are considering G-CSF use. The messages include links to additional, evidence-based references. In general, they state that patients may be treated at full ABVD dose without G-CSF, on time, regardless of hematologic counts. Dr. Knudsen and his colleagues hypothesized that the prompts in the system (KP HealthConnect, a version of EPIC) would persuade clinicians to be more aggressive in maintaining dose intensity and not delay treatment or reduce chemotherapy dose. Based on their pilot study, they were right. The study was based on a retrospective chart review of adult HL patients who were treated before and after therapeutic messaging about the updated ABVD protocol appeared in the EMR. Before embedded messaging, 11 of 18 (61%) patients received G-CSF compared with three of 20 (15%) patients after the messaging. Moreover, full-dose intensity was maintained in 12 of 18 patients before the change to all 20 patients after the start of message embedding. No cases of febrile neutropenia or bleomcyininduced pulmonary toxicity occurred. In addition to the reduced G-CSF use, “we also found that updating the EMR protocol resulted in a change in clinician workflow, with fewer treatment deferrals and therapy delays, which we didn’t expect,” Dr. Knudsen noted. “But that was certainly a good [outcome].” Dr. Knudsen acknowledged that the study’s small sample size limits definitive conclusions about the efficacy of message embedding. His study team plans to examine a larger population drawn from pooled data of several Kaiser Permanente regions. As for why so many prescribers at

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see TECH TRIO, page 30

30 Technology

TECH TRIO continued from page 29

Kaiser in this initial study seemed to favor G-CSF therapy before message embedding, “significant practice changes take some time for clinicians to fully adopt,” Dr. Knudsen said—a message that itself should be heeded by any hospital undertaking similar quality improvement efforts.

iPad Can Help Clinical pharmacists at Boston Children’s Hospital routinely participate in daily rounds with multidisciplinary care teams, and until recently, all had been equipped with laptops, which allow immediate access to pharmacy order systems, the EMR and other key information. But the laptops, weighing in at a hefty five pounds, proved to be somewhat unwieldy for pharmacists on the move, according to Tsingyi Koh-Pham, PharmD, BCPS, a clinical pharmacist. To lighten their load and speed access to crucial patient care data, rounding pharmacists were given iPads and surveyed about their experiences with the devices. In a pilot trial, 10 of the devices were given to rounding pharmacists, who were then asked to gauge the tablet’s relative utility, how well it could be incorporated into daily work patterns and whether using the iPads enabled them to overcome some of the functional limitations associated with laptops. The response was overwhelmingly favorable and led the department to issue 31 additional iPads to all decentralized pharmacists—as well as to some centralized pharmacists—who wished to use them. Surveys of 41 iPad users were conducted in September 2011 (n=23) and again in June 2012 (n=25). In the first survey, 70% of respondents said they were extremely or moderately satisfied with their iPad experience. Ninety percent responded similarly in the second survey. Dr. Koh-Pham attributes the increase in satisfaction to growing levels of comfort and proficiency with the device over time. The device’s connectivity was another key benefit that contributed to its high marks—specifically, its ability to link seamlessly to the hospital’s Cerner EMR, Dr. Koh-Pham said.

Pharmacy Practice News • May 2013

Additional benefits of the device include much longer battery life than most laptops, Dr. Koh-Pham said. The devices also cost about one-third as much as a laptop: $562 versus about $1,560. Although iPad users consistently preferred their new devices over laptops for mobility and accessibility, they found that the iPads did not necessarily increase work efficiency. An average of the two surveys showed that overall scores for ease of use favored the laptops in all categories measured, including multiple-order verification,

document viewing and responding to or composing emails. One comment from an iPad user represented the broader sentiment: “Verifying orders and looking up lab data and references are still definitely easier on the laptop if you have access to one. However it’s much easier to be mobile and verify orders on the iPad.” Dr. Koh-Pham acknowledged that “some of the tasks that are easily completed on a laptop are more cumbersome on an iPad, particularly anything that requires complex finger movements.”

Typing and multitasking on iPads, she added, “are often more difficult.” Despite the disadvantages, pharmacists said that the iPads allow them to more consistently attend patient care rounds and conduct timely interventions, Dr. Koh-Pham noted. In fact, only one pharmacist chose to forgo use of the iPad, she pointed out. The Pharmacy Department plans to continue supporting the device and will purchase iPad-specific medication management software. —Steve Frandzel

INDICATION: Venofer ® (iron sucrose injection, USP) is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). IMPORTANT SAFETY INFORMATION: • Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been lifethreatening and fatal, have been reported in patients receiving Venofer ® (iron sucrose injection, USP). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer ® immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer ® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. • Venofer ® may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer ®. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered. Leading anemia management.™

Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2011 American Regent, Inc. VEN040 • Rev. 12/2011 • venofer.com

Technology 31

Pharmacy Practice News • May 2013

Rural Pharmacy

Building Versus Buying Telepharmacy a Personal Preference

F

or time-strapped rural hospital pharmacists, implementing a telepharmacy service to supplement a thin staff can be a time-consuming process that often is weighed down by exploring a crucial early consideration: whether to outsource the service or develop a homegrown solution. However, if the experiences of two rural hospital pharmacy directors are representative, commercial vendors and hospital-based telepharma-

cy services are largely comparable and the choice of one or another arrangement may depend more on individual considerations. When Dave Johnson, RPh, the director of pharmacy at Cuyuna Regional Medical Center, in Crosby, Minn., began considering a telepharmacy service, he was quickly faced with the “build it or buy it” dilemma. He said the quotes he received from both a com-

mercial vendor and a hospital-partnering arrangement were comparable and well below the cost of hiring a full-time pharmacist. However, he and his staff ultimately felt more comfortable partnering with a hospital. “We weren’t sure how much hospital practice the pharmacists in a standalone telepharmacy facility would have had and felt a hospital pharmacist would be better able to answer ques-

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• Venofer ® is contraindicated in patients with known hypersensitivity to Venofer ®. Do not administer to patients with evidence of iron overload. • In efficacy studies in non-dialysis dependent-CKD patients (N=139), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were nausea (8.6%), taste disturbance (7.9%), peripheral edema (7.2%), diarrhea (7.2%), dizziness (6.5%), hypertension (6.5%), infusion site pain or burning (5.8%), dyspnea (5.8%), and vomiting (5.0%). • In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the most frequent adverse events (>5%) whether or not related to Venofer® administration, were hypotension (39.4%), muscle cramps (29.4%), nausea (14.7%), headache (12.6%), graft complications (9.5%), vomiting (9.1%), dizziness (6.5%), hypertension (6.5%), chest pain (6.1%), and diarrhea (5.2%). In the study of peritoneal dialysis-CKD patients (N=75), the most frequent adverse events, whether or not related to Venofer ®, reported by 5% of these patients were infections and infestations (nasopharyngitis, sinusitis, upper respiratory tract, pharyngitis) (16.0%), diarrhea (8.0%), vomiting (8.0%), hypertension (8.0%), peripheral edema (5.3%), and nausea (5.3%). *100 mg vials and ampules worldwide from 1992 to February 2011. Reference: 1. Data on file. American Regent, Inc. Shirley, NY.

Please see brief Prescribing Information on adjacent page.

tions from a nurse,” he said. Mr. Johnson’s search to find a partner hospital is indicative of the increasing popularity of telepharmacy services. He initially inquired about receiving the telepharmacy services offered by one of the member sites of the 16-hospital consortium of which Cuyuna Regional Medical Center is part. However, he was told they were at capacity.

•

see TELEPHARMACY, page 32

32 Technology

Pharmacy Practice News • May 2013

Rural Pharmacy

TELEPHARMACY

pital to a CPOE [computerized prescriber order entry] system,” he noted.

continued from page 31

“We ended up partnering with another hospital within a health system that is in the same purchasing group as us, although they’re outside of our consortium,” Mr. Johnson said. “Since we already had a relationship with that hospital, it made sense to work with them.” The “service has been excellent,” he said, and orders are typically approved within 15 minutes of being placed. However, there have been minor med-

Benefits of Commercial Partnerships

ication errors related to the remote order verification service, mostly due

(Table 1. Continued)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Adverse Reactions (Preferred Term)

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Venofer safely and effectively. See full prescribing information for Venofer. Initial U.S. Approval: 2000 RECENT MAJOR CHANGES Warnings and Precautions 6/2011 INDICATIONS AND USAGE Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). DOSAGE AND ADMINISTRATION Administer Venofer intravenously either by slow injection or by infusion. CKD patients on hemodialysis: 100 mg undiluted slow intravenous injection over 2 to 5 minutes or as an infusion of 100 mg, diluted in a maximum of 100 mL of 0.9% NaCl, over a period of at least 15 minutes. CKD patients not on dialysis: 200 mg undiluted slow IV injection over 2 to 5 minutes. • CKD patients receiving peritoneal dialysis: infuse 300 mg over 1.5 hours given on two occasions 14 days apart followed by a single infusion 14 days later of 400 mg given over 2.5 hours. Dilute each Venofer dose in a maximum volume of 250 mL of 0.9% NaCl. DOSAGE FORMS AND STRENGTHS • 10 mL single use vial / 200 mg elemental iron (20 mg/mL) • 5 mL single use vial / 100 mg elemental iron (20 mg/mL) • 2.5 mL single use vial / 50 mg elemental iron (20 mg/mL) CONTRAINDICATIONS • Known hypersensitivity to Venofer WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. • Hypotension:Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Venofer. • Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer to patients with iron overload. ADVERSE REACTIONS • The most common adverse reactions (≥ 2%) following the administration of Venofer are diarrhea, nausea, vomiting, headache, dizziness,hypotension,pruritus,pain in extremity,arthralgia,back pain,muscle cramp,injection site reactions,chest pain,and peripheral edema. To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION 2 DOSAGE AND ADMINISTRATION Venofer must only be administered intravenously either by slow injection or by infusion. The dosage of Venofer is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron. The usual total treatment course of Venofer is 1000 mg. Venofer treatment may be repeated if iron deficiency reoccurs. 2.1 Adult Patients with CKD on dialysis Administer Venofer 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session.Venofer should be administered early during the dialysis session. 2.2 Adult Patients CKD not on dialysis Administer Venofer 200 mg undiluted as a slow IV injection undiluted over 2 to 5 minutes on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on day 1 and day 14. 2.3 Adult Patients with CKD receiving peritoneal dialysis Administer Venofer in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg overr 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Venofer in a maximum of 250 mL of 0.9% NaCl. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion. 5.2 Hypotension Venofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer. Hypotension following administration of Venofer may be related to the rate of administration and/or total dose administered. 5.3 Iron Overload Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Patients receiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Venofer to patients with evidence of iron overload. Transferrin saturation values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing. 6 ADVERSE REACTIONS Venofer injection may cause serious hypersensitivity reactions and hypotension. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice. 6.1 Adverse Reactions in Clinical Studies The frequency of adverse reactions associated with the use of Venofer has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse events reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Venofer exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks. Table 1. Treatment-Emergent Adverse Reactions Reported in ≥ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate for Comparator Adverse Reactions (Preferred Term) Subjects with any adverse reaction Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain Diarrhea Dysgeusia Nausea Vomiting

HDD-CKD Venofer (N=231) %

NDD-CKD Venofer Oral Iron (N=139) (N=139) % %

Venofer (N=75) %

PDD-CKD EPO* Only (N=46) %

78.8

76.3

73.4

72.0

65.2

0

2.2

0.7

0

0

0.4

0

0

2.7

0

2.9 10.1 0 12.2 8.6

4.0 8.0 0 5.3 8.0

6.5 4.3 0 4.3 2.2

3.5 5.2 0.9 14.7 9.1

1.4 7.2 7.9 8.6 5.0

to illegible physician handwriting. “We haven’t converted our entire hos-

General Disorders and Administration Site Conditions Asthenia Chest pain Feeling abnormal Infusion site painor burning Injection site extravasation Peripheral edema Pyrexia Infections and Infestations Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis Injury, Poisoning and Procedural Complications Graft complication Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia Hypoglycemia Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Nasal congestion Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension Hypotension

HDD-CKD Venofer (N=231) %

NDD-CKD Venofer Oral Iron (N=139) (N=139) % %

Venofer (N=75) %

PDD-CKD EPO* Only (N=46) %

2.2 6.1 3.0 0 0 2.6 3.0

0.7 1.4 0 5.8 2.2 7.2 0.7

2.2 0 0 0 0 5.0 0.7

2.7 2.7 0 0 0 5.3 1.3

0 0 0 0 0 10.9 0

2.6

2.2

4.3

16.0

4.3

9.5

1.4

0

0

0

3.0 0 0 0.4

1.4 2.9 2.9 0.7

0.7 1.4 0 0.7

1.3 0 0 4.0

0 0 2.2 0

3.5 2.2 29.4 0 5.6

1.4 2.2 0.7 3.6 4.3

2.2 3.6 0.7 0 0

4.0 1.3 2.7 1.3 2.7

4.3 4.3 0 0 6.5

6.5 12.6

6.5 2.9

1.4 0.7

1.3 4.0

4.3 0

3.0 3.5 0

2.2 5.8 1.4

0.7 1.4 2.2

1.3 1.3 1.3

0 2.2 0

3.9

2.2

4.3

2.7

0

6.5 39.4

6.5 2.2

4.3 0.7

8.0 2.7

6.5 2.2

*EPO=ERYTHROPOIETIN 6.2 Adverse Reactions from Post-Marketing Spontaneous Reports In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia. The following additional adverse reactions have been identified with the use of Venofer from postmarketing spontaneous reports: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia. 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. Symptoms associated with Venofer total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Symptoms may respond to IV fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms. 7 DRUG INTERACTIONS Drug interactions involving Venofer have not been studied. However, Venofer may reduce the absorption of concomitantly administered oral iron preparations. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Venofer should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether iron sucrose is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Venofer is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of Venofer in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of Venofer did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGE No data are available regarding overdosage of Venofer in humans. excessive dosages of Venofer may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. do not administer Venofer to patients with iron overload. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How supplied Venofer is supplied sterile in 10 mL, 5 mL, and 2.5 mL single use vials. Each 10 mL vial contains 200 mg elemental iron, each 5 mL vial contains 100 mg elemental iron, and each 2.5 mL vial contains 50 mg elemental iron (20 mg/mL). 16.2 Stability and storage Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Do not freeze. Do not dilute to concentrations below 1 mg/mL. Do not mix Venofer with other medications or add to parenteral nutrition solutions for intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion. 17 PATIENT COUNSELING INFORMATION Prior to Venofer administration: • Question patients regarding any prior history of reactions to parenteral iron products. • Advise patients of the risks associated with Venofer • Advise patients to report any symptoms of hypersensitivity that may develop during and following Venofer administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems.

AMERICAN REGENT, INC. SHIRLEY, NY 11967 Venofer is manufactured under license from Vifor (International) Inc., Switzerland.

IN2340BS, Rev. 6/2011

Hospitals with integrated CPOE and electronic medication administration record systems are turning to telepharmacy to meet the government-mandated requirement that nonemergent medication orders be prospectively verified by a pharmacist on a 24-hour basis. Kelly Morrison, the director of product management at Cardinal Health, believes a vendor like hers can take on the burden of ensuring all of the telepharmacy guidelines are met. “State regulations can be difficult to interpret and subject to change; therefore, hospitals must continually review them to ensure compliance,” said Ms. Morrison, who led a roundtable discussion on telepharmacy at the American Hospital Association’s recent Rural Health Care Leadership Conference, in Phoenix. “Cardinal Health’s Remote Order Entry Service [ROES] meets or exceeds all Joint Commission standards and National Patient Safety Goals, federal and state regulations as well as American Health-System Pharmacists’ guidelines.” To date, Erin Sherwood, BPharm, the director of pharmacy at the HealthSouth Rehabilitation Hospital of Northern Virginia, in Stoneridge, has had more than 14,000 remote orders processed by Cardinal Health’s ROES telepharmacists. Ms. Sherwood prides herself on responding to medication orders typically within five minutes, and said a quick telepharmacy response time is important to her. Although the average 20-minute turnaround time she has seen with Cardinal’s telepharmacists does not match her own response time, “for most pharmacies, a 20-minute response time is pretty good,” she said. The $60,000 annual price tag her hospital pays for the Cardinal Health ROES has been more than offset by the estimated $400,000 they saved on inhouse pharmacy staff costs, Ms. Sherwood said. In terms of patient safety, she noted several instances where telepharmacists changed an ordered drug or modified the dose because of potential drug–drug interactions or patient characteristics. Ms. Sherwood said that knowing her patients’ safety is being preserved by the telepharmacists has increased her job satisfaction and improved her quality of life. “I can sleep better at night,” she said, “knowing that someone is watching over my pharmacy orders.” —David Wild Ms. Sherwood and Mr. Johnson reported no relevant financial conflicts of interest.

Q & A 33

Pharmacy Practice News • May 2013

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34 Policy

Pharmacy Practice News • May 2013

Medication Safety

COMPOUNDERS continued from page 1

assurance.” The recall came as a result of an earlier FDA inspection of the facility, which uncovered gram-negative bacteria in samples of the firm’s chromium chloride formulation for injection. On March 20, Clinical Specialties, of Augusta, Ga., recalled all of its sterile products, also due to a lack of sterility assurance. The action grew out of an earlier investigation into the company’s repackaged injectable bevacizumab (Avastin, Genentech) following reports of five serious eye infections linked to physicians’ off-label use of the cancer drug for patients with macular edema. Two days earlier, Pallimed Solutions Inc., of Woburn, Mass., launched a recall of all sterile products after investigators from the FDA and the Massachusetts Board of Pharmacy observed particulates in vials containing injectable alprostadil and other solutions. And on March 17, Med Prep Consulting, of Tinton Falls, N.J., issued a total sterile product recall when a Connecticut hospital reported particulates in bags of the company’s magnesium sulfate preparation. Except for the injectable bevacizumab, none of the recalled products have yet been linked to known adverse events. But coming on top of more than 50 deaths from fungal meningitis and other infections associated with

there,” he said, “is that many hospital administrators are telling their directors of pharmacy, ‘No more outsourcing. We’re scared of this. We want you to do it all in-house.’ And many of these pharmacies may not be equipped to do it.” Dr. Vaida further explained that many hospitals are not equipped environmentally to carry out compounding activities internally. “They may not be set up or have the staff to follow USP <797> standards,” he said. “I’m not even talking about non-sterile to sterile [compounding]. Very few hospitals are even looking at that. I’m talking about making parenteral nutrition, cardioplegic solutions, and about doing some repackaging into unit-dose sizes.” In such cases, Dr. Vaida noted, a safer option may be to partner with an established, vetted compounder that has a solid track record of following safe manufacturing practices and has documented proof that they have been adhering to USP Chapter <797> policies and procedures. “The ASHP’s guidelines on outsourcing sterile compounding services [[Am J Health Syst Pharm 2010;67:757-765] can really be a big help in evaluating a vendor based on these types of determinations,” he added.

A ‘Wake-up Call’ for More Action Dr. Thompson noted that the NECC tragedy “was a real wake-up call about how the regulatory system worked as

‘Many hospital administrators are telling their directors of pharmacy, “No more outsourcing. We’re scared of this. We want you to do it all in-house.” And many of these pharmacies may not be equipped to do it.’ —Allen J. Vaida, PharmD injections of tainted methylprednisolone made by the New England Compounding Center (NECC), the inspection reports and recalls have raised apprehension levels among hospitals and other health care providers that rely on outsourcers to fill at least part of their sterile compounding needs. “There is a legitimate heightened concern out there,” said Kasey Thompson, PharmD, the vice president of policy, planning and communications at the American Society of Health-System Pharmacists (ASHP). “We could say that as the months have passed, perhaps it has gotten worse.” The concern may even be having an effect on hospital pharmacy ordering practices, noted Allen Vaida, PharmD, the executive vice president of the Institute for Safe Medication Practices. “A big issue that we’ve been hearing out

it related to large-scale compounding.” He said one area that has proven to be murky is the degree to which site inspections are done for FDA-registered compounders. “Many of these entities were, and still are, registered with the FDA,” he said. “I think most practitioners thought that this meant that the FDA did routine inspections and regulated those entities. It turned out not to have been the case.” Dr. Vaida echoed Dr. Thompson’s point that being registered with the FDA is no guarantee that routine inspections will occur. “Many of the [cited compounders] said they were registered with the FDA, and a lot of pharmacies who purchased from them relied on that,” he said. “But now the FDA is basically saying that doesn’t mean anything—it doesn’t mean the FDA inspects them. [The agency is] only called in

‘I think most practitioners thought that … the FDA did routine inspections and regulated [FDA-registered] entities. It turned out not to have been the case.’ —Kasey Thompson, PharmD when something happens.” Tom Rasnic, MBA, the vice president of Quality Assurance and Regulatory at PharMEDium Services LLC, one of several large-scale pharmacy compounders to undergo federal and state inspections in recent months, took issue with the idea that such inspections are an infrequent and haphazard affair. “Our experience has been that having [been] registered with the FDA resulted in frequent and routine inspections,” Mr. Rasnic noted in an email to Pharmacy Practice News. The lack of a consistently implemented policy on inspections is only one challenge facing the industry. A larger issue, experts note, is the lack of federal oversight of compounding pharmacies that produce large batches of often high-risk injectable medications without patientspecific prescriptions. This practice has opened a huge medication safety gap that the FDA, Congress and state pharmacy boards are now scrambling to address. “This is something that has fallen into a big black hole,” Dr. Vaida said. “From a regulation standpoint, there needs to be changes,” and federal and state governments “need to get together and define who has authority for what.” In late March, Margaret Hamburg, MD, the commissioner of the FDA, issued a new call for federal legislation giving the agency clear authority to regulate large compounding pharmacies that operate in the murky zone between traditional compounding for individual patients and manufacturing for anticipated population needs. “The magnitude and complexity of these operations have outpaced the current patchwork of state laws that differ in prescription requirements and quality control rules,” Dr. Hamburg wrote in an FDA Voice blog posting. In mid-April, during a congressional hearing on the compounding crisis, Ms. Hamburg reiterated her call that the FDA should be given more defined enforcement authority over compounding facilities (see related article, page 36). The commissioner’s call for clarifying legislation was quickly endorsed by PharMEDium. “We support the passage of federal legislation to establish a new FDA category for sterile compounders governed by applicable current Good Manufacturing Practices [GMP],” Mr. Rasnic noted in a statement issued by the company. “We believe FDA over-

sight of interstate shipments of sterile compounders is necessary.” Mr. Rasnic added that PharMEDium “supports ... that there be a new FDA category” containing the applicable GMP standards for sterile compounders. Such a category, he noted, would “provide FDA with clear oversight.” ASHP, along with the National Association of Boards of Pharmacy and other pharmacy organizations, has been an outspoken advocate for new laws that clearly define federal and state roles in regulating the entire continuum of pharmacy compounding practice. “It’s a very delicate, careful set of discussions that we need to have here,” ASHP’s Dr. Thompson said. “You can’t have situations where these entities are preparing copies of commercially available brandname products. Or situations where you’ve created a regulatory pathway to allow an entity to produce a generic drug without submitting an abbreviated new drug application.” On the other hand, he said, hospitals have come to depend on these largescale compounders to supply customized dosage forms and fill voids due to drug shortages. “We can’t just shut down the compounding industry. That would not be good for patient care,” he said. “But at the same time, we have to make sure that the right things are happening and bad things are not. We’re hoping Congress will take action sooner than later and get some draft legislation out there that the communities of interest can respond to.” Mr. Rasnic commented that drug shortages are not the primary reason why pharmacies choose to outsource. In most cases, he said, hospitals buy from PharMEDium and other established, responsible compounders “to fill voids due to required anticipatory premixed drugs for IV and epidural therapies that are not commercially available.” In partnering with potential outsourcers, he added, it’s important to choose companies “who play by the rules and adhere to USP <Chapter> 797” to ensure the safety of the purchased products.

Concerns Over Liability Another concern that has emerged is the question of liability. Without new laws establishing clear authority for large compounding pharmacies to produce batch quantities of products in

•

see COMPOUNDERS, page 36

36 Policy

Pharmacy Practice News • May 2013

Medication Safety

FDA Seeks More Muscle After NECC F

DA Commissioner Margaret A. Hamburg, MD, told a congressional panel investigating the deadly fungal meningitis outbreak tied to the New England Compounding Center (NECC), in Framingham, Mass., that current law “is not well suited” to regulate large compounding pharmacies. “Sterile products produced in advance of or without a prescription and shipped interstate should be subject to the highest levels of controls, established by FDA and appropriate to the activity, similar to cGMP [current Good Manufacturing Practices] standards applicable to conventional drug manufacturing,” Dr. Hamburg told the House Energy and Commerce Subcommittee on Oversight and Investigations during a hearing in mid-April. “We have been hampered in our ability to protect the American people because of ambiguities regarding FDA’s enforcement authority, legal challenges and adverse court decisions” surrounding what she termed nontraditional compounders—companies that produce large quantities of sterile products “in advance of or without receiving a prescription, where the drug is distributed out of [the] state in which it was produced.”

COMPOUNDERS continued from page 34

anticipation of patient needs, hospitals that dispense medications ordered from them may find themselves in legal jeopardy if another public health crisis were to occur, like the meningitis outbreak tied to NECC, according to Dan Ross, PharmD, the president of D Ross Consulting, in Glendale, Calif. “If you’re still buying without performing the necessary due diligence,” he said, “you’re putting your hospital at some risk.” Bonnie Kirschenbaum, MS, a health care consultant based in Boulder, Colo., said that Dr. Ross’ stated concerns over liability are legitimate. But she said they are most relevant for a compounding pharmacy that has gone beyond compounding and into manufacturing from raw nonsterile ingredients, without exerting the same controls that a manufacturer would be subject to, or if the company does not follow strict compounding technique with appropriate quality control measures. Some of these concerns over safety and liability “can be mitigated by carefully vetting any sterile compounding pharmacy that the facility considers doing business with,” noted Ms. Kirschenbaum, a member of the editorial advisory board of Pharmacy Practice News. Dr. Ross, formerly the director of pharmacy and medication safety at Catholic Healthcare West (now California-based

The House hearing was the latest in a series of congressional inquiries following last year’s deadly outbreak of meningitis associated with contaminated compounded methylprednisolone acetate produced by NECC. To date, more than 50 people have died and about 730 have been stricken in 20 states. Energy and Commerce Committee Chairman Rep. Fred Upton (R-MI) questioned whether the FDA had done its job effectively. “What did the FDA know about NECC and Ameridose [a company tied to NECC] and what did FDA do about it?” Mr. Upton asked, in reference to numerous warnings that the agency had received about NECC and the lack of follow-up to its own inspections and warning letters. “It sickens me that this could have been prevented,” he said. “Ten years of warning signs, alarm bells and flashing red lights were deliberately ignored,” added subcommittee chairman Rep. Tim Murphy (R-PA). Dr. Hamburg testified that the FDA’s oversight authority of compounding pharmacies has been “hampered by gaps and ambiguities in the law” created by conflicting court decisions. For example, although provisions of the Food and

Drug Administration Modernization Act of 1997 exempts compounded drugs from many aspects of FDA oversight, various courts have issued conflicting rulings about the matter. “As a result, FDA has limited knowledge of pharmacy compounders and compounding practices and limited ability to oversee their activities. I wish we had been more aggressive, and I can assure you that we are being more aggressive now,” she said. Rep. Henry Waxman (D-CA), the committee’s ranking minority member, noted that although the FDA had missed important opportunities to act in regard to NECC, “it’s Congress’ job to fix the law; we must do more than blame the agency.”

Increased Investigations From February to April 2013, the FDA sent inspectors to 31 compounding facilities in 18 states. There they uncovered dozens of unsafe practices, including unidentified black particles floating in vials of supposedly sterile medicine; rust and mold in clean rooms where sterile injectable medications were produced; technicians handling supposedly sterile

‘If administrators want the in-house pharmacy to do all the compounding in lieu of outsourcing, then the administrators had better supply the capital dollars to make the pharmacy USP 797–compliant and the staff to do so as well.’ —Ernest R. Anderson Jr., MS, RPh Dignity Health), said it can be hard to determine, at least initially, whether a given manufacturer is in fact exceeding guidelines for safe compounding. The ongoing problem of drug shortages adds further pressure and complications. “If you’re a hospital pharmacy director and there’s a shortage of succinylcholine, you may be tempted to buy anything you can,” he said. “But I’d caution against any rash purchasing decisions.” In fact, there are several precautions pharmacy directors can take to mitigate the risks of partnering with a third-party compounder. First, Dr. Ross said, they should review ASHP’s resources for vetting outside compounders. What’s more, they also should make their own firsthand inspections of prospective compounding pharmacies, if possible. Additionally, he said, they should consult with hospital administration and legal “to make sure that you and your organization are going into it with your eyes wide

open, because your pharmacy directors are going to get hung out to dry” if things go wrong in the end. One effective strategy for reducing both legal and drug safety risks is to limit the number of “special concoctions” ordered by ophthalmologists, surgeons and other practitioners to when they are medically necessary, Dr. Vaida noted. “This is an opportunity to sit down at pharmacy and therapeutics committee meetings and say that, hey, there is not a lot of evidence for [having so many formulations].” The time to do that, Dr. Vaida stressed, is right now. “If you have [that conversation] a year from now, people may forget,” he said, “and if you say, “Look at what happened last year,’ they might respond, ‘Oh, that was something that happened in Tennessee, wasn’t it?’”

Putting It all in Perspective Ernest R. Anderson Jr., MS, RPh, former system vice president of phar-

FDA Commissioner Margaret A. Hamburg, MD

products with their bare hands; and a lack of appropriate air filtration systems. The FDA has posted copies of Form 483 for each facility documenting unsafe conditions it uncovered. In her written testimony, Dr. Hamburg proposed legislation based on a “riskbased framework” that would differentiate between “traditional compounding” in which medication is prepared for a specific patient from a prescription or order from a licensed practitioner and “nontraditional compounding” in which products are prepared in advance of or without receiving a prescription and distributed out of state. Traditional compounding activities would continue to be overseen by state pharmacy boards, she said, whereas nontraditional compounding would come under “clear and appropriate federal standards and oversight,” including the ability to collect

macy at Steward Health Care System, in Boston, and a member of the editorial advisory board of Pharmacy Practice News, said these are all difficult issues—especially when drug shortages are thrown into the mix. “On one hand, patients need drugs that are often in short supply, but when seeking those solutions one has to be certain of the integrity of the repackager that you are purchasing from,” he said. “PharMEDium, as one example, is manufacturing from sterile, commercially available products and not compounding from unsterile powders as the base to manufacture the sterile product. We need to steer clear of those products made in compounding pharmacies from nonsterile powders.” In his experience doing site inspections of reputable, established, FDAregistered compounding facilities, Mr. Anderson added, he has found that those facilities “far exceed most hospital pharmacies” in their environmental control practices and adherence to compounding guidelines. “But if your administrators still want the in-house pharmacy to do all the compounding in lieu of outsourcing,” he noted, “then the administrators had better supply the capital dollars to make the pharmacy USP <797>–compliant and the staff to do so as well.” —Bruce Buckley, with additional reporting by David Bronstein

Policy 37

Pharmacy Practice News • May 2013

Medication Safety and test samples and examine records. “We look forward to working with Congress in striking the right balance,” Dr. Hamburg said. This proposed framework is an outgrowth of the so-called “three-prong test” that the FDA has been privately discussing with lawmakers based on whether the product is sterile, is shipped interstate and compounded before a prescription is received, according to the International Academy of Compounding Pharmacists (IACP), a trade association. In a March 20, 2013 letter to senators, the IACP called the establishment of a new regulatory category “premature” and warned that the three-prong test could infringe on state oversight of compounding pharmacies. “Since FDA is already empowered by Congress to govern the manufacture of drugs, FDA has the existing authority to apply drug manufacturing regulations as they see fit within the law,” the IACP wrote. Not every large compounding company agrees with the IACP. In a March 26 statement, PharMEDium Services LLC, a large outsource producer of customized sterile compounds for hospital IV and epidural therapies, said that it supports “the passage of federal legislation to establish a new FDA category for sterile compounders governed by applicable current Good Manufacturing Practices.” In an April 15 statement posted on its website, PharMEDium reiterated its faith in FDA taking on a stronger— and better defined—role in the oversight of compounding. “The production of compounded sterile preparations in anticipation of a prescription is a difficult practice for states to oversee, especially when these preparations are shipped across state lines,” the company noted. “Accordingly, PharMEDium believes Congress must move swiftly to clarify FDA’s legal authority over the compounding pharmacy industry, distinguish it from the appropriate role of state boards of pharmacy, strengthen governing standards, and facilitate effective inspections and enforcement.” The company’s position on the regulation of compounding is particularly relevant, given the fact that FDA inspectors observed various problems at the company’s compounding facilities during inspections this year. In February 2013, PharMEDium said it was “committed to maintaining the highest levels of quality and safety in sterile preparations,” and that it has been “fully responsive” to all FDA concerns (see Pharmacy Practice News March 2013). Other groups, including the American Society of Health-System Pharmacists (ASHP), also support strengthening the FDA’s oversight of large-scale compounding pharmacies that produce large amounts of products and then sell them to entities other than the end user. In a

Jan. 18, 2013 letter to the FDA, Christopher J. Topoleski, ASHP’s federal regulatory affairs director, said that the society “believes that compounding service providers that operate at the scale and scope of manufacturers should be required to register with the FDA, share details about their operations with the Agency, and submit to routine inspections.” Such oversight is not needed for hospital-based compounding services, Mr. Topoleski added, because those facilities prepare medications for patients within a hospital or hospital system,

strengthen federal oversight of compounding activities not currently overseen by states that represent higher risk due to product volume, category of product, whether product is patient-specific and breadth of distribution; better define and standardize licensing categories for patient care sites, companies and others involved in compounding; and explore creation of new standards that combine US Pharmacopeia Chapter <797> and current cGMPs to facilitate oversight of largescale compounding facilities. —Ted Agres

which also are accredited and have significant internal safeguards, formularies and infection control and risk management committees. On Feb. 6, 2013, ASHP, the Pew Charitable Trusts and the American Hospital Association convened a Pharmacy Compounding Summit, which brought together stakeholders from health-system organizations, government, compounding companies and others. Consensus recommendations included the need to clarify the roles of federal and state authorities over sterile compounding practices;

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Volu ume 40 • Number 4 • April 2013

Printer-friendly versions available online

in this issue CLINICAL

3 12

Safety, quality pearls: collaboration a key to successs. E-alerts boost venous thromboembolism prevention.

TECHNOLOGY

16 23

Health IT pearls: telepharmacy, smarter IV pumps and more. When the carousel stops: a plan for drug dispensing.

POLICY

26

IOM urges trackand-trace system for protecting drug supply

OPERATIONS & MGMT

30

The case against overuse of proton pump inhibitors.

EDUCATIONAL REVIEW

Medication Errors: A Year in Review See insert after page 8.

REPORT Teflaro® (ceftaroline fosamil) for the Treatment of Acute Bacterial Skin and Skin Structure Infections Caused by Designated Susceptible Bacteria See insert after page 16.

OIG Says REMS Program Falling Short Of Goals

A

fter four years, the effectiveness of the FDA’s mandatory Risk Evaluation and Mitigation Strategies (REMS) program remains open to question because drug companies have failed to comply with key reporting requirements and the agency lacks adequate enforcement authority to take action against them, according to a report by the Department of Health and Human Services’ Office of Inspector General (OIG). Nearly one-fourth of the drug companies with medications in the REMS program were found to be in violation of legislatively approved timetables for data reporting, according to the OIG report. Furthermore, less than 15% of the companies had met all of the safety goals stipulated in their products’ REMS. As for the FDA, the agency has reviewed only one of 32 drugs whose REMS contain “elements to assure safe use” (ETASU)—usually reserved

•

H

ospital pharmacists face several ral challenges in h helping l i manage antibiotic-resistant, gram-negative superbugs that produce carbapen nemases. One of the most worrisome is carba-penemase-producing Klebsiella pneumoniae (KPC). A report in the March issue off Infection Control and Hospital Epiidemiology (2013;34:259-268) foun nd that the proportion of K. pneumon niae cases resistant to carbapenems increa creaased d from 0.1% in 2001 to 4.5% in 2010 0. ““That is huge,” said Robert Rapp, PhaarmD, a professor of pharmacy and sur-gery emeritus at the University of Kentucky Medical Center in Lexington, who is one of manyy pharmacists concerned about KPC C. Those concerns were compound ded by a Centers for Disease Control aand Prevention’s report on the rising prrevalence of carbapenem-resistant en nterobacteriaceae (CRE). According to the h report, in the last decade, hospitals have seen a fourfold increase in CRE, with most of the increase attrib-utable to Klebsiella species (MMWR ( 2013;62:1-6).

•

see REMS, page 24

Addiction Cited As Powerful Diversion Driver

C

ontrolled substance diversion is a major challenge for hospitals across the country. The problem is being fueled, in part, by the power of addiction: It is estimated that 10% to 15% of health professionals will develop serious substance abuse/addiction problems during their career (Crit Care Med 2007;35:S106-S116). Experts warned during a recent webinar

•

In Ranking of Superbugs, Klebsiella Takes the Lead

see CHALLENGE, page 20

see SUPERBUGS, pag ge 6

Shifting the Main Focus off Acid id Suppression to the Critically Ill Las Vegas—A San Antonio health care system markedly reduced unnecessary use of proton pump inhibitors (PPIs) for stress ulcer prophylaxis (SUP) in the ICU and ended up saving $80,000 annually. At a Boston-area hospital, researchers determined that reducing inappropriate PPI use among general medicine patients could lead to yearly cost avoidance in the neighborhood of $1 million. Both initiatives, presented at the Decem-

ber 2012 Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP), were undertaken to address persistent inappropriate use of PPIs, which has been linked to higher hospital costs and an increased risk for Clostridium difficile infections (sidebar, page 30). “Many of our general medicine patients were on PPIs or H2-receptor agonists constantly, and

•

see STRESS ULCERS, page 30

New Products GlucoCareTM IGC System insulin dosing calculator.

A new medication safety initiative from Medi-Dose®, Inc./ EPS®, Inc.

See page 19.

See page 27.

9

t

ANTI-INFECTIVES

ONCOLOGY

CRITICAL CARE

ANESTHESIA/ ANALGESIA

COMMITMENT

IN ACTION Fresenius Kabi USA provides a broad portfolio of quality products. Behind each of these products is our responsiveness and dedication to providing reliable treatment options. That's our commitment in action.

A PROVEN RECORD OF RESPONSE. APP® and are trademarks of Fresenius Kabi USA, LLC. ©2013, Fresenius Kabi USA, LLC. All Rights Reserved. 0504-COP-05-01/13

www.APPpharma.com

ADVERTISEMENT

Pharmacy Practice News • May 2013

The APP Brand of Specialty Injectable Products From Fresenius Kabi USA

39

CORPORATE SPOTLIGHT

F

resenius Kabi is a leading global health care company that focuses on medicines and medical devices for critically and chronically ill patients inside and outside the hospital. Its APP brand of specialty injectable products is well known to hospitals and other health care providers in the United States. Fresenius Kabi provides a full line of critical care, anesthesia/analgesia, oncology and anti-infective products under the APP brand. APP products are produced at multiple FDA-registered facilities located throughout the United States, Europe and Asia. To help further ensure that the company can reliably meet the needs of its customers, the global manufacturing capabilities of Fresenius Kabi have been utilized in times of great customer need. What this ultimately means to health care providers and the patients they serve is that Fresenius Kabi USA has the commitment and resources to provide specialty injectable products that meet the highest quality standards.

Well Prepared To Serve Customer and Patient Needs Today, providing reliable access to quality specialty injectable products is more important than ever before. As part of a global company, Fresenius Kabi USA is positioned to provide high-quality products to its customers based on the following capabilities: • Access to multiple U.S.-based and global manufacturing locations • Redundant production lines that can be used when needed • Well-established relationships with suppliers • A secure global distribution network Together, these capabilities define what customers and patients expect and rely on from a leader focused on supporting the care of critically and chronically ill patients inside and outside the hospital.

A Growing Portfolio of Quality Products In 2012, Fresenius Kabi USA was the second largest supplier of multisource products based on the number of units sold in the United States and Canada.1 The company ranks first in terms of the number of injectable drugs offered across four key therapeutic areas (Table). There is a commitment to continually expand its already broad portfolio. Recently, Fresenius Kabi added Meropenem for Injection, USP (IV) and Imipenem and Cilastatin Injection, USP (IV) to its anti-infective portfolio; Acetylcysteine Injection, Tranexamic Acid Injection, Benztropine Mesylate Injection and Levetiracetam Injection to its critical care product line; and Oxaliplatin Injection, USP to its oncology portfolio.

Table. APP Injectable Drug Products

Address

Number of Product Families

Number of Products

Analgesia and anesthesia

16

124

Anti-infectives

28

79

Critical care

54

139

Oncology

27

63

Therapeutic Area

Commitment in Action Fresenius Kabi USA has the resources to maintain its commitment to providing quality essential medicines. The company’s processes, production capabilities and people demonstrate its commitment in action on a daily basis.

Reference 1. IMS Health, September 2012.

AT A GLANCE Three Corporate Drive Lake Zurich, Illinois 60047 T (847) 550-2300 T (888) 391-6300 www.fresenius-kabi.us

Customer Service (Ordering) Toll-Free: (888) 386-1300 FAX: (800) 743-7082

Medical Affairs Toll-Free: (800) 551-7176 FAX: (847) 413-8571

Products A leading supplier of multisource and branded injectable pharmaceutical products, primarily focused on the anesthesia/ analgesia, anti-infective, critical care and oncology markets.

40 Policy

Pharmacy Practice News • May 2013

Medication Safety

FIP Panel: Pharmacists Are an ‘Untapped Resource’

T

he lack of responsible use of medications worldwide leads to at least $500 billion in wasteful health care spending every year. Although no single sector of the health care system can redress this situation on its own, pharmacists should play a more active role in ensuring the safe and effective use of medications and improving overall medical care, according to a range of experts convened by the International

‘This report provides a useful framework to help improve the medication-use system on a global scale.’ —Kathryn R. Schultz, PharmD Pharmaceutical Federation (FIP). Panelists on four stakeholder roundtables, held during FIP’s Centennial

World Congress in Amsterdam, “highlighted the need for countries to recognize and utilize the untapped potential

of pharmacists around the world,” said FIP President Michel Buchmann, PhD, in a report issued in March. “We can no longer consider medicines solely based on their price, but on the benefits that medicines and their responsible use can bring to health,” Dr. Buchmann stated in the report. “We must embrace a shared vision to shift away from short-term gains and move toward longer-term, integrated and more effective policies, which consider the real and full range of the costs and benefits of medicines, from their invention to their responsible use and impact on health.”

Key Role of Pharmacists More than half of the $500 billion in annual wasteful spending is tied to medication nonadherence, mostly among patients in high-income countries, according to a report prepared for FIP by the IMS Institute for Health Informatics. Nonadherence is caused, in part, by health care professionals not spending enough time with their patients, resulting in poor information and communication, concluded panelists on a roundtable discussing adherence issues. Medication adherence can be improved by addressing incentives, remuneration and system capabilities starting with drug development, continuing through more patient-centered care (including patient education and health literacy), and concluding with strengthening the role of

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Policy 41

Pharmacy Practice News • May 2013

Medication Safety pharmacists to use their full potential in medication review and credibility with the community. “Pharmacists are the most underutilized resource that patients trust,” said panelist Durhane Wong-Rieger, chair of the International Alliance of Patient Organizations, Canada. Several examples of interventions to improve the use of and adherence to prescriptions were identified. These included using centralized monitoring systems to oversee medication supplies and electronic dispensing tools to document use; improving medication dosage regimens through fixeddose combinations; developing more appropriate pediatric dosage forms; and using mobile messaging and other technologies to remind patients and provide feedback on their medication use (see related article, page 1).

Getting It Right Another part of the solution involves getting the right medicine to the right patient, at the right time and delivered in the right way. Panelists on this roundtable recommended the entire health care workforce be better utilized, including pharmacy capacity and pharmacists’ ability to provide direct support to patients to enhance their responsible medication use. “Pharmacists, medical doctors and nurses should learn to work together and share their expertise, forming a truly multidisciplinary team devoted to patients’ best interest,” said panelist Pierre Chirac, the vice president of the Association Mieux Prescrire, in France. Additionally, pharmacies and pharmacists must be included in electronic record systems to enable the appropriate sharing of health information, concluded panelists on a third roundtable discussing the transformative power of shared information. The interoperability of standards and systems is essential if data and records are to be effectively used in practice. But the mere availability of electronic health records is not nearly as important as are applications of these systems to enable clinicians, including pharmacists, to perform to their full capacity. “We have power because we really have the ability to change when we use and share the information available,” noted panelist Per Troein, the vice president of strategic partners at IMS Health in London. Members of a fourth roundtable discussing the effect of innovation noted that the high cost of drug development is a current barrier to producing innovative medicines. Drug developers should consider “real-world” evidence on medication use, and the health professional community should be trained to understand the science underlying new therapies and be willing to be test and document new medications. “We are discussing with regulatory bodies

‘We can no longer consider medicines solely based on their price, but on the benefits that medicines and their responsible use can bring to health.’ —Michel Buchmann, PhD to shift to using real-world data earlier in the [drug] development phase,” said panelist Michel Dutrée of the European Federation of Pharmaceutical Industries and Associations.

The FIP is a global federation of national associations headquartered in The Hague that represents 3 million pharmacists and pharmaceutical scientists through its 127 member organizations.

Commenting on the report in an interview, Kathryn R. Schultz, PharmD, the president of the American Society of Health-System Pharmacists, said, “This report provides a useful framework to help improve the medication-use system on a global scale. Focusing on improvement of all aspects of the system, including how patients get their medications, how they take them and how information is shared among health care providers will play a big role in advancing the responsible use of medication.” —Ted Agres

YOUR PATIENTS DON’T NEED TO WAIT DAYS FOR RELIEF! Betamethasone Sodium Phosphate & Betamethasone Acetate Injectable Suspension, USP and

corticosteroid formulation in

– Betamethasone* Sodium Phosphate & Betamethasone Acetate Injectable Suspension, USP

Kenalog® Acetonide) Injectable Suspension, USP

–

– ®

(Methylprednisolone Acetate Injectable Suspension, USP)

Dexamethasone Sodium Phosphate Injection, USP

*AB rated to Celestone® Soluspan®

- Begins to reduce inflammation in 1-2 hours - Provides sustained relief The intra-articular or soft tissue administration of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid oid arthritis, synovitis of osteoarthritis. Important Safety Information: As with any potent corticosteroid, adverse events have been associated with Betamethasone ne Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP, including fluid and electrolyte disturbances, as well as adverse reactions involving the following systems: allergic reactions, cardiovascular, dermatologic, endocrine, gastrointestinal, al, metabolic, musculoskeletal, neurological/psychiatric, and ophthalmic. Corticosteroids may also affect immune response. Rare instances es of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. Betamethasone Sodium Phosphate and nd Betamethasone Acetate Injectable Suspension, USP should not be administered intravenously or used in systemic mic fungal infections. Vaccination administration of live or live, attenuated vaccines is contraindicated in patients ts ds receiving immunosuppressive doses of corticosteroids. Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice ce at once should they develop fever or other signs of infections. Persons who are on corticosteroids should be warned to avoid exposure re to chicken pox or measles and to seek medical advice without delay if exposed. Depo-Medrol® is a registered trademark of Pfizer, Inc. Kenalog® is a registered trademark of Apothecon, Inc. Celestone® and Soluspan® are registered trademarks of Schering Corp.

See following page for brief summary of full prescribing information on

www.americanregent.com

BB023 Iss. 1/2012 2

42 Policy

Pharmacy Practice News • May 2013

Generics

Support Grows for Abuse-Deterrent Generic Opioid Mandate

S

tate attorneys general (AGs) have joined the chorus of brand-name drug companies, medical associations and legislators urging the FDA to mandate more difficult-to-abuse versions of prescription pain medications—specifically, generic opioid analgesics. Yet some clinicians worry that forcing generic companies to make their opioid analgesics abuse-deterrent will ultimately pass the financial costs of

doing so on to pain patients who may be ill-equipped to foot the bill. Meanwhile, a supplemental approval to the labeling of an abuse-deterrent formulation of oxycodone may point the way in which the FDA will ultimately head on this contentious issue. In a March letter, 48 state AGs asked the FDA to adopt drug development standards outlining how manufacturers of generic prescription opioids

should develop abuse- and tamperresistant versions of the analgesics. The FDA has issued a draft directive defining the requirements for developing tamper-resistant opioids that does not make it mandatory. The letter noted that brand-name versions of opioids such as OxyContin (Purdue) and Opana ER (Endo) have taken steps to make it more difficult to abuse their drugs. Yet, the FDA is faced

with the contentious issue of generic opioids. Purdue and Endo have filed Citizen Petitions separately with the FDA over the past year in an effort to force generic formulations to prove they are abuse-deterrent in order to enter the market. The concern is that unless they are forced to develop abusedeterrent formulations, generics will soon fill the market with opioids that are easier to abuse and misuse.” “In our states, nonmedical users are shifting away from the new tamperresistant formulations to non–tamperresistant formulations of other opioids as well as to illegal drugs,” the AGs wrote in their letter to the FDA. “There is great concern in our law enforcement community that many non–tamper-resistant products are available for abuse when only a few products have been formulated with tamper-resistant features.” On April 16, the FDA approved a supplemental application for the reformulated OxyContin, with the new labeling highlighting its abuse-deterrent properties. “Accordingly, the agency will not accept or approve any abbreviated new drug applications (generics) that rely upon the approval of original OxyContin,” the FDA noted in a statement, thus closing the door for many, but not all, generic non–abuse-deterrent opioids. The website FDALawyersBlog.com reported in January that FDA Commissioner Margaret A Hamburg, MD, sent a letter to several U.S. senators concerned about opioids that are not abuse-deterrent, acknowledging that “if the FDA determines that a formulation of a product significantly deters abuse, we have legal authority, under the drug approval and drug safety provisions of the Federal Food, Drug, and Cosmetic Act, to require generic versions of that product to have abusedeterrent formulations as well.”

Research Supports Tamper-Resistant Agents Although the FDA and some pain medicine thought leaders have said that data supporting the effectiveness of abuse-deterrent formulations are wanting, pharmaceutical company– sponsored research has filled in some gaps in the literature, such as three studies presented at the 2012 annual meeting of the American Pain Society and sponsored by Purdue. Data provided from the American Association of Poison Control Centers’ National Poison Data System between July 2009 and June 2011 compared the incidence of OxyContin exposure cases reported to poison control centers with those of single-entity oxycodone

Pharmacy Practice News • May 2013

Policy 43

Generics and heroin—both before and after the introduction of the reformulated product. The study showed that all OxyContin exposures (both original and reformulated) declined 18% after the reformulated drug was introduced to market in August 2010, compared with single-entity oxycodone (13%) and heroin (17%). An observational study using data from the National Addictions Vigilance Intervention and Prevention Program found that after reformulated OxyContin was introduced, there was a 49% reduction in the number of individuals abusing OxyContin among prescription opioid abusers. Within this population, the number of people who abused OxyContin orally declined by 30% and non-oral abuse (i.e., injection, snorting) of the drug in this population declined by 73%. A third study, based on a survey of law enforcement officials participating in Purdue’s Researched Abuse Diversion and Addiction-Related Surveillance system, found that reformulated OxyContin had a geometric mean street price of 65 cents/mg, 22% lower than that of original OxyContin (8081 cents/mg) and 31% lower than that of instant-release oxycodone products (95 cents/mg).”

Divided Opinion Lynn Webster, MD, American Academy of Pain Medicine (AAPM) president, said that pushing for “legislative and administrative preventative measures, including extending tamper-resistant requirements to generic drugs” is a chief focus of the AAPM for 2013. “It would be ironic and counterproductive if the FDA allows generics without tamper-resistant properties to compete with the tamper-resistant formulations that are branded or not, because they also have mandated a comprehensive Risk Evaluation and Mitigation Strategy [REMS] for the same long-acting/extended-release opioid formulations,” Dr. Webster said. “It seems schizophrenic. Failure to require comparable tamper-resistant properties would be a setback in the battle to fight prescription drug abuse and unintentional overdose deaths.” In a recent podcast posted on PainMedicineNews.com, a sister website to PharmacyPracticeNews.com, David Craig, PharmD, BCPS, a clinical pharmacist specialist and the director of the Pain and Palliative Care Specialty Residency at the H. Lee Moffitt Cancer Center and Research Institute, in Tampa, Fla., acknowledged the safety advantages of tamper-resistant formulations, but worried that a mandate could have serious cost implications for some patients. “I have mixed feelings,’’ he said. “Yes, there could be some potential safety

advantages, but who is going to pay 10 times the cost of these medicines—is the federal government going to pay for it, is private insurance? I think about the patients who we have here who are uninsured or underinsured, who can barely meet the costs of all their monthly requirements now, and we are going to add an additional layer on their costs? That’s one of the questions that still remain. Mandating it for everybody is going to increase the costs for everybody.” —Donald M. Pizzi

Another Successful Year For the McMahon Group

2012

to recognize the best of an outstanding group of empployees. Now into its fifth decade, the company continues to publish best-read medical newspapers and must-view meddical websites covering several clinical areas, and also creates medical education platforms for physicians, nurses andd pharmacists. All of which proves yet again that a company pow powered wered by talented people will necessarily generate su success. uccess

Here is a review of the winners of the 2012 employee awards: MANAGEMENT/SUPPORT/IT/FINANCE/PRODUCTION

MANAGEMENT/SUPPORT/IT/FINANCE/PRODUCTION

Each year employees are asked to select two outstanding mem mbers representing these diverse departments. The first winner was DIANE LODISE, who is both the director of facilities managemeent, overseeing the facilities owned by the company, and the conveentions coordinator, planning the many details of our extensive convenntion coverage.

The second winner was HYON NG KWON, the company’s development manager for IT, for his continuuing efforts in improving the company’s digital presence.

MAX GRAPHICS PERSON OF THE YEAR

MOST IMPROVED SALESPERSON OF THE YEAR

BLAKE DENNIS was recognized for her excellence as art directtor for Anesthesiology News as well as her graphic design of a varietyy of special projects. Blake is dedicated to creating the most visually appeaaling projects possible.

BRIAN HIGGINSON, publicatioon director for Gastroenterology & Endoscopy News, was recogniized for the increase in that publication’s sales in 2012, which in part ledd to one of its most profitable years ever. His dedication to his clients’ needs and understanding of their products ensure his continued success in sales.

ASSOCIATE/SENIOR/PROJECTS EDITOR OF THE YEAR

MANAGING EDITOR OF THE YEAR

Editorial director of the special projects division, division KATHERINE REIDER was recognized for her contributions as an editor and for providingg leadership and direction to the members of the department. Her diplomacy skills and focus on process have helped ensure that projects are devveloped with the highest level of accuracy and in a timely manner. Katherinee also was recognized for her 10 years of service at McMahon.

GEORGE OCHOA was voted editor ed of the year for his efforts and dedication to McMahon Groupp through his exemplary writing and editing. His stories appear in every McMahon Group publication and on every website and provide the manaaging editors with articles that exemplify editorial excellence.

SALES ACHIEVEMENT AWARD

SALESPERSON OF THE YEAR

The publication director for General Surgery News, MICHAEL ENRIGHT, T was selected for this award in recognition of his strong commitment to his clients and his innovative thinking to create unique marketing platforms, which included the publication’s first international edition as well as the initiation of a website video arcade.

For an unprecedented seventhh year in a row, RICHARD TUORTO earned the salesperson of the year aw ward. Unlike the other awards, which are decided by peer votes, this aw ward is presented to the individual who brings in the most revenue in the calendar year. Richard manages the Anesthesiology News and Painn Medicine News teams as senior group publication director.

THE MCMAHON GROUP PERSON OF THE YEAR

PARTNERS’ AWARD

The top award each year is for the person of the year, which gooes to the employee who goes above and beyond the call throughout thee year. JEANNIE MOYER, associate director of human resources, received the honor this year. Jeannie oversees personnel and works tirelessly to provide the best possible atmosphere for employees each day. She is integral to helping McMahon Group continue to grow every year.

From time to time, the partner--owners of the company recognize the contributions of those who havee had a significant effect on the company’s success through the years. The 22012 award was given to WARD BYRNE, who served as publication director foor Anesthesiology Newss for several years, starting in the early 1990s. He w was responsible for the excellent growth of that newspaper, which today dominates the market. Ward eventually left McMahon Group to start what would be ann 11-year career working at a medical education company, after which he returneed to his true love — teaching. Today, Ward teaches special education in thee New Jersey school system.

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Geoff Hanlon; Norman Hodges February 18, 2013 This text is an essential study guide for undergraduates studying microbiology modules on degree courses in pharmacy and the pharmaceutical sciences. It distills the subject down into the essential elements that pharmacists and pharmaceutical scientists need to know.

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Information Technology in Pharmacy: An Integrated Approach

Stephen Goundrey-Smith October 5, 2012 This book provides a concise and practical general introduction to pharr macy IT, discusses issues surrounding the adoption of technology and how technologies may be used by the pharmacy profession to exercise new professional roles and achieve new professional aspirations.

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Katzung & Trevor’s Pharmacology Examination and Board Review, 10th Edition

Anthony Trevor; Bertram Katzung; Susan Masters; Marieke Knuidering-Hall October 9, 2012 This book delivers a clear, concise review of fundamental concepts backed by more than 1,000 review questions and answers. The chapterbased approach facilitates use with course notes or larger texts.

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Mosby’s Drug Reference for Health Professions

Mosby April 15, 2013 From Abilify to Zyrtec and nearly every drug in between, Mosby’s Drug Reference for Health Professions s is the must-have portable drug handbook for every current or aspiring health professional in the field today. This updated edition features concise, reliable information that is easy to navigate, with alphabetically listed monographs for over 900 generic d ugs, including drugs, c ud g 4,500 ,500 trade-name t ade a e drugs d ugs for o both bot U.S. U S and a d Canada. Ca ada

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PharmPrep: ASHP’s NAPLEX Review, Fourth Edition

Lea Eiland; Diane Ginsburg May 10, 2011 Using real patient cases accompanied by questions that address all NAPLEX® competency statements, the new edition gives you the flexibility to review information by specific disease state and provides 78 sample cases, as well as calculations and law review sections. As drug therapy becomes more complex, PharmPrep has continued to update and revise cases so they reflect contemporary clinical practice.

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Remington: An Introduction to Pharmacy

Loyd V. Allen May 31, 2013 Remington: An introduction to Pharmacy y is a companion to the 22nd edition of Remington: The Science and Practice of Pharmacy. It addresses the core concepts in the field of pharmacy, providing a broad overview of key pharmaceutical science and practice-related topics.

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Roadmap to Postgraduate Training in Pharmacy

P. Brandon Bookstaver; April D. Miller; Celeste N. Rudisill; Kelly M. Smith February 5, 2013

Roadmap to Postgraduate Training in Pharmacyy provides the information and expertise pharmacy students need to make confident, informed decisions regarding residency programs, fellowships and additional degrees.

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Stockley’s Drug Interactions Pocket Companion 2013

Karen Baxter; Claire L. Preston January 10, 2013 This conveniently sized quick reference continues to provide the busy health care professional with a trustworthy, affordable and practical clinical reference on drug interactions and their management. It draws on the wealth of clinically evaluated, evidence-based information on drug– – drug, drug–herb and drug–food interactions that is presented in the latest revalidated updates of the full reference work, Stockley’s Drug g Interactions. PPN0513

46 Policy

Pharmacy Practice News • May 2013

Medical Marijuana

Growing Pains at N.J. Marijuana Dispensary W

hen New Jersey’s first alternative treatment center opened for business in December 2012 in Montclair, patients from all corners of the state began trickling into the urban-suburban town 12 miles west of Manhattan. Residents with chronic pain and 13 other diagnoses joined a growing number of people across the country now able to fill legal prescriptions for marijuana. But then, overwhelmed by servicing the entire state, the dispensary (Greenleaf Compassion Center) said in late March it would only take new customers residing in seven northern counties. It took almost three years for the Garden State to move from legalizing its medical marijuana program (MMP) to implementing it. Some involved in that process express strong satisfaction with its outcome. Others say a combination of overly zealous regulations— only one of six slated dispensaries is operational—and reticence on the part of physicians to prescribe a drug that still has stigma attached to it have hampered real progress.

Not De Facto Legislation According to Joseph Stevens, the co-founder of the Greenleaf Compassion Center, new patients receive about half an hour of education that includes advice on risks and benefits of medical cannabis and methods of ingestion, which include smoking, vaporizing and potentially, cooking products in their homes. “We tell patients to start slowly. If they have been using it illegally, we explain that ours is a little different, it’s truly medical grade. Patient feedback is ‘Wow, I’m using a quarter of what I used in the past.’” Patients fill prescriptions for up to two ounces of the dry flower (three strains are available)—the state-mandated maximum allowed for a 30-day period. Doctors set the time period for which patients can obtain the medicine (30, 60 or 90 days), after which they must reassess the patient’s status before renewing. Health care providers and scientists at a February conference sponsored by Americans for Safe Access (ASA), an organization that works to advance legal medical marijuana therapeutics and research, presented extensively on the developing area of science of cannabinoids. Attendees from other areas of the country who have been prescribing the medicine for patients dealing with pain emphasized the drug’s usefulness, in addition to, and sometimes instead of, standard opioid treatment. Deborah Malka, MD, who is board certified in integrative and holistic medicine, holds a PhD in molecular genetics, and is the former director of

rity that they put in place, the oversight on the centers—it’s a great program. It’s limited to patients. Only they can get it. As Gov. [Chris] Christie [R] said, it’s not de facto legalization.”

health services with MediCann, a California-based network of medical cannabis doctors, noted that she has seen many older patients who were looking for another option, encouraged to do so by their children. “The side effects are the main thing. People get so hooked on opioids. There are better ways with less toxic side effects.” But getting in the door in New Jersey isn’t easy. Wait times for new patients were about two months as of early March, and no one is allowed in the building who hasn’t already been diagnosed with one of 14 qualifying conditions. That diagnosis must be made by a physician registered to participate in the MMP and with whom the patient has a “bona fide” relationship. The doctor in turn certifies the patient online, a step that allows the patient to then register, which itself costs $200 ($20 for those on state or federal assistance programs). As of March 1, 206 New Jersey physicians in more than 20 specialties were registered in the MMP, in areas ranging from internal medicine and oncology to anesthesia and ophthalmology. (All are searchable on the state’s website by specialty and geographic location.)

Legal experts say the system will give access to those with legitimate conditions but prevent abuse of the Schedule I controlled substance. They suggest that New Jersey was able to learn from the mistakes of other states. “California was the first state to decriminalize medical marijuana. Initially, it was very loose in terms of regulations, and didn’t have a statute with restrictions or ounces allowed or anything about dispensaries,” said Diane Hoffmann, JD, the director of the Law and Health Care Program and a professor of law at University of Maryland Francis King Carey School of Law, in Baltimore, who has written on the issue of decriminalization. “[Los Angeles] had hundreds of dispensaries. They’ve subsequently attempted to scale back, but this has been challenged at every turn. It’s hard once you have an unregulated situation to pull it back in.”

One busy family doctor practicing within a couple of miles of the Montclair center said she saw the program as something for specialists, such as oncologists and neurologists, and doubted there would be widespread physician involvement, adding, “I wouldn’t use it in my practice. That doesn’t mean I wouldn’t refer someone to another doctor. These days, it’s easier, especially when the government is involved, to not do it. There’s too much paperwork involved for my office.” Mr. Stevens acknowledged that there is a degree of bureaucracy for doctors and patients to work through but insisted that it was manageable and noted that most of the physicians calling him have educated themselves on medical marijuana and the program, which is spelled out with step-by-step instructions on the state’s Department of Health website. “It’s been a long process to navigate rules and regulations and a little difficult, but the state has done a great job in creating the program and setting a standard in the United States. The secu-

Ms. Hoffmann believes that states forming MMPs now are watching what has happened in California and other states that passed laws early on, and are taking measures to avoid what they see as abuse of the system. New Jersey, she noted, “doesn’t allow cultivation. They are saying you can only get it [through the alternative treatment centers]. They are tightening up but are trying to balance access for medical purposes with concerns about diversion to those who are not lawfully approved to possess marijuana, especially minors.” Mr. Stevens said he has already witnessed a number of what he describes as success stories. “On the first day [Greenleaf was in operation] a guy came in. He was on 300 mg of morphine a day. He was like a zombie. He would take his dose of morphine and he would lie on the couch and his wife would go to work. She would come back and he was still in the same position. One and a half months later, he’s vibrant and full of life. His life is back.”

Learning From Others

But some say the restrictions mean few will see any benefit. Ken Wolski, RN, MPA, the executive director of the Coalition for Medical Marijuana in New Jersey, said, “We consider the program pretty dysfunctional at this point. Less than 200 patients have gotten access to medical marijuana, despite the bill passing into law more than three years ago.” Mr. Wolski, who estimates that potential beneficiaries of medical marijuana in the state could number in the hundreds of thousands, asserted, “Regulations were designed to make this program fail.” He noted that home cultivation was taken out of the bill during the legislative process, the drug is only available at alternative treatment centers—which are more heavily regulated than pharmacies—and that the Christie administration added restrictions that were not in the bill, including the requirement that physicians be registered. Physician registration is not a requirement in most other states, and 15 of the 18 states that have decriminalized medical marijuana allow for some or all of the patients and caregivers to cultivate their own plants. Another obstacle, according to Mr. Wolski, is mindset. “Doctors have to recognize there’s a whole new field of emerging science on the endocannabinoid system. There is so much misinformation about it. That has to be overcome and the only way to do that is by physician education. This science about cannabinoids and how they work in the human body was discovered in the 1980s and 1990s. Doctors didn’t learn about this in med school. It’s incumbent on them to figure this out. They should be taking continuing medical education credits devoted to this. “Marijuana works synergistically with opioids—it’s not one plus one equals two, it equals three or four. With marijuana, the body needs less opioid. Analgesic properties are enhanced, and some patients say they manage to go off these dangerous, potentially lethal drugs entirely when they use marijuana.” Whether New Jersey’s system will achieve the delicate balance between truly meeting public health needs and addressing concerns about misuse remains to be seen. One thing is clear, however: The state brings yet another model to the patchwork of solutions popping up across the country, and it’s attracting interest. Mr. Stevens has been busy fielding calls, not just from physicians and patients, but also representatives from other states. “I’ve spoken to states looking to create their program— New York, Connecticut, Delaware—they are looking at New Jersey as a guide.” —Jennifer Hanawald

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High-, Moderate-, and Low-Penetrance Genes Involved in the

Pathogenesis of a Hereditary Predisposition to Breast Cancer LARISSA A. KORDE, MD, MPH Director Prevention Center Shared Resource Assistant Professor Department of Medicine, Division of Oncology

STACEY A. SHIOVITZ, MD Hematology-Oncology Fellow Fred Hutchinson Cancer Research Center University of Washington hington Seattle, Washington on

B

reast cancer is the most common malignancy in women in the United States

and the second leading cause of cancer-related death. The American Cancer

Society estimates that in 2013, there will be approximately 232,000 new

cases of breast cancer (of which 2,000 will be in males) and 40,000 related deaths.1

A family history of breast or ovarian cancer, bilateral breast cancer, and early age of onset suggest a hereditary predisposition. However, a predisposing gene is identified in less than 30% of cases with suggestive features.2 The vast majority of these cases are due to highly penetrant, but rare, genes. In recent years, additional rare, moderate-penetrance genes and

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

common, low-penetrance alleles also have been identified. Despite this, in many cases of suspected familial breast cancer, no predisposing gene is identified. This review will discuss the known genetic causes of breast cancer and the issues associated with characterizing and understanding hereditary predispositions to breast cancer.

M AY/J U N E 2 0 1 3

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Table 1. Breast Cancer High-Penetrance Genes and Their Associated Syndromes Breast Cancer Incidence

Gene

Syndrome

Other Associated Cancers

BRCA1 BRCA2

Hereditary breastovarian cancer syndromea

82% lifetime risk

Ovarian and fallopian tube cancer, prostate cancer, pancreas and biliary cancer, melanoma

PTEN

PTEN hamartoma tumor syndrome, Cowden syndrome

85% lifetime risk

Non-medullary thyroid cancer, endometrial cancer, GU tumors, especially renal cell carcinoma

TP53

Li-Fraumeni syndrome

25% by age 74

Sarcoma, brain tumor, adrenocortical carcinoma, leukemia, bronchoalveolar cancer; multiple other cancers are seen but more rarely

CDH1

Hereditary diffuse gastric cancer

39% lifetime risk of lobular breast cancer

Gastric cancer (diffuse subtype), colorectal cancer

STK11

Peutz-Jeghers syndrome

32% by age 60

GI cancers (esophagus, stomach, small bowel, colon), pancreatic cancer, sex-cord stromal tumors

Non-malignant Syndrome Features

Pathognomonic skin changes, macrocephaly, benign breast and thyroid disease, uterine fibroids, Lhermitte-Duclos disease, fibromas, lipomas, intestinal hamartomas, mental retardation

GI hamartomatous polyposis, hyperpigmented macules, hyperestrogenism

GI, gastrointestinal; GU, genitourinary a

There are additional patients with this clinical phenotype, but they do not have an identified mutation in either BRCA1 or BRCA2.

High-Penetrance Genes The first major gene associated with hereditary breast cancer was BRCA1, which was identified in 1990 via linkage analysis of families with suggestive pedigrees.3 In 1994, BRCA2 was mapped to chromosome 13.4 A mutation in either BRCA1 or BRCA2 confers an increased risk for breast and other cancers. Clinically, this is referred to as the hereditary breast-ovarian cancer (HBOC) syndrome, although there are patients with this same clinical picture who are found to be negative for mutations in both BRCA1 and BRCA2. Research into HBOC has focused on determining the associated risk for breast and other cancers, identifying specific clinical and histopathologic features, and developing therapeutic and prevention strategies. Tumors due to mutations in BRCA1 tend to be of the basal-like phenotype, with a higher histologic grade; they commonly are negative for the estrogen receptor (ER), progesterone receptor (PR), and Her2/neu, the so-called “triple-negative� tumor.5 BRCA2-related tumors more closely resemble sporadic tumors.6 BRCA1 and BRCA2 mutations are inherited in an autosomal dominant fashion but act recessively on the

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cellular level as tumor-suppressor genes involved in double-stranded DNA (dsDNA) break repair.2 Female carriers of mutations in BRCA1 or BRCA2 have a lifetime risk for breast cancer of 50% to 85%, which is greater than 10 times the average population risk.7 Male carriers of BRCA1 have an increased risk for breast cancer, although to a lesser degree than carriers of BRCA2, who have a 7% lifetime risk.8 Additional features of the syndromes are detailed in Table 1, most notably an increased risk for ovarian cancer, with an estimated lifetime risk of 54% for BRCA1 carriers and 23% for BRCA2 carriers.7,9,10 Bi-allelic BRCA2 greatly increases the risk for childhood cancers with the clinical picture of Fanconi anemia type D. There is no corresponding effect noted for BRCA1, and, thus, it is thought to be embryonically lethal.2 Mutations in BRCA1 and BRCA2 are estimated to explain only 15% of familial breast cancers.2,11 There are subpopulations with higher cancer frequencies due to founder mutations, most prominently the Ashkenazi Jewish population, in which 3 major mutations (BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT) alone account for approximately 10% of hereditary

cases.7 With sequencing and haplotype analysis, additional population subgroups also have demonstrated founder mutations.12 Additional rare but highly penetrant genes include PTEN,13,14 TP53,15-17 CDH1,18 and STK11,19,20 each connoting a distinct clinical syndrome, as described in Table 1. Collectively with BRCA1 and BRCA2, it is estimated that the known high-penetrance genes account for no more than 25% of cases based on prior studies and mathematical modeling.11,21 It is crucial to recognize individuals with a hereditary cancer syndrome because this greatly affects their clinical management. The National Comprehensive Cancer Network guidelines recommend that women with mutations in BRCA1, BRCA2, or one of the other high-penetrance genes should perform monthly breast self-examinations starting at age 18.22 From age 25 (or 10 years before the youngest case in the family, whichever is earlier), clinical breast exam, mammogram, and breast magnetic resonance imaging (MRI) should be performed annually. Prophylactic salpingo-oophorectomy is recommended for women with mutations in BRCA1/2 by age 35 to 40, or earlier if child bearing is complete or there is indication based on the family history.23 This reduces the risk for ovarian cancer (although there is a residual risk for primary peritoneal cancer), and reduces breast cancer risk if it is performed before menopause.23,24 Prophylactic mastectomy, with discussion of a nipple-sparing approach, also may be considered due to the high lifetime risk for both primary and contralateral breast cancers.25,26 Tamoxifen has been shown to reduce the risk for ER-positive breast cancer in women with increased risk based on the Gail model, but it has not been well studied in BRCA mutation carriers. Biologic characteristics and limited clinical data suggest that tamoxifen may reduce the risk for breast cancer in women with a BRCA2 mutation who have not undergone prophylactic oophorectomy before menopause.27-29 As for sporadic tumors, medical treatment of hereditary breast cancer historically has been dictated by histology, immunohistochemistry, and stage. Early clinical data suggest that BRCA-associated tumors are exquisitely sensitive to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, agents that inhibit the DNA damage-repair mechanism PARP, but these currently are only available in the setting of clinical trials.30

Moderate-Penetrance Genes Linkage studies have failed to demonstrate additional reproducible loci for highly penetrant genes that predispose individuals to breast cancer,11 prompting new directions for efforts to elucidate hereditary causes for this disease. Specifically, genes proposed to increase the risk for breast cancer based on their known cellular functions have been screened for mutations in families with pedigrees suggestive of a predisposition to breast cancer. Positive studies have found CHEK2,31 BRIP1 (BACH1),32 ATM,33 and PALB234 to be

associated with breast cancer; each confers about a 2-fold increase in risk for breast cancer. As described in Table 2, these genes play a role in DNA repair, interacting with either BRCA1 or BRCA2. CHEK2 *1100delC, the most common mutation, is seen in 1% of the population overall but in higher numbers in breast cancer patients.31 There is no additional increase in risk for cocarriers of a mutation in BRCA1 or BRCA2 with CHEK2, possibly due to an overlapping effect on DNA repair.31 Additional genes involved in DNA damage repair, including RAD51C and genes in the MRN DNA repair pathway (MRE11, RAD50, NBN [NBS1]) also have been investigated. However, when high-risk families were screened, no mutations were clearly associated with cancer.35-37 It still is possible that somatic mutations within tumors, or founder effects in unique populations, are present and contribute to cancer development and progression.36,38,39 Studies performed in the United Kingdom in BRCA mutation–negative women with a personal or family history have estimated that these moderate-penetrance genes account for 2.3% of familial breast cancer cases. Some of these studies are underpowered to comment on an earlier age of onset or other associated syndrome features.2 Because these genes confer a lower lifetime risk for breast cancer than the highly penetrant genes described earlier, clinical management, including screening and preventive interventions, of women with mutations in moderate-penetrance genes is less clearly defined. Clinical management should incorporate risk assessment tools, such as the Gail and Tyrer-Cuzick models,40 which emphasize a woman’s personal and family history of cancer and precancerous lesions, along with established breast cancer risk factors, to determine risk. For women with a calculated lifetime risk for breast cancer of at least 20% by virtue of a family history, annual breast MRI is recommended in addition to standard mammography.41,42 Additionally, all women with a higher than average risk for breast cancer should have a clinical breast examination performed every 6 months.

Low-Penetrance Alleles As laboratory techniques and sequencing capabilities have advanced, genome-wide studies have been performed to identify single-nucleotide polymorphisms (SNPs) that may contribute to breast cancer risk in a polygenic fashion. These studies require thousands of cases and controls to have sufficient power to appreciate a change in risk because individual alleles may be relatively common and even found in a majority of the population.2 An extremely stringent P-value (P<0.0001 or better) is required to minimize false-positives.11 A small number of polymorphisms associated with breast cancer risk have been noted in known breast cancer–associated genes. For example, a Pro919Ser polymorphism in BRIP1 is associated with an odds ratio of 1.39 (P=0.002) in premenopausal women but was

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Table 2. Breast Cancer Moderate-Penetrance Genes and Associated Breast Cancer Risks Gene

Gene Function

Breast Cancer Risk

Bi-allelic Phenotype

CHEK2

Protein kinase involved in cell cycle regulation at G2; rapidly phosphorylated in response to DNA damage; activated CHEK2 stabilizes p53 and interacts with BRCA1

Female: RR, 1.70; 95% CI, 1.3-2.2 Male: RR, 10.3; 95% CI, 3.5-30.0

None known –presumed to be embryonic lethal

BRIP1 (BACH1)

Interacts with the BRCA1 C-Terminus (BRCT) domain of BRCA1

All women: RR, 2.0; 95% CI, 1.2-3.2 Women younger than 50 y: RR, 3.5; 95% CI, 1.9-5.7

Fanconi anemia, type J –no significant increase in childhood cancers

ATM

Protein kinase involved in monitoring RR, 2.37; 95% CI, 1.5-3.8 and repair of dsDNA and regulation of BRCA1 and CHEK2

Ataxia-telangiectasia –autosomal recessive inheritance

PALB2

Associates with BRCA2. Involved in nuclear localization and stability

Fanconi anemia type N –higher incidence of childhood cancers

All women: RR, 2.3; 95% CI, 1.4-3.9 Women older than 50 y: RR, 3.0; 95% CI, 1.4-5.5

CI, confidence interval; RR, relative risk

not associated with an increased risk for breast cancer in the overall population.43 Often, low-penetrance SNPs are located in noncoding regions of the genome (eg, 2q35, 8q24), making it more difficult to identify an associated gene. The mutation mechanism may be activation of growth-promoting genes rather than inactivation of DNA repair. On average, each allele only mildly increases risk and is additive per allele rather than multiplicative, with a 1.07- to 1.26-fold increase in risk for heterozygotes and a 1.65-fold increase for homozygotes.2 The majority of studies thus far have focused on one or a few variants at a time. However, a recent large meta-analysis assessed the examined variants to date, excluding those in highly penetrant genes.44 This analysis excluded the first report of a variant, as well as small studies (<500 samples) and studies involving groups not deemed to be in Harvey-Weinberg equilibrium. Strong associations were seen for 10 variants across 6 genes—ATM, CASP8 (cysteineaspartic acid protease family with a role in apoptosis), CHEK2, CTLA4 (encodes an inhibitory signal to T cells, affecting carcinogenesis via anti-tumor immunity), NBN, and TP53—and moderate associations were seen for 4 variants across 4 genes—ATM, CYP19A1, TERT, and XRCC3. Odds ratios greater than 2 were seen for truncating mutations in ATM and NBN and for 3 rare variants in CHEK2. However, the remainder had a more minor calculated effect. Additional studies have not yet been published regarding the clinical application, frequency, or relative risk of these variants.44 Thus, evaluation for low-penetrance alleles is not part of standard clinical evaluation for breast cancer, and management of individuals found to carry

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these variants should be based on their estimated risk as calculated by validated risk assessment models, such as the Tyrer-Cuzick and Gail models.

Mutation Testing in Those With Suspected Hereditary Predisposition to Breast Cancer Individuals with a family and personal history suspicious for a familial syndrome should be referred to a genetic counselor for a comprehensive evaluation. Testing for mutations in cancer-associated genes is individually based, and requires a high index of suspicion for a particular gene based on the clinical situation. In general, when a family history is suggestive, it is best to test an individual with a cancer diagnosis because this increases the probability of a positive test result. Standard clinical BRCA1 and BRCA2 testing has been performed using polymerase chain reaction amplification and Sanger sequencing. For the Ashkenazi Jewish population, testing can be targeted to the 3 major founder mutations. In 2007, testing for large rearrangements was added for secondary analysis after research studies published the relatively frequent finding of missed large insertions and deletions.21,45 If a mutation is identified in one family member, targeted testing can be done for other members of the family to assess risk. With testing, possible outcomes are a true positive, a true negative (ie, an individual in a family with a known mutation tests negative for that mutation), uninformative (ie, a negative test in a family where a mutation has yet to be identified), or a variant of unknown significance (VUS). By definition, a VUS is a detected genetic change without good description of any correlating clinical risk.

In patients who test negative for mutations in BRCA1 and BRCA2 but in whom the family history is suggestive of an inherited predisposition, there are emerging options for additional evaluation. For example, the BROCA assay, developed by researchers at the University of Washington, is a 21-gene assay that includes the 10 previously mentioned high- and moderate-penetrance genes, the panel of genes known to predispose to colon cancer, and promising low-penetrance genes. With nextgeneration sequencing, multiple genes can be tested for mutations at a fraction of the cost of sequencing genes individually,45 and this may be useful in detecting mutation changes not identified by conventional sequencing, such as large rearrangements.46 This is especially helpful in patients with a more rare cause for their hereditary predisposition to cancer or women with a less obvious history, including those with fewer female relatives, paternal inheritance of the gene, and few other relatives who have inherited the predisposing gene.45 However, with more detailed genetic analysis, an increased amount of indeterminate information often is obtained. Thus, next-generation sequencing testing will require careful analysis and interpretation of VUS. As costs for genomic assays have decreased, the number of commercially available assays billed as personal genomic testing (PGT) has increased substantially, but our ability to interpret the results of these assays remains limited. A major concern with this new avenue of medical risk assessment is that patients and physicians often feel underinformed regarding the interpretation of results. In a survey of more than 10,000 physicians, 98% felt that PGT results may influence drug therapy, but only 10% believed they were adequately informed about how to interpret the results.47 In a survey of individuals who elected PGT testing, 10% discussed their results with the company genetic counselor and only 27% chose to share results with their physician, increasing risk that the test would be associated with inadequate counseling and interpretation.48 Limited data suggest that in the appropriate clinical setting, PGT can be effective in modulating clinical behavior.47

Conclusion A hereditary predisposition to breast cancer significantly influences screening, treatment, and surveillance recommendations. However, despite decades of medical research, less than 30% of cases with a suggestive personal and/or family history of hereditary breast cancer have an identified causative gene mutation. The vast majority of these cases are due to a mutation in one of the highly penetrant breast cancer genes (BRCA1, BRCA2, PTEN, TP53, CDH1, and STK11), and current guidelines provide concrete direction for the management of these patients. A minority of cases is due to mutations in moderate-penetrance genes (CHEK2, ATM, BRIP1, and PALB2). A small number of low-penetrance alleles have been identified using advanced genetic testing methods. Although these may contribute to risk

in a polygenic fashion, this is likely to be relevant to a minority of cases, and identification of these low-penetrance alleles is not part of routine practice patterns. In such patients, standard models are used to predict an individual’s lifetime risk by clinical history rather than genomic information. At this point, mutation testing requires a high index of suspicion for a specific contributing etiology, but next-generation sequencing may improve the identification of such genes and the clinical management of breast cancer.

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National Cancer Institute. Breast cancer. http://www.cancer.gov/ cancertopics/types/breast. Accessed March 5, 2013.

2. Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet. 2008;40(1):17-22, PMID: 18163131. 3. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250(4988):1684-1689, PMID: 2270482. 4. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265(5181):2088-2090, PMID: 8091231. 5. Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26(15):2568-2581, PMID: 18487574. 6. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002;20(9):2310-2318, PMID: 11981002. 7.

King MC, Marks JH, Mandell JB, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643-646, PMID: 14576434.

8. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004;22(4):735-742, PMID: 14966099. 9. No authors listed. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999;91(15):1310-1316, PMID: 10433620. 10. Thompson D, Easton DF. Breast cancer linkage C: cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94(18):13581365, PMID: 12237281. 11. Antoniou AC, Easton DF. Models of genetic susceptibility to breast cancer. Oncogene. 2006;25(43):5898-5905, PMID: 16998504. 12. Kwong A, Ng EK, Law FB, et al. Novel BRCA1 and BRCA2 genomic rearrangements in Southern Chinese breast/ovarian cancer patients. Breast Cancer Res Treat. 2012;136(35):931-933, PMID: 23099436. 13. FitzGerald MG, Marsh DJ, Wahrer D, et al. Germline mutations in PTEN are an infrequent cause of genetic predisposition to breast cancer. Oncogene. 1998;17(6):727-731, PMID: 9715274. 14. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400-407, PMID: 22252256. 15. Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Fraumeni JR Jr, Li FP. Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res. 1991;51(22):6094-6097, PMID: 1933872. 16. Rapakko K, Allinen M, Syrjakoski K, et al. Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites. Br J Cancer. 2001;84(1):116-119, PMID: 11139324. 17. Birch JM, Alston RD, McNally RJ, et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene. 2001;20(34):4621-4628, PMID: 11498785.

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18. Pharoah PD, Guilford P, Caldas C, International Gastric Cancer Linkage Consortium. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001;121(6): 1348-1353, PMID: 11729114. 19. Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med. 1998;128(11):896-899, PMID: 9634427. 20. Lim W, Olschwang S, Keller JJ, et al. Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology. 2004;126(7):1788-1794, PMID: 15188174. 21. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295(12):1379-1388, PMID: 16551709. 22. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Genetic/Familial High-Risk Assessment: Breast and Ovarian V.1.2012. http://www. nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed March 5, 2013. 23. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21):1616-1622, PMID: 12023993. 24. Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346(21):1609-1615, PMID: 12023992. 25. Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22(6):1055-1062, PMID: 14981104. 26. Reynolds C, Davidson JA, Lindor NM, et al. Prophylactic and therapeutic mastectomy in BRCA mutation carriers: can the nipple be preserved? Ann Surg Oncol. 2011;18(11):3102-3109, PMID: 21947588. 27. Gail MH, Costantino JP, Bryant J, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst. 1999;91(21):1829-1846, PMID: 10547390. 28. Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer. 2006;118(9):2281-2284, PMID: 16331614. 29. King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286(18):2251-2256, PMID: 11710890. 30. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-134, PMID: 19553641. 31. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31(1):55-59, PMID: 11967536. 32. Seal S, Thompson D, Renwick A, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38(11):1239-1241, PMID: 17033622.

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33. Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38(8):873-875, PMID: 16832357. 34. Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165-167, PMID: 17200668. 35. De Leeneer K, Van Bockstal M, De Brouwer S, et al. Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing. Breast Cancer Res Treat. 2012;133(1):393-398, PMID: 22370629. 36. Le Calvez-Kelm F, Oliver J, Damiola F, et al. RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry Study. PLoS One. 2012;7(12):e52374, PMID: 233300655. 37. He M, Di GH, Cao AY, et al. RAD50 and NBS1 are not likely to be susceptibility genes in Chinese non-BRCA1/2 hereditary breast cancer. Breast Cancer Res Treat. 2012;133(1):111-116, PMID: 21811815. 38. Shaag A, Walsh T, Renbaum P, et al. Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet. 2005;14(4):555-563, PMID: 15649950. 39. Vaz F, Hanenberg H, Schuster B, et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010;42(5): 406-409, PMID: 20400963. 40. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879-1886, PMID: 2593165. 41. Mainiero MB, Lourenco A, Mahoney MC, et al. ACR Appropriateness Criteria Breast Cancer Screening. J Am Coll Radiol. 2013;10:11-14, PMID: 23290667. 42. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75-89, PMID: 17392385. 43. Pabalan N, Jarjanazi H, Ozcelik H. Association between BRIP1 (BACH1) polymorphisms and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2013;137(2):553-558, PMID: 23225146. 44. Zhang B, Beeghly-Fadiel A, Long J, et al. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol. 2011;12(5):477-488, PMID: 21514219. 45. Walsh T, Lee MK, Casadei S, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A. 2010;107(28):12629-12633, PMID: 20616022. 46. Rouleau E, Jesson B, Briaux A, et al. Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition. Breast Cancer Res Treat. 2012;133(3):1179-1190, PMID: 22476849. 47. Riordan S, Rodriguez DF, Kieran S. Personal genomic testing as part of the complete breast cancer risk assessment: a case report. J Genet Couns. 2012;21(15):638-644, PMID: 22610652. 48. Bloss CS, Schork NJ, Topol EJ. Effect of direct-to-consumer genomewide profiling to assess disease risk. N Engl J Med. 2011;364(6):524-534, PMID: 21226570.

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REPORT Understanding Key Differences Between Biosimilars and Small Molecule Generics T

he majority of therapeutic agents used in clinical medicine today are traditional small molecule drugs (SMDs). However, biologics have become prominent in the treatment of many conditions and, over the past 2 decades, the development of biologics has revolutionized the treatment of many diseases, including anemia, diabetes, cancer, hepatitis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.1-3 More than 100 different biologic therapeutic agents have been approved for use in the United States, with many more in development.4 Because of the differences in size, complexity, and manufacturing methods between SMDs and biologics, there are unique considerations for the development and approval of biosimilars.

Small Molecule Drugs and Biologics SMDs are inorganic low-weight molecules (typically <1,000 Da) that can be fully characterized by analytical techniques. They produce a desired therapeutic effect via modulation of the structure and function of endogenous biologic materials, usually cell-surface receptors, intracellular signal transduction elements, or circulating proteins.2,5,6 Examples include acetylsalicylic acid and other oral medications. They are relatively stable and are introduced into the bloodstream via varied routes of administration.2 Because of their small size, they are generally

distributed widely throughout the body and can permeate cells, thereby exerting their action by modulating intracellular or extracellular elements.2,6 Biologics are proteins derived from living cells and are produced through various processes, such as recombinant DNA, controlled gene expression, or antibody methods (Figure 1).2,7 Examples include specific therapeutic agents such as human recombinant insulin and erythropoietin, as well as classes of agents such as growth hormones and monoclonal antibodies directed against cytokines or cell surface molecules.7,8 Biologics are produced in biotechnological processes via genetic modification of microorganisms, such as yeast or mammalian cell lines.9 Because of their complexity and vulnerability to degradation in the gastrointestinal tract, biologics are administered by injection or infusion.2 Similarly, because of their relatively large size (generally 5 to 200 kDa), most (but not all) biologics have a complex mechanism of action that targets multiple cell-surface sites and encounter more extracellular barriers than traditional SMDs (Figure 2).2,10-19 Because SMDs are synthesized through a series of chemical reactions, the manufacturing process can be reproduced in a fairly reliable manner to yield an identical end product, called a generic.2,9 In this article, generics refer to SMDs where the active ingredient is identical to the small molecule innovator product. Conversely,

Supported by

REPORT biologics are much larger and inherently more complex products produced in living systems (Table 1).2,9 Because of this, similar but not exact copies are possible, called biosimilars.2,9 The manufacture of biologics from unique cellular-expression systems requires extensive interdisciplinary effort and experience in molecular and cell biology, biochemistry, and protein, biochemical, and industrial engineering. There are many steps in the manufacturing process that can influence the purity, potency, clinical efficacy, and safety of the finished product.9,20 Since a protein can be folded in several ways to impart unique physicochemical and immunological characteristics, differences in the source and extraction purification processes can alter its 3-dimensional structure. These characteristics can be modified by post-translational changes such as glycosylation. Cells are sensitive to their culture environment and so are cultivated via a complex process with strict control of pH, temperature, and oxygen levels. Contaminants and impurities (eg, trace DNA, endotoxins, viral proteins, and unwanted host cell proteins) produced as a result of the manufacturing process are removed via several purification steps.9

Generic Drugs and Biosimilars Governments and regulatory agencies throughout the world have processes by which new SMDs can be manufactured and sold exclusively by the developer for a certain period of time. This system creates a favorable economic environment for the development of new SMDs by providing an avenue for the manufacturer to recoup research and development (R&D)

costs. However, after expiration of the patent period, other companies can develop and market generic formulations of the original SMD. Because development of generic compounds is associated with lower up-front R&D costs than development of innovator SMDs, they typically are less expensive, resulting in an economic incentive to payers and consumers to switch to the generic form of the drug.21 Because generics are SMDs where the active ingredient is chemically identical to the product they copy, the regulatory requirements for approval of a generic are more abbreviated when compared to the original innovator SMD. In the United States, an Abbreviated New Drug Application (ANDA) process, as outlined by the US Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act of 1984), states that large clinical trials for safety and efficacy are not required.22 Thus, companies that develop generic products can rely on the FDA’s previous findings of safety and effectiveness for the innovator drug, and the generic drug approval is based on the principles of “sameness” (ie, the same active ingredient, identical in dose, strength, route of administration, safety, efficacy, and intended use). 22 Large-scale clinical trials are not required and generic drugs only need to show bioequivalence to the innovator drugs typically based on pharmacokinetic parameters, such as the rate of absorption or bioavailability in at least 24 to 36 healthy volunteers. 22 Similar to the patent system for SMDs, developers can obtain exclusive rights to the manufacture and distribution of their innovator biologic agent for a period of time, thereby increasing

Cloning and Protein Expression Cloning into DNA Vector

Transfer into Host Cell Expression Screening/Selection

Source DNA

Target DNA Possibly same gene sequence

Probably different vector

Different cell expression system

Protein Production, Purification, and Validation Cell Expansion

Cell Production in Bioreactors

Recovery Through Filtration or Centrifugation

Purification Through Chromatography

Characterization and Stability

Purified Bulk Drug

Different cell line, growth media, method of expansion

Different cell line, growth media, bioreactor conditions

Different operating conditions

Different binding and elution conditions

Different methods, reagents, reference standards

Figure 1. Recombinant protein production: sources of variation between manufacturers. From reference 7.

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REPORT the likelihood of recouping up-front R&D costs.8,23-25 After expiration of the patent period, competitors have the option to develop and market “biosimilar” drugs. The FDA defines a biosimilar drug as “a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences from the approved biological product in terms of safety, purity, and potency.”26 While manufacturing steps may be similar between different manufacturers of biologics, they will not be identical. Moreover, because of differences in unique cell lines, glycosylation patterns, and the inherent sensitivity of the cells to differences in nutrients and environment, the same biologic manufactured by 2 different companies may be different in a number of ways.27 For this reason, regulatory authorities around the world have developed separate approval pathways for biosimilars. The rest of this review will discuss the global regulatory outlook for biologics and biosimilars and the development of an abbreviated regulatory pathway for biologics in the United States.

Global Regulatory Pathways For Biosimilars European Union The European Union has led the way in establishing regulations for biosimilars (sometimes called “follow-on biologics” in Europe), including a directive outlining the process to gain regulatory approval for these agents. In 2005, the European

SMD

Acetaminophen (151.16 kDa)

Union and the European Medicines Agency (EMA) established the first regulatory pathway for biosimilars that is distinct from the generic pathway.28 There are 3 scientific guidelines issued by the EMA that have established a process for demonstrating similarity between a biosimilar product and the reference innovator product.28 First, the EMA issued an overarching guideline in 2005 that defined biosimilars and established a process for demonstrating similarity between a biosimilar product and the reference innovator product. 29 The second guideline addressed quality issues (physiochemical properties, biological activity, and purity), and the third described nonclinical and clinical issues.30,31 A separate set of distinct guidelines established detailed data requirements for class-specific products, including recombinant follicle-stimulating hormone, recombinant interferon-beta, monoclonal antibodies, recombinant erythropoietins, low-molecular-weight heparins, recombinant interferon-alpha, recombinant granulocyte colony-stimulating factor, somatotropin, and recombinant human insulin.28 These class-specific guidelines outlined the non clinical and clinical requirements, and recommended study designs and postmarketing commitments. All of these guidelines, including updates, revisions, and appendices, are currently available through the EMA website (http://www. ema.europa.eu). The first biosimilars were approved and marketed in Europe in 2006, and there are currently 6 on the market, including 1 epoetin alfa, 3 filgrastims, 1 epoetin zeta, and 1 somatropin.32,33

Biologics

Leuprolide (1,229.44 kDa)

Urokinase (28,336.31 kDa)

Streptokinase (136,958.00 kDa)

Figure 2. Comparative molecular weights of representative biologics and SMDs. SMD, small molecule drug Adapted from references 13-19.

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REPORT Table 1. Comparison of Traditional Small Molecule Drugs and Biologic Agents Feature

Small Molecule Drug

Biologic Agent

Example

Acetylsalicylic acid (180 Da)

Monoclonal antibody (~150,000 Da)

Entity

Chemical

Protein

Structure

Small, simple, well characterized

Large, complex, heterogeneous

Stability

Stable

Unstable

Mode of administration

Usually amenable to ingestion

Usually requires injection or infusion

Manufacturing process

Predictable and precise method; identical copies in batches

Living cell-based complex technology; batch-tobatch variation, sensitive to storage and handling

Immunogenicity

Mostly nonimmunogenic

Immunogenic

Adapted from references 2 and 9.

The European framework has helped to guide thinking about requirements and issues for creating a pathway elsewhere in the world, including Korea, Japan, and Canada.34

World Health Organization The World Health Organization (WHO) plays an active role in fostering the development of regulatory guidelines for therapeutic agents in the interest of standardization of data requirements, thereby decreasing barriers to the international use of beneficial drugs. In doing so, the WHO issued guidelines for the evaluation of biosimilars (called Similar Biotherapeutic Products [SBPs] in its terminology) in October 2009, with a view toward ensuring better access to safe and effective SBPs worldwide through global harmonization of the regulatory framework for licensure.35 This guideline describes a stepwise approach, starting with characterization of quality attributes of the product, followed by nonclinical and clinical evaluations. The WHO guidelines indicate that manufacturers should submit a full quality dossier that includes a complete characterization of the product, the demonstration of consistent and robust manufacture of their product, and the comparability evaluation between the biosimilar and the reference biologic agent in the quality part, which together serve as the basis for the possible reduction in data requirements in the nonclinical and clinical development phases.35 (Full WHO guidelines are available at http://www.who.int/biologicals.)

United States Prior to 2010, the only approval pathway for a biosimilar was to file a full Biologic License Application (BLA) as a new biologic agent under 351(a) of the Public Health Service (PHS) Act. However, submission of the BLA could only be achieved after sufficient clinical trials had been performed to obtain marketing approval.36 At the end of March 2010, the United States enacted the Biologics Price Competition and Innovation (BPCI) Act (Table 2), amending the PHS Act to establish an alternate approval pathway for biological products that are highly similar to or interchangeable with an FDA-approved biologic drug, and giving the FDA the authority to approve biosimilars under

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the new section 351(k) of the PHS Act.34,37,38 Through this new approval pathway, biological products are approved based on demonstrating they are biosimilar to a biological product that is already approved by the FDA, which is called a reference product.26 The designation of interchangeability is one critical area in which the US law differs from that of the EU and all other jurisdictions. The law defines interchangeable to mean that the biosimilar product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.37,39 Once approved, most generic drugs can be substituted automatically for the reference product without the intervention of the healthcare provider in many states. However, for biosimilars, a product must be designated as interchangeable before such a substitution can occur automatically without any notification. To achieve the interchangability designation, a product is first determined to be a biosimilar, and then may be considered for a determination of interchangability with the reference product. Determination of interchangeability not only requires demonstration of biosimilarity, but also that the product is expected to produce the same clinical result in any given patient and presents no additional risk to safety or efficacy as a result of switching between the biosimilar and the reference product.37,39 On Feb. 9, 2012, the FDA announced the publication of draft guidance documents to assist the industry in developing biosimilar products.26 The abbreviated Biologic License Application pathway guidance consists of 3 documents, one each covering the scientific and quality considerations in demonstrating biosimilarity and the other a question and answer section discussing implementation of the BPCI Act (“Scientific Considerations in Demonstrating Biosimilarity to a Reference Product,” “Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product,” and “Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009,” respectively).40 Similar to the requirement of the EMA, a number of factors are considered important by the FDA when assessing

REPORT Table 2. Requirements of the Biologics Price Competition and Innovation Act of 2009 Issue

Requirements

Establishing biosimilarity

1. The biologic product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components. This determination is based on data from analytical studies, animal studies, and a clinical study or studies. 2. No clinically meaningful differences exist between the biological product and the reference product in terms of the safety, purity, and potency of the product.

Interchangeability

1. The biosimilar can be expected to produce the same clinical result as the reference product in any given patient. 2. For products that are administered more than once to the patient, switching between innovator and biosimilar products is safe and efficacious.

Mechanism of action

The biosimilar and the reference product have the same mechanism of action for the condition(s) prescribed, recommended, or suggested in the labeling.

Indications

The condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product has been previously approved for the reference product.

Route/dose/strength

The route of administration, dosage form, and strength of the biosimilar product are the same as those of the reference product.

Exclusivity

12 years of data exclusivity for innovator products.

Adapted from references 37 and 38.

applications for biosimilars, including the robustness of the manufacturing process; the demonstrated structural similarity; the extent to which the mechanism of action was understood; the existence of valid, mechanistically related pharmacodynamic (PD) assays; comparative pharmacokinetics (PK) and immunogenicity, and the amount of clinical data and experience available for the reference products.41 The FDA draft guidelines also are similar to those issued by the WHO in that they recommend a stepwise approach to establishing the comparability of the original biologic and its proposed biosimilars. This approach should begin with an extensive structural and functional characterization of the proposed biosimilar product and reference product. The more comprehensive and robust this characterization, the more useful such characterization will be in determining what additional studies may be needed. The sponsor should then consider the role of animal data in assessing toxicity as well as providing additional support for demonstrating biosimilarity. Comparative human PK and PD studies should be conducted in an appropriate population along with a consideration of the clinical immunogenicity to evaluate the potential incidence and severity of human responses. At each step, sponsors should assess the extent to which there may be residual uncertainties about the proposed biosimilarity and identify ways to address that uncertainty.41 Therefore, by integrating various types of information, including structure, function, animal toxicity, human PK and PD, human immunogenicity, and clinical safety and effectiveness, the FDA indicated that the agency wished to consider the “totality of the evidence� provided by the manufacturer.41 This suggests that, due to the complexity of biologics, the FDA will rely heavily on scientific justification and rationale when making decisions on what types of additional studies are needed for biosimilar approval.41

In the draft guidance it is noted that a clinical program for a 351(k) application must include a human trial or trials sufficient to demonstrate safety, purity, and potency in one or more appropriate indications for which the reference product is licensed. At least 2 trials generally will be required for a biosimilar, one examining the PK and PD and the other evaluating the safety and efficacy as well as addressing any immunogenicity issues.37,41

Considerations and Exceptions There are several considerations related to this abbreviated approval pathway. First, some older biologics, such as human recombinant insulin and growth hormone, were approved as new drugs through the New Drug Application 505(b)2 pathway, under the Federal Food, Drug, and Cosmetic Act. That act allows the FDA to rely on published scientific literature or its previous findings for similar products as the basis for approval.42,43 Thus, biosimilars of those older biologics might not necessarily follow the newer abbreviated approval pathway, but instead could be approved under an abbreviated pathway similar to that for generics. The FDA’s position on this is unclear. The second consideration is that some manufacturers have chosen to proceed with applications for regulatory approval through the BLA pathway designed for innovator biologic agents.36 As an example, the biologic agent, Tbo-filgrastim (XM02 filgrastim) for the management of neutropenia, was submitted and approved under the standard BLA in the United States in August 2012.44 The third consideration is that the draft guidance documents indicate that the FDA has not settled some important biosimilars policy questions, including exact requirements for demonstrating interchangeability of a biosimilar with a reference product.45,46 Thus, while the FDA continues to consider

5

REPORT what type of information ultimately will be required to demonstrate interchangeability, manufacturers seeking an interchangeable designation for their biosimilar product likely will be required to provide a higher level of data than for a biosimilar approval without an interchangeable desgination.45,46 Currently, state laws provide guidance for pharmacists regarding substitution of generics with or without consulting the provider. Once the FDA has established detailed guidelines for interchangeability, there may be similar regulation for biologics at the state level.47

Pharmacovigilance As biosimilars become available, it will be important to determine how adverse events (AEs) will be tracked and accurately attributed to the correct product and manufacturer.27 Ideally, a method to accurately record the specific drug, manufacturer, and drug lot would be optimal. This will require an evolution in health technology platforms to capture and seamlessly provide this information to treating health care professionals, manufacturers, and regulatory bodies. Until that time, collection of accurate post-approval data will rely on product identifiers to distinguish between biologic products.41 According to the EMA, elements of a proposed biosimilar pharmacovigilance system include qualified staff, identification of the organization and locations of activities and databases, documented data collection procedures, and mandatory reporting of individual case safety and general safety updates.48 In 2002, the EMA introduced the European Risk Management Strategy, a program aimed at strengthening safety monitoring of medical products by promoting early detection, assessment, minimization, and communication of risks. Even though the EMA guideline addresses a host of issues surrounding biosimilars, national and local involvement still will be necessary.49 The current EU and US pharmacovigilance systems rely heavily on voluntary and spontaneous reporting. However, only a minority of AEs are ever reported and the quality of these reports may vary and do not always identify the product in question.50,51 Improvements in these systems will depend on the ability of the reporter (either health care provider or patient) to correctly identify and report the associated product. A robust post-approval safety surveillance program will have to include precise AE tracking and tracing capabilities to detect and evaluate potential safety issues and promote efficient and coordinated responses. This will be predicated on the requirement of specific nomenclature of each biosimilar, including a unique nonproprietary name, Healthcare Common Procedure Coding System (HCPCS)/ National Drug Code (NDC), and lot number.7,51-53 The FDA has not released a guideline on how biosimilars will be named. Generics do not go through the U.S. Adopted Names Council process and are automatically assigned the same nonproprietary name as the innovator product. The challenge of biosimilars is that each innovator biologic agent may have multiple biosimilars, and each of those biosimilars can have its own variant characteristics.54 Thus, a distinguishable United States Adopted Name may aid in keeping product post-approval data distinct. Protocol-based switching between SMDs and their formulary generic or nongeneric equivalents is an important and widespread strategy within health care systems as a method of containing costs. Due to potential differences, switching between innovator biologics and biosimilars will require a much

6

more comprehensive formulary decision-making process than generic substitution, taking into account whether the FDA has determined a product to be interchangeable.7 This decision process may involve reviewing available data and indications as well as considerations including manufacturer services. The ability of a manufacturer to provide consistent supply is an important consideration.55 Potential switching also poses challenges for tracking which product a patient has received, making attribution of AEs difficult.53 This is especially important if the immunogenicity profile of the product changes over time. The current surveillance methods available are limited in that they only allow for qualitative event signals and do not indicate the frequency of an AE in a given population.52 Systematic and ongoing safety monitoring systems will be necessary to recognize and evaluate the effect of intrinsic differences in immunogenicity and the detection of rare AEs unique to a particular product.51,52,56 These systems would be practical and encourage reporting by healthcare professionals, provide manufacturers with a framework to monitor and report events, and ensure traceability of AEs to the specific product in question.53

Pharmacy Education on Biosimilars The clinical use of biosimilars is a new and complex field, and the standards of care regarding their use have not been definitively established. Pharmacists will play a vital role in directing the use of biosimilars and in disseminating information to the other members of the clinical team. Yet, there is a significant knowledge gap for health care professionals with regard to regulatory pathways; a survey of 277 physicians, nurses and pharmacists, and other clinicians conducted by the National Comprehensive Cancer Network (NCCN) Work Group revealed that more than half were either not at all familiar or only slightly familiar with recent developments surrounding biosimilars, a fact that points to the necessity of education about these medications.27 Marcie Bough, senior director of government affairs, American Pharmacists Association, who spoke to the FDA during a public hearing in 2012, echoed this sentiment, commenting, “Pharmacists need additional guidance on the handling of biosimilar products in the pharmacy when these products become more widely available following the approval of the biosimilar pathway.�57 It is incumbent on pharmacists to familiarize themselves with the regulatory and clinical aspects regarding biosimilars. The American Society of Health-System Pharmacists (ASHP) is highly engaged in advising the FDA in establishing the biosimilar regulatory process, with the goal of assuring that patients have access to safe, effective, and less expensive biologic therapies. ASHP has launched an educational initiative (http://www. biosimcentral.org) to provide an in-depth review of the various clinical and regulatory aspects concerning the introduction of biosimilars in the United States. A primer on biosimilars also is available online (http://www.ashpmedia.org/symposia/biosimseries/primer), and ongoing continuing education opportunities are available at ASHP meetings.

Conclusion Biologic therapeutics have revolutionized the treatment of many diseases, and biosimilars will have similar therapeutic efficacy with potentially lower costs to the health care system. The

REPORT complexity of the manufacture of biologics makes the development of biosimilars more complex than the development of generics. Because of this complexity, the regulatory pathway required for biosimilar approval is distinct. The EMA and the WHO paved the way in establishing regulatory guidelines for biosimilars. The FDA draft guidelines emphasize a “totality of evidence” approach by which various types of information, including structural and functional characterization, nonclinical evaluation, human PK and PD data, clinical immunogenicity

data, and clinical safety and effectiveness data will be considered as part of a biosimilar application. Biosimilars will likely require a more extensive formulary evaluation than generics when used for protocol-based switching, and pharmacists will play a key role in considering the available data, indications, and other considerations. Pharmacists will also play an important role in establishing systematic and ongoing safety monitoring systems to detect AEs and attribute them to the respective product as biosimilars enter the larger patient population.

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Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Amgen, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature. Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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