The November 2012 Digital Edition of Pharmacy Practice New by McMahon Group

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The Pharmacist’s News Source

pharmacypracticenews.com Printer-friendly versions available online

in this issue OPERATIONS & MGMT

6 10

Centers of excellence revamp care transitions, cut 30-day hospital readmissions.

A pharmacisthospitalist partnership improves patient care and reduces cost.

CLINICAL

24 28

Pharmacogenetics, nanotechnology prove fertile ground for 2012 ASHP Foundation Literature Awardees. ISMP webinar: data-mining voluntary medication error reports may be key to boosting opioid safety.

TECHNOLOGY

Why it’s time to close the medication safety loop in emergency departments.

EDUCATIONAL REVIEW

Management of Gastroesophageal Reﬂux Disease See page 35.

40th ANNIVERSARY YEAR 1972–2012

After NECC, Whom Can You Trust?

Chicago hospital’s strategy for enhancing accuracy, safety of warfarin dosing.

Volum me 39 • Number 11 • November 2012

lthough the clinical fallout from the largest outbreak of illness ever tied to a pharmacy compounder is alarming, it may be the most straightforward to document. By Nov. 1, nearly 350 patients treated with an injectable steroid prepared by the New England Compounding Center (NECC) had been infected, with 29 fatalities reported in 19 states, according to health officials.

‘This is what keeps pharmacy directors up at night.’ —Tom Van Hassel, RPh, MPA But those numbers haven’t helped clear up more challenging questions. How, for example, could the Framingham, Mass., facility have been allowed to mass-produce compounded drugs and ship them across state lines, potentially in violation of state pharmacy laws? And why was NECC allowed to operate despite a history of safety violations—some involving the same steroid that has been implicated in the current outbreak? State boards of pharmacy, the FDA and compounding pharmacy trade associations have been cast as villains in allowing this regulatory morass to persist. With no fixes likely to emerge anytime soon—aside from NECC shuttered and Ameridose, which shares owners with NECC, voluntarily recalling all of its products—a more immediate question now looms for health systems that still need to buy compounded medications: Whom can you trust? “That’s certainly one of the key

•

see MENINGITIS, page 40

On the CUSP of Eliminating Central-Line Infections Pharmacists playy integral role in multidisciplinaryy effort

comprehensive unitt-based safety program reduced d central line–associated blood dstream infections by 40% in 1,100 intensive care uniits between 2008 and 20112. Some of the ICUs have remained free of these infections for more than two years—a statistic once thought unattainable by many clinicians. “With these resultts, health care is takingg a giant step forward,” saaid Peter Pronovost, MD, P PhD, the senior vice presid dent for patient safety and quality ty at Johns Hopkins Medicine, in Baltimore, who created the comprehensive unit-based safety program (CUSP). After initial evaluation of the program at Johns Hopkins in 2001,

CUSP was investigated at 100 centers in Michigan g between 2003 and 2005, and then promoted nationwide by the Agency for Healthcare Research and Quality (AHRQ).

•

see CLABSIs, page 46

The Great Opioid Debate: PROP, PROMPT Square Off

hould the reins be tightened ened on the use of long-term opioid o therapy for patients with chrronic noncancer pain (CNCP)? That question is at the heaart of a controversy that has boilled over since July when 37 phyysicians in pain management, public health, psychiatry and other specialties issued a citizen petition calling on the FDA to require opioid label changes that would strike the word “moderate” from

The Book Page Handbook on Injectable Drugs: 17th Edition

CNCP opioid treatment indications and limit the drug’s use solely to severe pain—and then only for a maximum of 90 days at no more than the equivalent of 100 mg of morphine daily. The petition from Physicians for Responsible Opioid Prescribing (PROP) cited growing U.S. rates of opioid addiction and overdose deaths along with

•

see OPIOID DEBATE page 26

New Product

Lawrence A. Trissel, FASHP

CareFusion, Cerner announce Pyxis Medstation® 4000 system and the Cerner Millennium® EMR.

See page 49.

See page 16.

Give me solutions that help simplify and standardize processes. With so many variables to balance, pharmacists rely on CareFusion to provide a comprehensive medication management solution that ®

helps hospitals save time, lower costs and prevent medication errors at all points of care. The Pyxis ES platform—the next generation of Pyxis solutions—enhances the medication management process through meaningful integration. From providing secure inventory management to efficiently tracking meds to providing web-based system management, our solutions help you keep meds moving, to keep clinicians focused on patient care and satisfaction. That’s the CareFusion difference. Join us at ASHP booth 1949 to see the next offering on the Pyxis ES platform! Visit carefusion.com/ASHPconference to learn more.

Pyxis

© 2012 CareFusion Corporation or one of its subsidiaries. All rights reserved. Pyxis, CareFusion and the CareFusion logo are trademarks or registered trademarks of CareFusion Corporation or one of its subsidiaries. DI738

Up Front 3

Pharmacy Practice News • November 2012

Capsules

Abraxane Approved for Advanced NSCLC

surf

NOVEMBER 2012

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Scope of Meningitis Outbreak Widens (web version)

he FDA has approved Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) for a new indication, first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), the manufacturer, Celgene Corp., recently announced. The medication is to be used in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy. This is the second approved indication for Abraxane; the drug was first approved in 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy.

2. Med Management Standards from JC Still a Challenge 3. FDA Denies Being To Blame for Drug Shortages 4. Automation Shines Light on ‘Black Hole’ of OR Drugs 5. Vancomycin Plus Piperacillin-Tazo May Trigger Acute Kidney Injury Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here

“I was certainly surprised at the variety of products we were purchasing from

first

[NECC]. So we are taking a hard look at our purchasing processes for all of our

compounded medications.” See article, page 43

—Anonymous pharmacy director from a health system in the northeast

According to a Celgene press release, a Phase III, multicenter, randomized openlabel study divided patients with advanced NSCLC into two groups: one group received Abraxane (100 mg/m2) weekly plus carboplatin (area under the curve [AUC]=6) every three weeks (n=521); the other group received paclitaxel (200 mg/ m2) every three weeks plus carboplatin (AUC=6) (n=531). The study met its primary end point, with patients in the Abraxane group showing a higher overall response rate than those in the paclitaxel group (33% vs. 25%). Abraxane demonstrated a higher overall response rate than paclitaxel for squamous cell carcinoma (41% vs. 24%) and large cell carcinoma (33% vs. 15%). For carcinoma/adenocarcinoma, the overall response rate for Abraxane and paclitaxel was similar (26% vs. 27%). The most common adverse reactions (≥20%) of Abraxane in combination with carboplatin for NSCLC are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea and fatigue. Abraxane carries a boxed warning regarding neutropenia. “Non-small cell is the most common type of lung cancer, the leading cause of cancer death in the United States,” Mark A. Socinski, MD, the director of the Lung Cancer Section in the Division of Hematology/Oncology at the University of Pittsburgh, and the lead investigator of Abraxane lung cancer Phase II and III trials, said in a statement. “The FDA approval of Abraxane is exciting for health care professionals because it offers an important new treatment option for all types of non-small cell lung cancer patients, in an area that has seen few treatment advancements in recent years.” —George Ochoa

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, Boston, MA

Volume 39 • Number 11 • November 2012 • 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, BCPP, FASHP, FCCP, Spokane, WA 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

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

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TECHNOLOGY

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Thomas Van Hassel, RPh, Yuma, AZ

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

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4 Up Front

Pharmacy Practice News • November 2012

Events

A Clinton Hug Coming to Vegas T

he 47th Midyear Clinical Meeting and Exhibition of the American Society of Health-System Pharmacists (ASHP) opens Sunday, Dec. 2, in Las Vegas. The five-day meeting—the largest gathering of pharmacy professionals in the world—is expected to draw more than 20,000 hospital pharmacists and pharmacy technicians, pharmacy leaders and related professionals. Former President Bill Clinton will give the keynote speech at the conference’s official opening session on Monday. His address, “Embracing our Common Humanity,” will describe the challenge of globalization; emphasize the world’s growing interdependence; and point the way toward a common future based on shared goals and values. Also at the opening session, the ASHP will bestow its Board of Directors Award of Honor to June L. Dahl, PhD, a professor of neuroscience at the University of Wisconsin School of Medicine and Public Health, in Madison, for her extraordinary contributions to the field of pain management. At the heart of the meeting are dozens of educational sessions, workshops, symposia, networking sessions and case studies that reach across a spectrum of topics essential to contemporary pharmacy practice. “We always strive to include the hottest subjects and the most important developments at this meeting,” said JoAnn Harris, RPh, MBA, ASHP’s director of educational services. “That includes the Pharmacy Practice Model Initiative [PPMI], medication safe-

Former President Bill Clinton’s keynote speech, “Embracing our Common Humanity,” will help kick off the 2012 ASHP Midyear Clinical Meeting.

ty, practice management and leadership, pharmacy processes, informatics, career development, residency training, the fast-growing specialties of ambulatory care and emergency medicine pharmacy, and medical breakthroughs.” The Spotlight on Science lecture on Wednesday features Mansoor M. Amiji, PhD, RPh, a distinguished professor and the chairman of the Department of Pharmaceutical Sciences at Northeastern University’s School of Pharmacy, in Boston. In his talk, “Nanotechnology in Medicine: How Very Tiny Solutions Can Impact Big Problems,” Dr. Amiji will explain the latest advances in

Come See Us at Booth #1638 Be sure to pick up one of our Special Projects and Publications At the ASHP meeting, we’re giving away free copies of our annual Special Edition, as well as medical education resources on ESA therapy, immune globulins, and more. Plus, our publication team welcomes meeting with readers, so stop by our booth and say hello!

biocompatible materials, from natural and synthetic polymers; target-specific drug and gene delivery systems for cancer and infectious diseases; and nanotechnology applications for medical diagnosis, imaging and therapy.

PPMI Remains a Key Focus The PPMI once again occupies a prominent place at the conference. A number of sessions incorporate various facets of the pioneering framework that has already begun to change the course of pharmacy practice. In Thursday’s session, “Strategies Worth Sharing: Practice Innovations,” clini-

cians and managers from various settings will describe how they adopted elements of PPMI recommendations into the workplace, and describe common barriers to PPMI advancement, explained program chair Jennifer Edwards-Schultz, PharmD, FASHP, the pharmacy residency program director and a clinical pharmacist at Bozeman Deaconess Hospital, in Montana. The speakers will tackle an assortment of PPMI recommendations, including those that deal with ambulatory care, pharmacy practice management, informatics, new practitioners and pharmacy students. “Last year, PPMI was still very new, so we took a broad view: here’s where we want to go and here are some ideas,” Dr. Edwards-Schultz said. “This time around, we’ve asked people who have actually implemented elements of PPMI to share their experiences—their successes and the challenges they faced—and perhaps inspire others to advance the PPMI process within their institutions.” Medication safety, as always, is another conspicuous theme. The poignant Monday session, “The Emily Jerry Story: Lessons Learned from a Fatal Medication Error,” will revisit a tragedy that rocked the profession. In 2006, 2-year-old Emily died after a catastrophic dosing error. Christopher Jerry, Emily’s father and founder of the Emily Jerry Foundation, and Eric Cropp, BSPharm, who was the supervising pharmacist on duty when a

•

see VEGAS, page 8

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6 Operations & Management

Pharmacy Practice News â&#x20AC;˘ November 2012

Practice Pearls

Advances in personalized medicine:

A Team Approach to Warfarin Pharmacogenetics Larisa Cavallari, PharmD, FCCP Associate Professor Department of Pharmacy Practice

Edith Nutescu, PharmD, FCCP Clinical Professor Departments of Pharmacy Practice and Administration College of Pharmacy University of Illinois at Chicago Hospital & Health Sciences System Chicago, Illinois

lthough it has been used for more than 60 years, warfarin remains a difficult drug to manage due to its narrow therapeutic index and the wide interpatient variability in its dose requirements. The VKORC1 and CYP2C9 genotypes together account for approximately 25% to 30% of the interpatient warfarin dose variability. Guiding warfarin dosing using VKORC1 and CYP2C9 genetic information has the potential to improve dosing accuracy and shorten the time to dose stabilization, thus reducing the risk for adverse bleeding and thrombotic events during warfarin initiation. How-

ever, the translation of warfarin genetic data into clinical practice has been slow to catch on. The nuances of considering both genetic and clinical factors for warfarin dose estimation requires a level of expertise to support clinical decision making that can be best provided via a specialized clinical pharmacogenetics service. Thus, to potentially improve warfarin dosing and safety, we developed a coordinated, genotype-guided dosing and management approach for patients newly initiating warfarin at the University of Illinois Hospital & Health Sciences System (UI-Health). We formed a multidisciplinary team, consisting of experts in pharmacogenetics, anticoagulation, clinical pathology, and clinical decision support, to develop genotype and clinical strategies for implementing warfarin genetics at UI-Health. Specific responsibilities of the pharmacogenetics team are listed in Table 1. Members of the team also serve as co-directors of the newly formed warfarin genetics consult service, which serves an integral role in translating genetic information in the context of clinical factors to provide an informed warfarin dose recommendation to the

Table 1. Responsibilities of Warfarin Pharmacogenetics Service Select genotyping methodology. Validate genetic tests. Build the information technology infrastructure to support genetic testing. Coordinate provider education. Provide consultative services. Serve as an information resource to support clinical decision making. Explore methods to improve workflow. Examine use of ancestry-specific dosing models.

Time received

Figure. Pharmacogenetics Consult Service workflow. CDS, clinical decision support; MP, molecular pathology; PGx, pharmacogenomic a

CDS rules: new order for warfarin (any indication, inpatient or 23-hour, no warfarin order within 6 months, no prior warfarin PGx test).

primary medical team. A supporting website provides resources and guidance on pharmacogenetics-based dosing and links to the UI Health Warfarin Clinical Care Guidelines. As of August 2012, all patients newly starting warfarin while hospitalized at UI-Health are routinely genotyped for variants influencing warfarin dose requirements. Each genotyping order is accompanied by an automatic consult with the warfarin genetics consult service (Figure). An automatic order for warfarin genotyping and consultation with the pharmacogenetics service is initiated in response to a warfarin order for a patient with no warfarin order documented in the medical record within the previous 6 months. At the time of the new warfarin order, an alert appears to notify the ordering physician that genetic testing and consultation are now routine for new patients starting warfarin. A residency-trained pharmacy fellow screens each genotype order for appropriateness, by checking whether the patient was receiving warfarin on admission. If

â&#x20AC;˘

see WARFARIN, page 8

Sometimes appearances are everything. New FDA-approved IV premix drug labeling from Baxter. To help reduce medication errors due to incorrect drug selection, we redesigned the labeling for some of our most widely used liquid premix medications. We decreased the clutter and placed information in a consistent manner. Contact your Baxter sales representative to see how with change comes clarity.

Drug delivery from Baxter Healthcare Corporation. ASHP Booth 1025. Doing our part, so you can do yours.

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8 Operations & Management

Pharmacy Practice News • November 2012

Practice Pearls

WARFARIN continued from page 6

the patient was, the fellow cancels the genotype and consult order and provides a note in the medical record to this effect. For genotyping orders deemed appropriate, the phlebotomy service draws blood, and the blood is sent to the CLIA-certified laboratory for genotyping. The aim is to have the genotype result available prior to the second warfarin dose. Table 2 shows the genotypes tested and related clinical consequences. Once the patient’s genotype is available, the pharmacy fellow initiates a consult note, discusses the case with the medical team, and estimates a warfarin maintenance dose based on genotype and clinical factors. A medical fellow from either the cardiology or hematology ser-

VEGAS continued from page 4

technician made the fatal chemotherapy compounding error, are among the presenters. Mr. Cropp lost his pharmacy license and served prison time after being convicted of involuntary manslaughter. He now serves as a patient and caregiver advocate for the foundation. In their unlikely partnership, the two men have teamed up to encourage hospitals to take concrete actions that reduce human errors in pharmacy systems. “The primary message that Eric and I want to convey is that the medical community must not focus on the criminalization of medication errors,” Mr. Jerry said. “That takes the focus off fixing the real problem, which is that the system failed. What happened to Eric Cropp set a horrible precedent going forward.” The other speakers will be Michael R. Cohen, RPh, MS, the president of the Institute for Safe Medication Practices (ISMP), and Douglas J. Scheckelhoff, MS, ASHP’s vice president for professional development.

ISMP To Highlight Top 10 Medication Safety Issues Wednesday also will feature “Top Ten Medication Safety Issues Related to Hospital Accreditation Standards,” presented

Table 2. Genotypes Interrogated And Effect on Warfarin Dose Gene

Variant(s)

Effect on Warfarin Dose

VKORC1

-1639G>A

AA genotype: decreased dose requirement (approximately 3 mg/d) AG genotype: intermediate dose requirement (approximately 5 mg/d) GG genotype: increased dose requirement (approximately 6 mg/d)

CYP2C9

*2, *3, *5, *6, *11, *14, *15, *16

Decreased warfarin dose requirement (by approximately 20% to 30% per allele)

vice then assesses the patient, addends the pharmacy fellow’s note, and forwards the completed note to the attending physician for signature. The pharmacy fellow continues to provide a daily dose recommendation until the patient is dis-

charged or reaches stable international normalized ratio. A pharmacy faculty member provides attending oversight to the pharmacy fellows and manages daily issues related to the service. To our knowledge, the UI-Health ini-

by noted drug safety expert Darryl S. Rich, PharmD, MBA, FASHP, a medication safety specialist with the ISMP. Dr. Rich will describe strategies for tackling the most problematic and potentially dangerous safety issues that also are cited frequently by the Joint Commission during accreditation surveys. A prime example: Many facilities do not include opioids on their list of high-alert drugs, even though they top the list for causing serious errors among hospitalized patients, Dr. Rich said. Ambulatory care is among the emerging practice areas represented at the meeting. The “Super Sunday” workshop, “Ambulatory Care Review Course Intensives,” offers six hours of highlevel programming for board-certified ambulatory care pharmacists. Attendees also can take the recertification exam. (This workshop requires additional fees.) “We’ll also have quite a few regular educational sessions for ambulatory care pharmacists,” Ms. Harris said. The growing importance of emergency medicine pharmacy also is reflected on the schedule. At the Wednesday session, “Hot Topics in Emergency Medicine,” experts will discuss important emergency interventions such as thrombolytics for pulmonary embolism, and high-dose insulin therapy and intralipids for overdose patients,

according to Daniel Hays, PharmD, BCPS, FASHP, the clinical coordinator of Emergency Pharmacy Services in the Departments of Pharmacy and Emergency Medicine at the University of Arizona Health Network. “We’ve put together an advanced-level program for pharmacists currently practicing in the realm of emergency medicine or are interested in doing so,” he said. “When I started, very few pharmacists practiced emergency medicine. Now there are a few hundred or more—still a relatively small number, but an impressive growth rate.” Also on Wednesday, Dr. Hays will moderate “Emergency Medicine Pearls.” Each pearl comprises a three- to five-minute presentation that conveys a single useful idea or concept about clinical pharmacotherapy but may not be widely known or understood.

Idea Sharing for Residency Preceptors At another Wednesday session, “Residency Precepting: Strategies Worth Sharing,” speakers will offer ideas that residency program directors and preceptors can use to create highly productive residency experiences, according to program chair John E. Murphy, PharmD, a professor of pharmacy practice and science and associate dean at The Uni-

tiative to implement warfarin pharmacogenetics is among the first in the nation and is consistent with our commitment to providing personalized medicine and translating genetic information into optimal medication management. Our population consists largely of patients of African ancestry or Hispanic ethnicity. Thus, implementation of warfarin pharmacogenetics at our institution provides a unique opportunity to examine the feasibility and optimize the delivery of genotype-guided medicine to underrepresented patient populations. Our ultimate goal is to provide personalized medication to reduce health care disparities and improve outcomes in our underserved population. Drs. Cavallari and Nutescu reported no relevant ﬁnancial conﬂicts of interest.

versity of Arizona College of Pharmacy, in Phoenix. Dr. Murphy himself will explore how preceptors can shepherd residents toward residency projects that truly make a difference for themselves and their institutions and that can be completed comfortably within the time limitations of the program. “I think it’s best when preceptors help residents choose a project they really want to do,” he said. Other topics will include how to refine the orientation process to ensure that residents are thoroughly prepared for what lies ahead and to find the most effective ways to assess residents’ performance. The meeting pays special attention to pharmacists who have recently started their careers. At the premeeting workshop that runs Saturday and Sunday, “Great Expectations for New Practitioners,” pharmacists with fewer than five years in the profession can explore workplace challenges, mentorship and clinical issues in an encouraging, motivational atmosphere. Day 1 covers career management, such as navigating hospital politics and publishing and conquering certification exams. Day 2 is dedicated to improving clinical skills, regardless of practice area. Participation is included in the conference registration fee. —Steve Frandzel

If you missed any recent issues of Pharmacy Practice News, visit www.pharmacypracticenews.com.

WE’VE SPENT

20 YEARS AND 3 DAYS FIXATING ON ACCIDENTS THAT OCCUR

IN THE BLINK OF AN EYE BUT WHO’S COUNTING?

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10 Operations & Management

Pharmacy Practice News • November 2012

Care Transitions

Support Care Transitions With Smart Use of Time and Energy

osemont, Ill.—Pharmacists can capitalize on the strengths of their hospitals to foster improvements in transitions of care, according to presentations at the annual American Society of Health-System Pharmacists (ASHP) leadership conference. Find the people in your organization who are innovating in ways that support accountable care and effective care transitions, and capitalize on those

efforts with your own ideas, initiative and expertise, urged speaker Lindsey R. Kelley, PharmD, MS, the coordinator of ambulatory pharmacy initiatives and transitions of care at the University of Michigan Hospital and Health System (UMHS), in Ann Arbor. This year’s meeting, themed “Leading the Pharmacy Enterprise: Advancing Practice with Transitions in Health Care,” included a breakout session

devoted to helping pharmacists define their roles in improving care transitions. During the session, Dr. Kelley encouraged pharmacy leaders to use an “opportunistic” approach—to identify places where innovation around accountable care is already happening—and then to build on that work, with an eye on the smart use of pharmacists’ time and energy, “so that you are the best steward of your resources.”

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For example, said Dr. Kelley, “it’s possible that you might get involved with medication reconciliation. It’s possible that you might get involved with care coordination. It depends on … the strengths of your organization and the areas of opportunity. If the strength already exists, see if you can … partner with the people who are already doing it. You don’t … have to reinvent the wheel,” she said. At UMHS, Dr. Kelley and her colleagues saw an opportunity in the physician group practice demonstration that has served as the prototype for the institution’s accountable care organization (ACO). Following the completion of a successful pharmacist-driven pilot project, pharmacists now have scheduled, 30-minute, face-to-face visits or 15- to 30-minute phone consultations with patients at 14 of the system’s general medicine health centers, “and they bill for these visits,” said Dr. Kelley. Preliminary data from the first year showed that patients with a baseline A1c >7.0% (n=270) experienced a mean decrease in A1c of 0.8% (95% CI 0.6-1.0; P<0.001). Higher risk patients with a baseline A1c >9.0% (n=118) experienced a mean decrease of 1.4% (95% CI 1.1-1.8; P<0.001). In addition, pharmacists generated $150,000 in revenue during the first year in billings. Pharmacists participate in interdisciplinary care with physicians and nurses, verify orders, answer patients’ medication-related questions, lead inservices for nurses and handle medication reconciliation and other tasks. “The preliminary data is meaningful to the clinic because they’re meeting their goals,” she said. “And they’re doing it through pharmacist work. I think this is the way that we demonstrate our value and we continue to grow.” Several of the institutions recently cited for “best practices” by the Medication Management in Care Transitions Project (MMCT) of the American Pharmacists Association and ASHP employ similar strategies, according to Cynthia Reilly, BS Pharm, the director of practice development at ASHP (sidebar). “A lot of what I see in some of these care transition winners is the way in which they’ve bundled [interventions], really taking a comprehensive approach to care transitions,” she said. Several organizations have built on established medication reconciliation programs, for example, “and extended that outreach to the community,” noted Ms. Reilly. “So seven, 10, 15, sometimes even 30 days after the patient has been discharged, they are reaching out to patients to try to prevent readmissions by assuring that [patients are] under-

Operations & Management 11

Pharmacy Practice News • November 2012

Care Transitions standing how to use their medications correctly. In several of the programs, we’re seeing the same pharmacist who took care of the patient in the inpatient setting doing that intervention” to enhance continuity of care, she said. “Medicare drives what we do” for clear reasons, said Dr. Kelley. Research shows that 19.6% of Medicare patients are rehospitalized within 30 days of discharge; up to 19% of patients experience adverse events within five weeks of discharge, and approximately 66% of those adverse events are medicationrelated ((N Engl J Med d 2009;360:14181428; Ann Intern Med d 2003;138:161-167; Ann Intern Med d 2005;20:317-323).

iation performed by a medical assistant in the clinic’s hallway during patient check-in. The enhanced pharmacistled protocol includes phone calls to patients one to three days before clinic visits by pharmacy technicians. These technicians have physician authorization to enter updated information directly into the electronic medical record (EMR). The technicians also report changes and discrepancies to physicians via the EMR. A key component of the intervention is structured training for the medi-

cal assistants and pharmacy technicians on medication history taking and medication reconciliation, Dr. Kelley said. If a technician is not able to reach a patient by phone before a visit, an “enhanced” (trained) medical assistant takes the medication history in the examination room. The initiative illustrates the intelligent stewardship of pharmacy resources because pharmacists are using their expertise to drive process improvement rather than to perform all of the “handson” work of medication reconciliation.

In some instances, the best strategy is to use the people who are already doing the work, Dr. Kelley said. That approach reflects the goals and intent of ASHP’s Pharmacy Practice Model Initiative, which emphasizes “the idea of everyone working at the top of their license,” Dr. Kelley said in an interview with Pharmacy Practice News. “I really like that. It really engages staff. It encourages them to think of ways to be better and make the best use of their brain.” —Susan Birk

Outpatient Geriatrics a Focus At UMHS, a pharmacist spotted opportunities to address these medication-related issues in the outpatient geriatric clinic, and developed a multifaceted intervention to increase the accuracy and completeness of medication histories that involves providers, pharmacy technicians, pharmacy interns and medical assistants. “Usual care” consisted of medication reconcil-

‘Best Practices’ In Care Transitions

he American Pharmacists Association and the American Society of Health-System Pharmacists have recognized eight hospitalbased pharmacy programs for innovation in the area of care transitions through the Medication Management in Care Transitions Project. The “best practices” developed by these institutions will be shared with health care providers and organizations, government agencies and other stakeholders in a report published later this year. Case studies also will be presented in a session at the ASHP Midyear Meeting, Dec. 2-6, in Las Vegas. The models use a variety of strategies to address such overarching issues as preventing adverse drug events, reducing readmissions and increasing access to medications. The institutions are: • Einstein Healthcare Network, Philadelphia • Froedtert Hospital, Milwaukee • Hennepin County Medical Center, Minneapolis • The Johns Hopkins Hospital, Baltimore • Mission Hospitals, Asheville, N.C. • Sharp HealthCare, San Diego • University of Pittsburgh School of Pharmacy and University of Pittsburgh Medical Center • University of Utah Hospitals and Clinics, Salt Lake City —S.B.

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9LVLW www.RECOTHROM.com RU VFDQ WKH 45 FRGH ZLWK \RXU VPDU WSKRQH

RECOTHROM is a registered trademark of ZymoGenetics, Inc. Â&#x2039; =\PR*HQHWLFV ,QF $OO ULJKWV UHVHUYHG 57

7KURPELQ PDGH ZLWK D WZLVW RECOTHROM is human thrombin produced using recombinant DNA technology Â˛ ,Q D JHQHWLFDOO\ PRGLĂ&#x20AC;HG &+2 &KLQHVH KDPVWHU RYDU\ FHOO OLQH Q 1RW GHULYHG IURP FDWWOH RU KXPDQ SODVPD Q &RQYHQLHQW DQG HDV\ WR XVH Â˛ 5(&27+520 &RQYHQLHQFH .LWV DOORZ IRU TXLFN DQG HDV\ UHFRQVWLWXWLRQ Q )OH[LEOH SURGXFW OLQH ZLWK PXOWLSOH DSSOLFDWLRQ PHWKRGV Â˛ 0D\ EH DSSOLHG GLUHFWO\ RU LQ FRQMXQFWLRQ ZLWK DEVRUEDEOH JHODWLQ VSRQJH 863

INDICATION RECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical. IMPORTANT SAFETY INFORMATION Contraindications Â&#x2021; Topical use only â&#x20AC;&#x201C; DO NOT INJECT directly into the circulatory system Â&#x2021; Do not use for the treatment of massive or brisk arterial bleeding Â&#x2021; Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins Warnings and Precautions Â&#x2021; Potential risk of thrombosis if absorbed systemically Â&#x2021; In patients with known hypersensitivity to snake proteins, there may be a potential for allergic reaction Adverse Reactions Â&#x2021; 7KH VHULRXV DGYHUVH HYHQW WKDW RFFXUUHG LQ Â&#x2022; Q RI SDWLHQWV H[SRVHG WR 5(&27+520 LQ FRPSOHWHG FOLQLFDO WULDOV ZDV DWULDO ÂžEULOODWLRQ 7KH PRVW FRPPRQ DGYHUVH HYHQWV UHSRUWHG LQ WKHVH WULDOV 1 ZHUH LQFLVLRQ VLWH SDLQ SURFHGXUDO SDLQ DQG QDXVHD $GYHUVH HYHQWV UHSRUWHG LQ WKHVH WULDOV were consistent with those commonly observed in surgical patients Please see Brief Summary of Full Prescribing Information on following page.

14 Operations & Management

Pharmacy Practice News • November 2012

Care Transitions

Bridging the Gap Between In- and Outpatient Care

ollaboration between inpatient and ambulatory care pharmacists can improve the detection and resolution of drug therapy problems for patients about to be discharged from the hospital, according to a small clinical trial. The study was undertaken to assess whether this strategy could enhance the quality of care transitions at FirstLight Health System, a critical-access hospital in Mora, Minn., according to

Mariette Sourial, PharmD, who conducted the study while she was an ambulatory care pharmacy resident at the facility. Prior to implementation, there was a definite need for improvement, noted Dr. Sourial, who is now an assistant professor of pharmacy practice at Palm Beach Atlantic University, in West Palm Beach, Fla. “During the transition from inpatient to outpatient

[care settings], we saw great interventions being initiated by hospital pharmacists,” she said. “But the hospitalist often deferred carrying out those interventions because they were more focused on managing acute care conditions rather than chronic disease.” To help resolve that implementation gap, Dr. Sourial helped develop a protocol in which an inpatient pharmacist conducted medication reconciliations for

Immunogenicity The potential development of antibodies to RECOTHROM has been evaluated in multiple clinical trials. These pre-specified evaluations were performed in order to characterize the immunogenicity of RECOTHROM and the neutralizing potential of any detected antibodies. In completed clinical studies 5 of 552 (0.9%) patients exposed to RECOTHROM with both baseline and post-treatment antibody specimens available developed specific anti-RECOTHROM product antibodies. None of these antibodies were found to neutralize native human thrombin. BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION RECOTHROM® Thrombin, topical (Recombinant) Rx Only The following is a brief summary of the full prescribing information for RECOTHROM Thrombin, topical (Recombinant). CONTRAINDICATIONS Do not inject directly into the circulatory system. Do not use for the treatment of massive or brisk arterial bleeding. Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM, or hamster proteins. WARNINGS AND PRECAUTIONS Potential risk of thrombosis if absorbed systemically. In patients with known hypersensitivity to snake proteins, there may be a potential for allergic reaction. ADVERSE REACTIONS The serious adverse event that occurred in ≥ 1% (n=6/583) of patients exposed to RECOTHROM in completed clinical trials was atrial fibrillation. The most common adverse events in patients exposed to RECOTHROM in clinical trials (N=583) were incision site pain (51%), procedural pain (30%), and nausea (28%). Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical trials have been performed with RECOTHROM applied with absorbable gelatin sponge (Phase 2, Phase 3, and Phase 3b studies) and applied with a spray applicator (Phase 2 study). Adverse events reported in clinical trials were consistent with those commonly observed in surgical patients. Clinical Trials of RECOTHROM Used in Conjunction with Gelatin Sponge Among the 411 patients treated with study drug in the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, all but 2 patients (1 patient/treatment group) reported adverse events. Most events were moderate in severity and had a similar incidence in the RECOTHROM and bovine thrombin treatment groups. The most common adverse events were incision site pain (63% for both treatment groups), procedural pain (RECOTHROM 29%; bovine thrombin 34%), and nausea (RECOTHROM 28%; bovine thrombin 35%). Serious adverse events were reported by 18% of patients treated with RECOTHROM and 22% with bovine thrombin.

In the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, the development of specific anti-product antibodies was evaluated in both treatment groups. Blood samples were collected at baseline and at day 29 for 97% of the patients in both treatment groups. For patients randomized to RECOTHROM, the samples were analyzed by ELISA for antibodies to RECOTHROM, Chinese hamster ovary (CHO) host cell protein, and pro-thrombin activator (used in the conversion of single chain precursor to active RECOTHROM). For patients randomized to bovine thrombin, the samples were analyzed by ELISA for antibodies to bovine thrombin product. At baseline 1.5% of patients (n=3/198) in the RECOTHROM group had positive anti-product antibody titers compared with 5% of patients in the bovine thrombin group (n=10/200). Of the patients who had detectable anti-product antibodies at baseline, 0 of 3 in the RECOTHROM group and 8 of 10 in the bovine thrombin group exhibited ≥ 1.0 titer unit (≥ 10-fold) increases in antibody levels after study treatment. Treatment with RECOTHROM applied with absorbable gelatin sponge resulted in a statistically significantly lower incidence of specific anti-product antibody development. Three of 198 (1.5%; 95% CI, 0 to 4%) of the patients in the RECOTHROM arm developed specific anti-thrombin product antibodies (1 patient also developed anti-CHO host cell protein antibodies). No patients developed antibodies to pro-thrombin activator. Forty-three of 200 patients (22%; 95% CI, 16 to 28%) in the bovine thrombin arm developed specific antibodies to bovine thrombin product. None of the antibodies in the RECOTHROM group neutralized native human thrombin. Antibodies against bovine thrombin product were not tested for neutralization of native human thrombin. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study. In the open-label, single group, Phase 3b study in patients with a high likelihood of prior bovine thrombin exposure undergoing spinal, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, 15.6% of patients (n=32/205) had anti-bovine thrombin product antibodies at baseline prior to treatment with RECOTHROM. Following treatment, none of the 200 evaluable patients (patients for whom specimens were available for antibody testing at baseline and post-RECOTHROM treatment) developed antibodies to RECOTHROM. In the randomized, double-blind, controlled Phase 2 studies of RECOTHROM compared to placebo (RECOTHROM excipients reconstituted with 0.9% sodium chloride, USP) applied in conjunction with absorbable gelatin sponge, which were performed across a range of surgical settings (spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the incidence of antibody development to RECOTHROM was 1.2% in the RECOTHROM group (n=1/83) compared to 2.4% (n=1/41) in the placebo group. In the open-label, single group Phase 2 study of RECOTHROM applied with the spray applicator to excised burn wounds, 1 patient developed antibodies following treatment (1.6%, n=1/62).

Adverse events of interest were pre-speciﬁed, based on the thrombin mechanism of action, use of absorbable gelatin sponge, USP, historical reporting in association with cross-reacting antibodies to bovine thrombin product, and results from Phase 2 clinical trials of RECOTHROM applied with absorbable gelatin sponge. The incidences of these pre-speciﬁed adverse events were similar between treatment groups (see Table 1).

The detection of antibody formation is highly dependent upon the sensitivity and speciﬁcity of the assay. The absolute immunogenicity rates reported here are difﬁcult to compare with results from studies of other products due to differences in assay methodology, patient populations, and other underlying factors.

Table 1. Events of Interest in the RECOTHROM Phase 3 Study

To report p SUSPECTED ADVERSE REACTIONS,, contact ZymoGenetics, y , Inc. at 1-888-784-7662,, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. g

AE Category* Patients with any event category Bleeding Cardiac Hypersensitivity Nausea + vomiting Other infection Post-operative wound infection Thromboembolic *

RECOTHROM (N=205) n (%) 124 (60%) 27 (13%) 41 (20%) 30 (15%) 68 (33%) 26 (13%) 19 (9%) 12 (6%)

†

Thrombin-JMI (N=206) n (%) 136 (66%) 24 (12%) 38 (18%) 37 (18%) 83 (40%) 31 (15%) 22 (11%) 10 (5%)

Adverse events were included in event categories based on a blinded review of the investigator verbatim and coded terms. THROMBIN-JMI® Thrombin, Topical (Bovine).

†

In an open-label, single-group Phase 3b study, 209 patients with documented or highly likely prior exposure to bovine thrombin within the previous 3 years were treated with RECOTHROM when undergoing surgeries (spinal or peripheral arterial bypass or arteriovenous graft formation for hemodialysis access). The most common adverse events were incision site pain (45%), procedural pain (39%), and nausea (27%). Similar to the Phase 3 study, serious adverse events were reported by 22% of patients treated with RECOTHROM. Clinical Trials of RECOTHROM Applied with Spray Applicator In an open-label, single-group, Phase 2 study in burn patients, 72 patients were treated with RECOTHROM applied with a spray applicator at the burn wound excision site prior to autologous skin grafting. This study included both adults (≥ 17 years of age, n=68) and pediatric patients ≤ 16 years of age (n=4). The most common adverse events in the adult and pediatric age groups included procedural pain (35%), pruritis (25%), and constipation (19%).

DRUG INTERACTIONS Drug interactions have not been formally studied. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with RECOTHROM. It is also not known whether RECOTHROM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RECOTHROM should be given to a pregnant woman only if clearly needed.

hospitalized patientss, identified actual or potential drug therap py problems (DTPs), and proposed interrventions designed to resolve them to the hospitalist. Information about DTPs that were not successfully resolved at the hospital was relayed to an ambulatoryy care pharmacist, who addressed them at th he patient’s follow-up clinic visit, Dr. Sourial rep ported during a 2012 “Virtual Poster” session convvened by the American College of Clinical Pharmacy. Twenty patients were w enrolled in the program. The five subjects who were successfully followed had 27 DTPs, 21 of which were resolved in the ambulatory care setting. The most common medication-related problem was an indication without a drug—that is, a condition such as diabetes not treated with appropriate medications (11 instances). Rounding out the list were wrong drug administered (7); drug without indication—that is, an unneccessary drug being taken by the patient, which may include recreational drug use, duplicate therapy, etc. (4); drug overdose (3); adverse drug reaction (1); and issues with patient compliance (1). Although the study involved a very small number of patients, Dr. Sourial noted that the results demonstrate the ability that interpharmacy cooperation has to fill gaps in the continuum of care. That, in turn, may result in more comprehensive medication therapy management during the crucial period when patients shift between inpatient and outpatient environments—a time when medication management efforts can become scrambled because of inadequate communication between various providers, she noted. The success of Dr. Sourial’s initiative helped to advance some long-term process changes at the hospital. For example, follow-up visits with an ambulatory care

Follow PPN on

Pediatric Use Of the 72 patients undergoing burn wound excision and grafting treated with RECOTHROM applied with the spray applicator in the open-label, single group, Phase 2 study, 4 were pediatric patients. All were age 12 to 16 years. The safety and effectiveness of RECOTHROM in all pediatric age groups have not been fully established. Geriatric Use Of the total number of patients in Phase 2 and Phase 3 clinical studies of RECOTHROM with absorbable gelatin sponge, 38% were 65 years old and over, while 16% were 75 years old and over. No substantive differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identiﬁed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. For Full Prescribing Information, access www.RECOTHROM.com Manufactured for ZymoGenetics, Inc. RT022-06, January 2011

@PharmPracNews

Operations & Management 15

Pharmacy Practice News • November 2012

Care Transitions ‘This study, although small, is an example of how communication among pharmacists from different environments can improve the transition of care.’ —Marialice S. Bennett, RPh, FAPhA sh hould be stopped and which should be maintained,” Ms. Bennett said. “That missing information is key, but it’s very cu umbersome for hospitals to have to co oordinate with health care providers ou utside of their system.” pharmacist are now written into the discharge orders, according to Brent Thompson, PharmD, FirstLight’s pharmacy director. director “A A lot of the interventions take place here in the hospital, but more importantly, medication therapy management services are being provided to more discharged patients,” he said.

Building such ambitious networks among pharmacists and other providers will require insurers and health systems to act on the growing body of evidence showing that greater pharmacist involvement in transitions of care reduces the

numbers of medication-related errors and adverse events. That, in turn, can reduce the number of costly hospital readmissions, Ms. Bennett noted. “If health insurance plans would pay for services related to transitions of care,” she said, “the result likely would be far better communication among providers, including hospital pharmacists, community pharmacists and ambulatory care pharmacists, regardless of which health care network they belong to.” —Steve Frandzel

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Marialice S. Bennett, RPh, FAPhA, a professor of clinical pharmacy at The Ohio State University (OSU) College of Pharmacy, in Columbus, said the FirstLight Health System study is somewhat limited by the small number of patients included. Still, the initiative “is an example of how communication among pharmacists from different environments can improve the transition of care.” Many times, she noted, “the coordinated transition of care stops at discharge, and we don’t see much communication with community or ambulatory care pharmacists about medication-related issues.” That gap is unfortunate, because “relationships between inpatient and outpatient pharmacists are key to preventing [hospital] readmissions,” added Ms. Bennett, who is also the residency director of OSU’s ambulatory and community care residency programs. She cautioned that coordinated transitions of care are simpler to establish at a small, rural facility such as FirstLight than at larger facilities. For instance, the system’s ambulatory care clinics are in the same building as the hospital, or are located nearby, and the hospital and its clinics are linked by the same information technology system. In contrast, large urban medical centers draw patients from an immense geographic area, and many patients receive post-discharge care from providers who have no affiliation with the hospital. “Patients leave the hospital with a stack of prescriptions, drive many miles home and give them to a pharmacist who doesn’t know who wrote them and doesn’t know which old medications

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16 Operations & Management

Pharmacy Practice News • November 2012

Team Care

Pharmacist–Hospitalist Collaboration Pays Off Putting ASHP/SHM recommendations into action boosts safety—and savings Hollywood, Fla.—Enhanced partnerships between pharmacists and hospitalists can improve patient safety and reduce costs, according to a study presented at the annual meeting of the American College of Clinical Pharmacy. “The benefit of this type of interaction is that both groups are employees of the hospital [and are] … intensely focused on improving patient care and

cost containment,” according to investigator Jonathan D. Edwards, PharmD. “I believe this process could be used in any institution that employs hospitalists.” Dr. Edwards, a clinical pharmacy specialist at Huntsville Hospital, in Alabama, and his colleagues studied the effectiveness of such collaboration between pharmacists and hospitalists to standardize order sets, develop a

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patient contact program and increase appropriate interventions at the Huntsville Hospital between November 2011 and February 2012. They found that the approach improved patient care and reduced costs (abstract 247). Their real-world experience follows recommendations outlined in a joint statement from the American Society of Health-System Pharmacists and the

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Society of Hospital Medicine (Am ( J Health Syst Pharm 2008;65:260-263). The interdisciplinary collaboration at Huntsville Hospital featured three main components. It began with development of order sets for six disease states or situations: diabetic ketoacidosis, acute alcohol withdrawal, hypoglycemia, nicotine replacement, admission orders and contrast-induced nephropathy prophylaxis. The group identified these clinical areas based on the types of hospitalized patients they most frequently manage. “The order set development standardized the way we treat five disease states,” Dr. Edwards said in an interview. This strategy also decreased the time it takes physicians to write admission orders for these patients and New Product

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Operations & Management 17

Pharmacy Practice News • November 2012

Team Care ‘The most important component of the success of this project is knowing how your physicians prefer to be contacted regarding recommendations.’ —Jonathan D. Edwards, PharmD helped to streamline use of formulary agents. The process also strengthened the relationship between the two disciplines, facilitating further collaboration, Dr. Edwards added. To enhance the collaboration beyond the order sets, Dr. Edwards proposed that a clinical pharmacist review the drug regimens for hospitalists’ patients to identify potential cost savings and therapeutic adjustments. “The group agreed, and I started making recommendations via face-to-face communications with the appropriate physician.”

Dos and Don’ts When Contacting Physicians Dr. Edwards learned a crucial strategy in the process. “The most important component of the success of this project is knowing how your physicians prefer to be contacted regarding recommendations. I did not realize that most physicians do not like notes in the medical record but prefer to have a face-to-face conversation with the pharmacist.” This more personal method of interacting with physicians has additional benefits, he said. It promotes the positive perception of pharmacists as team members and avoids any negative perception that chart notes mean pharmacy is “policing” medication use. During the study period, the Alabama researchers identified $5,602 in cost avoidance associated with 77 patient recommendations. The recommendations included converting IV medications to oral forms, monitoring duration of therapy, adjusting medication regimens, initiating new medication therapy and discontinuing therapy. The collaboration program had a third phase that was aimed at strengthening pharmacy’s role in patient care. “We interacted with patients on our family medicine floor on a daily basis,” Dr. Edwards said. “We asked patients about their allergies and pain control, and answered questions about their current medications and the side effects associated with these medications.” The pharmacists then shared this important information with the hospitalists. These patient-interaction initiatives yielded an additional 79 interventions during the study period. Identification and clarification of allergies, and assessment of pain management were the primary actions taken. These actions resulted in $5,287 of cost avoidance. “The three programs were successful in improving patient outcomes and

reducing cost,” Dr. Edwards said. Added together, the pharmacist-hospitalist collaboration resulted in the development of six order sets, 165 total interventions and a total cost avoidance of $10,889 over a four-month period.

Broader Research Needed Commenting on the study, Thomas Bookwalter, PharmD, an associate professor of health sciences at the University of California, San Francisco School of Pharmacy, called the Alabama study “a fine report.” He urged the investigators to “continue to work in this area … with a somewhat larger scope.” Dr. Bookwalter noted that several unanswered questions remain. For example, future research could determine if collaboration between pharmacists and hospitalists prevents any medical

errors, lowers hospital readmission rates and/or improves patient satisfaction. He also suggested that future research should be designed to compare two groups of hospitalized patients, one treated with traditional care and another group managed through this interdisciplinary collaboration. —Damian McNamara Drs. Edwards and Bookwalter reported no relevant ﬁnancial conﬂicts of interest.

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IMPORTANT SAFETY INFORMATION FOR INTRAMUSCUL CULAR AR USE ON ONLY. LY. Proge gesterone injection in sesame oil is contraindicated in patients with current or past history of thrombophlebitis, thrombo boemb emboli olicc diso disorde rders, rs, orr ce cerebral apoplexy; liver dysfunction or disease; known or suspected malignancy of breast or genita tall organs; undiagnose osed d vagi vaginal nal bleed bleeding ing;; missed m abortion; and known sensitivity to progesterone injection in sesame oil. Since progestero one metabolites are seecre creted ted mainl i ly by b the kidneys, progesterone should be administered with caution and careful monitoring in patients with renal insufficiency. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulm monary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately. Meedication should be discontinued pending examination if there is a sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn. Because progestational drugs may cause some degree of fluid retention, conditions which might be influenced by this co condition, such as epilepsy, migraine, asthma, cardiac, or renal dysfunction, require careful observation. Patients who have a history of psychi hicc depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree. There are possible risks wh which may be associated with the use of progestin treatment, including adverse effects on carbohydrate and lipid metabolism. A decrease in glucose gl tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. For this reason, diabetic ic patients should be carefully observed while receiving such therapy. Progesterone at high doses is an antifertility drug and high doses woul uld d be expected to impair fertility until the cessation of treatment. A statistically significant association has been demonstrated between use of estrogen-progestin combination on drugs and pulmonary embolism and cerebral thrombosis and embolism. For this reason patients on progestin therapy should be carefullllyy observed. There is also evidence suggestive of an association with neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis. Adverse events associated with use of Progesterone injection in sesame oil include breakthrough bleedi ding; ng; sp spott otting; change in menstrual flow; amenorrhea; edema; change in weight (increase or decrease); changes in cervical erosion and ce cervi rvical secretions; cholestatic jaundice; breast tenderness and galactorrhea; pain, irritation, and/or redness at the injection area; ski sk n sens ensitivity reactions consisting of urticaria, pruritus, edema and generalized rash; acne, alopecia and hirsutism; rash (allergic) with and d without w pruritus; anaphylactoid reactions; mental depression; pyrexia; insomnia; nausea; and somnolence. Because laboratory results may be altered by the use of estrogenprogestin combination drugs, pathologists should be advised of progestin therapy when spec pe imenss are submitted. One Luitpold Drive | PO Box 9001 | Shirley, NY 11967 | Phone 800-645-1706 | Fax 631-924-1731

Visit us online at: www.americanregent.com

18 Operations & Management

Pharmacy Practice News • November 2012

Leadership in Action

Let Go of Blame and Gain Inner Peace “Forgiveness is a secret that is hidden in plain sight. It costs nothing and is worth millions. It is available to everyone and used by few. If you harness the power of forgiveness, you will be sought after and regarded highly. And not coincidently you will also be forgiven by others.” —Abraham Lincoln

s a society, it seems we often need to find fault, place blame and get revenge. We see this over and over again in movies and television shows. Life is full of injustices, we are told, and

so it only seems fair to get even. When we are the victims, we sometimes feel as though the only way to recapture a sense of peace is to get back at the offending person. But Ken Sande

PROGESTERONE INJECTION, USP IN SESAME OIL FOR INTRAMUSCULAR USE ONLY

Rx Only

DESCRIPTION Progesterone injection, USP, a progestin, is a sterile solution of progesterone in a suitable vegetable oil available for intramuscular use. INDICATIONS AND USAGE This drug is indicated in amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. CONTRAINDICATIONS 1. Current or past history of thrombophlebitis, thromboembolic disorders, or cerebral apoplexy. 2. Liver dysfunction or disease. 3. Known or suspected malignancy of breast or genital organs. 4. Undiagnosed vaginal bleeding. 5. Missed abortion. 6. Known sensitivity to progesterone injection, USP. WARNINGS The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately. Medication should be discontinued pending examination if there is a sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn. PRECAUTIONS General The pretreatment physical examination should include special reference to breast and pelvic organs, as well as a Papanicolaou smear. Because progestational drugs may cause some degree of fluid retention, conditions which might be influenced by this condition, such as epilepsy, migraine, asthma, cardiac, or renal dysfunction, require careful observation. In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind, and adequate diagnostic measures undertaken. Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree. The age of the patient constitutes no absolute limiting factor although treatment with progestin may mask the onset of the climacteric. The pathologist should be advised of progestin therapy when relevant specimens are submitted. There are possible risks which may be associated with the use of progestin treatment, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving such therapy. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term intramuscular administration of Medroxyprogesterone acetate (MPA) has been shown to produce mammary tumors in beagle dogs. There is no evidence of a carcinogenic effect associated with the oral administration of MPA to rats and mice. Medroxyprogesterone acetate was not mutagenic in a battery of in vitroo or in vivoo genetic toxicity assays. Progesterone at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment. Geriatric Use: The safety and effectiveness in geriatric patients (over age 65) have not been established. Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

in “The Peace Maker” (third edition; Baker Books, 2004) suggests otherwise. Genuine forgiveness, he notes, is a far more lasting source for finding inner peace. And although it is one of the most

Hepatic Insufficiency: The safety and effectiveness in patients with hepatic insufficiency have not been established. Since progesterone is metabolized by the liver, use in patients with liver dysfunction or disease is contraindicated. Drug Interactions: The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC50 < 01 μM). Ketoconazole is a known inhibitor of cytochrome P450 3A4 and these data suggest that ketoconazole or other known inhibitors of this enzyme may increase the bioavailability of progesterone. The clinical relevance of the in vitroo findings is unknown. ADVERSE REACTIONS Breakthrough bleeding; spotting; change in menstrual flow; amenorrhea; edema; change in weight (increase or decrease); changes in cervical erosion and cervical secretions; cholestatic jaundice; breast tenderness and galactorrhea; pain, irritation, and/or redness at the injection area; skin sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash; acne, alopecia and hirsutism; rash (allergic) with and without pruritus; anaphylactoid reactions; mental depression; pyrexia; insomnia; nausea; and somnolence. A statistically significant association has been demonstrated between use of estrogenprogestin combination drugs and pulmonary embolism and cerebral thrombosis and embolism. For this reason patients on progestin therapy should be carefully observed. There is also evidence suggestive of an association with neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis. The following adverse reactions have been observed in patients receiving estrogen-progestin combination drugs: Rise in blood pressure in susceptible individual, premenstrual syndrome, changes in libido, changes in appetite, cystitis-like syndrome, headache, nervousness, fatigue, backache, hirsutism, loss of scalp hair, erythema multiforme, erythema nodosum, hemorrhagic eruption, itching, and dizziness. The following laboratory results may be altered by the use of estrogen-progestin combination drugs: increased sulfobromophthalein retention and other hepatic function tests; coagulation tests: increase in prothrombin factors VII, VIII, IX, and X; metyrapone test; pregnanediol determinations; thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values. DOSAGE AND ADMINISTRATION Progesterone injection, USP is administered by intramuscular injection. It differs from other commonly used steroids in that it is irritating at the place of injection. Amenorrhea: Five to 10 mg are given for six to eight consecutive days. If there has been sufficient ovarian activity to produce a proliferative endometrium, one can expect withdrawal bleeding forty-eight to seventy-two hours after the last injection. This may be followed by spontaneous normal cycles. Functional Uterine Bleeding: Five to 10 mg are given daily for six doses. Bleeding may be expected to cease within six days. When estrogen is given as well, the administration of progesterone is begun after two weeks of estrogen therapy. If menstrual flow begins during the course of injections of progesterone, they are discontinued. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. HOW SUPPLIED Progesterone Injection USP, 50 mg/mL is available in 10 mL multiple dose vials, individually boxed.

Ernest R. Anderson Jr., MS, RPh

difficult gifts to give to each other, if we can learn this secret of forgiveness, it can be incredibly liberating. The first step in this journey is to understand the cost of holding onto feelings of bitterness and anger toward someone whom you feel has offended you. Oftentimes, that other person is not even aware of the offense, and so we turn our bitterness inward and poison our own soul. And we don’t just suffer emotionally; that level of unhappiness takes a physical toll as well. Fortunately, these feelings do not have to last forever; you can choose to let go of them; you can forgive. When you make that choice honestly and truly commit to it, a huge weight is lifted from your shoulders and a sense of personal peace seeps in. You might be saying, yes but you don’t understand. I lost my job because my boss doesn’t understand me, or my professional life was destroyed by the actions of another, or I was personally hurt and marred for life when this person took that action against me. You mean I should forgive in those circumstances too? Well, it really is your choice of how you want to live your life. Bitterness and strife can sour the one who holds onto these destructive emotions. Letting go of them, in contrast, can truly be restorative. Think about it from a professional standpoint. Who are the successful people you like to be around? Is it not those who have a positive attitude despite their circumstances, along with their talents and skills? If you are hiring a pharmacist and have two equally qualified candidates, but only one has a smile on his or her face and a positive attitude, which person will you choose? I know my choice. We are all overworked and under an extreme amount of pressure in health care as well as many other industries. That is the nature of our existence. When we harbor bitterness, it comes across

Store at 20° C to 25° C (68° F to 77° F) [See USP Controlled Room Temperature]. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Do not use Progesterone Injection after the expiration date which is printed on the vial label.

Nursing Mothers: Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the nursing infant has not been determined. Special Populations: Renal Insufficiency: The safety and effectiveness in patients with renal insufficiency have not been established. Since progesterone metabolites are excreted mainly by the kidneys, progesterone should be administered with caution and careful monitoring in this patient population.

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Steward Health Care System, Boston, Mass. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ steward.org.

AR154 Iss. Date 6/2012

in Your Inbox

Operations & Management 19

Pharmacy Practice News • November 2012

Leadership in Action to others, even if unintended. People don’t want to “hang out” with—and bosses don’t want to promote—the person with the sour attitude. An insightful person once gave me a wise saying that I have long followed and shared with others: “Attitude is everything.” I have even put this saying on a slide that I often try to weave into lectures at the appropriate time.

Make the First Move What about when someone offends you and you both know it? You could take the attitude that it’s up to that other person to come on bended knee and beg your forgiveness. You may be waiting quite a while for that to happen! A humble, wise person instead would go to the offender and say something like, “I sense that there is an issue between us. I would like to clear the air. Have I done something to offend you?” If the person tells you there was an offense, then you can ask for forgiveness for what you have done. In many cases, that approach will open a dialogue. The other person may even apologize for how he or she treated you. If, however, the person denies having offended you, then you need to tell that person you sense there is a problem between the two of you, and that you need to get to the root of the problem to solve the issue. When you make that effort and forgiveness is sought and given, bonds often can be mended and peace can ensue. It’s important to note, however, that forgiveness is not a free pass when someone has done something wrong. Sometimes there are offenses that have consequences that go beyond “I’m sorry” and “I forgive you.” In a job situation, stealing, for example, is usually an offense that costs the person his or her job. All too often in our medical profession I have seen many people bear the consequences of drug diversion, such as losing their job, their license to practice and bearing additional consequences with the authorities. If the individual is truly sorry for what he or she has done, forgiveness is possible, but that person still will bear the consequences of the offending actions.

Can Unforgiveness Be Overcome? Is it possible that you have offended another and have asked the person for forgiveness, only to be refused? Perhaps the person wants to “make you suffer” as punishment for your perceived transgressions. If the other person makes a choice not to forgive, then you have done all you can do and the burden lies with that individual. These are difficult situations that may require the intervention of a mediator. Perhaps you as the manager can serve

When forgiveness is sought and given, bonds can be mended and peace can ensue. in that role. You may need to dig deep to uncover hidden agendas that need to be resolved to reach true peace.

How To Promote Forgiveness Forgiveness starts the difficult and sometimes lengthy process of reconciliation. The goal of these efforts is to restore the relationship to its prior

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place. It may not mean that you are going to be best friends forever, but you are able to coexist in the workplace. Occasionally, however, if deep forgiveness and true reconciliation have taken place, it is possible that a deeper understanding of each other will allow empathy and compassion to build a relationship that was greater than when you started. It can happen!

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22 Operations & Management

Pharmacy Practice News • November 2012

Practice Pearl

Training Our Pharmacy Technicians for the Future Marissa C. Furman, PharmD Clinical Pharmacist Inova Alexandria Hospital Alexandria, Virginia

Table 1. Tips for Starting Technician Education Programs Keep it simple and short.

hange can be positive, change can be challenging, and change can require a shift in roles. We all are experiencing an empowering phase of pharmacy practice, but this time is especially exciting for pharmacy technicians. It brings accountability to technicians, as well as opportunities for them to seize a larger and a more direct role in improving patient safety. Change is inevitable in the health care field and it seems as if we are seeing it occur more quickly recently, especially with the rapid development and implementation of technology. The implementation of automation means expanded roles for technicians. Automation promotes safety and accuracy, and when used properly, it can save valuable time, freeing up technicians to work in other areas of patient care and enabling pharmacists to act as direct care providers. The American Society of Health-System Pharmacists’ (ASHP) Pharmacy Practice Model Initiative cites technicians as a cornerstone of the future of pharmacy practice and recommends increased educational requirements for technicians in the future. To meet these goals and to prepare technicians for these expanded roles, education is essential, but how do we best teach technicians and what are the real-world benefits afforded? Last year, Inova Alexandria Hospital’s Pharmacy Department began a journey to answer these critical questions. After returning from the ASHP 2011 Summer Meeting, I was asked to give 2 educational presentations summarizing key points gleaned from the conference— one for our pharmacists and another for pharmacy technicians. The technicians had many questions and the presentation quickly transformed into an interactive discussion. This experience revealed that not only is there a need for technicians to know this information, but also there is a desire to learn, and these types of presentations could be beneficial as a scheduled program. The team brainstormed initial ideas for creative programming and surveyed the technicians for topics of interest. A 6-month framework of presentations was created, and thus our pharmacy technician education forum was born. Each month we teach interactive sessions designed specifically for technicians, covering 2 to 3 drugs or a single disease state. Each presentation consists of approximately 20 minutes of material

Use a language technicians understand and make sure presentations are no more than 40 minutes. Keep technicians engaged. Ask questions, encourage attendees to ask questions, give “pop quizzes,” provide snacks and rewards for participation. Use simplistic patient cases to make your points (Case Studies). Show technicians how the information they are learning fits into the patient care in their job. Avoid the use of medical jargon. Don’t overwhelm them with terms they don’t understand; if you do use a medical term, also define that word in layman’s terms. Plan out your session 3 to 6 months at a time but always remain flexible. If there is a change in the department or protocol, these technician education sessions are an efficient and effective way to ensure technicians understand the changes. Have fun! Give out candy and prizes, use humor and visuals in the presentation. Don’t be afraid to make attendees laugh. It keeps them from getting overwhelmed and keeps them engaged.

and there are an additional 10 minutes built in so that technicians are free to ask questions at any point to help facilitate discussion. During each learning session, our technicians are given a pretest and posttest to assess their knowledge and quantify what they have learned in order to give them a chance to think critically, work together, and reinforce each lesson from the presentations. Presentations specifically are focused on what technicians need to know—everything from basic drug information, to side effects, to sterile IV compounding, to recognizing a standard dose versus a toxic dose, and even to knowing simplistic mechanisms of action—with a special emphasis on safety and the technician’s role as it relates to a drug or disease state. The presentation strategies used to engage technicians include keeping it simple and short, asking questions, giving out prizes, and using case studies (Tables 1 and 2). The benefits of the technician education forum are numerous. Technicians have become more engaged and accountable for their work and have reported an increased job satisfaction. Furthermore, teaching technicians about correct dosing and safety allows them to become a second set of eyes for pharmacists. Technicians present concerns or questions during daily activi-

ties based on topics and concepts previously presented. Based on these educational sessions, technicians even have helped to prevent medication errors by stopping incorrect orders before the drug ever leaves the shelf. For example, the agent dabigatran (Pradaxa, Boehringer Ingelheim) was reviewed during one of the sessions. Technicians learned key points

about this anticoagulant, including that capsules should not be crushed or opened due to the potential for serious adverse effects. A few months later, a pharmacy technician was completing medication reconciliation in the emergency department. During a patient interview, he discovered the patient was opening the dabigatran capsules and swallowing the powder. That technician notified pharmacy and the patient’s physician immediately. A pharmacist educated the patient regarding proper administration of dabigatran, preventing potential harm. It is evident that these programs promote teamwork. In addition to pharmacists educating technicians, technicians also are encouraged to teach one another through the questions posed during the educational sessions. Moreover, some of the technicians have volunteered to lead peer-to-peer presentations. As a result of these educational programs, technicians have become more engaged and involved in their work and now provide another set of eyes to improve medication safety. The programs also have provided pharmacists new opportunities for leadership and an avenue to help close the gap between themselves and technicians by raising the bar based on technicians’ newfound drug information knowledge base. Furthermore, our pharmacy technician education programs keep technicians engaged, help us with medication safety, and prepare our technicians for the future of pharmacy practice. With time, dedication, and a little creativity, any hospital pharmacy department can start a pharmacy technician education forum. If you have questions or need some advice, please feel free to contact me at Marissa.Furman@inova.org.

Table 2. How Best To Use Case Studies Case 1

Case 2

ID, DOB 6/1/1944, weight 154 lb, with paresthesia and dysarthria lasting for 150 minutes, is brought to the emergency department for suspected acute ischemic stroke. Is ID eligible for tPA? What dose and at which rate of tPA should ID receive? Why would this be confusing for a technician? • Medical jargon is used. • Extraneous information is provided. • It is challenging to extract needed information. The goal is to teach technicians about drug information using patient case examples, rather than teaching patient assessment.

Ima Droopie, a 68-year-old man who weighs 70 kg, has numbness in right arm, facial drooping, and slurred speech. Symptoms begin at 10:00 AM, and at 12:30 PM, Ima arrives at the ED. Ima appears to be having an “acute ischemic stroke” (stroke caused by a blood clot). Is he a candidate for tissue plasminogen activator (tPA) (alteplase)? If so, what dose should he receive and how fast should the rate be? Why is this presentation more suited for educating technicians? • The information is presented clearly. • Only the necessary information is provided. • Weight is provided in kilograms, which facilitates calculations. • The patient is described in a language technicians can understand. • Humor is used.

0 HP 95 AS th 1 o Bo

24 Clinical

Pharmacy Practice News • November 2012

Research

2012 ASHP Foundation Literature Awards Announced Honorees recognized for work in nanotechnology, pharmacogenetics and other cutting-edge areas of research Las Vegas—The five winners of the American Society of Health-System Pharmacists (ASHP) Research and Education Foundation’s 2012 Literature Awards will be recognized at the Midyear Clinical Meeting in Las Vegas. To honor their extraordinary contributions, Pharmacy Practice News spoke to each of the honorees.

Award for Sustained Contributions

Mary Ensom, BSPharm, PharmD

With nearly 70 teaching, scholarship, service and research awards, one might expect being recog-

nized yet again by her peers would be old hat for Mary H.H. Ensom, PharmD. However, she said that she was “honored and humbled” to receive the award for Sustained Contributions. With a modesty that belies her 34 years of service to the profession, Dr. Ensom partly attributed her success—and her

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marriage—to the ASHP. “I don’t think I would be Mary Ensom today if not for ASHP,” said Dr. Ensom, a professor in the Faculty of Pharmaceutical Sciences and a Distinguished University Scholar at the University of British Columbia (UBC) as well as a clinical pharmacy specialist at Children & Women’s Health Center of British Columbia, in Vancouver, Canada. “I met my husband, Robin, when I was working as a pharmacist at the Medical University of South Carolina in Charleston back in 1979—he happened to be the first of a series of Canadian pharmacists to pursue his PharmD degree there,” she recounted. “We lost contact for a few years, but it was at my first ASHP Midyear that we reconnected, and [we] eventually married in 1997.” The couple’s choice of occupation has proven contagious. Dr. Ensom’s 26-yearold daughter, Hannah Chandler, is pursuing a postgraduate year 1 residency in pharmacy at the University of Kentucky, with interests in emergency medicine, critical care and psychiatry. “I am one proud mama!” Dr. Ensom— or Mary, as she insists on being called— gushed in an interview. The award recipient has set a high bar for her daughter to meet: Her publications have been cited more than 1,800 times, also attesting to the seminal nature of some of her work. Of note, her team was the first to systematically and longitudinally study the pharmacoki-

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Clinical 25

Pharmacy Practice News • November 2012

Research netics of both unfractionated and lowmolecular-weight heparin as well as intravenous immunoglobulin in women with recurrent pregnancy loss. They also conducted some of the first pharmacokinetics studies of mycophenolate and its glucuronidated metabolites in lung transplant recipients. Accomplishments like these made nominating Dr. Ensom for this award an easy decision for Robert Sindelar, PhD, a professor and the dean of UBC’s Faculty of Pharmaceutical Sciences. “I cannot think of anyone more suited to being selected for such a prestigious award,” Dr. Sindelar said. “Dr. Ensom is unique in our faculty as she contributes substantially to the academic triad of teaching/learning, scholarship/research and service to the profession.”

phic enzymes and for which there is pharmacogenomic information. Pharmacists provide a written consultation that is included in a patient’s electronic medical record, and drug-specific alerts appear if a genotype contraindicates the use of a particular medication or suggests a higher- or lower-than-normal dose should be administered. With a growing list of gene–drug pairs, Dr. Crews believes pharmacists will see clinical pharmacogenomics become an important aspect of hospitalbased pharmacy. “With our knowledge

of medications, pharmacists are well positioned to lead new initiatives in the field,” she noted. Dr. Crews received praise from coauthor James Hoffman, PharmD, MS, BCPS, a medication outcomes & safety officer at St. Jude. She “was a pleasure to work with on this paper and on all of our ongoing efforts to implement pharmacogenetics,” Dr. Hoffman said. “Her broad knowledge of both laboratory research and patient care give Dr. Crews unique insights into the application of pharmacogenetics for our patients, and

her innovative practices continue well beyond this paper.”

Drug Therapy Research Award

Olivia Phung, PharmD

After a dinner out with a soon-to-becolleague from the University of Conn e c t i c u t / Ha r t f o rd Hospital’s EvidenceBased Practice Center, where Olivia Phung,

•

see LIT AWARDS, page 32

Award for Innovation In Pharmacy Practice

Automating for better medication management and improved patient care. At McKesson, everything we do and every system we produce is designed to support you and your work. We can help you improve both the health of your patients and the ﬁnancial ﬁ health of your organization, with solutions that let you respond faster, with fewer errors, while automating tasks to lower your costs and save you time. So you’ll have more time to spend on clinical duties that directly improve the quality of patient care.

For Kristine Crews, PharmD, BCPS, the theme of marriage transcends the 12-year partnership she has Kristine Crews, cultivated with her PharmD husband, James. Dr. Crews has coupled her research interests with a dedication to patient care and has managed to balance the infinitesimal nature of her work in pharmacogenetics with a love for expansive spaces, camping, hiking, swimming, and generally spending “lots of time outdoors” with her husband and three young children. Despite a “very busy” life, the awardee set aside a few minutes to discuss the pharmacist-led clinical pharmacogenetics service—one of the first in the country—that she helped establish and for which she is receiving recognition. “You could say the burgeoning field of clinical pharmacogenetics and my career have grown up together,” mused Dr. Crews, who is the director of the Translational Research Laboratory at St. Jude Children’s Research Hospital, in Memphis. Dr. Crews’ broad interest in research was sparked during her pharmacy school years at Rutgers University, in New Jersey, and she ultimately followed up a residency in clinical pharmacokinetics with a research fellowship focusing on clinical pharmacokinetics and drug development. The pharmacogenetics service she helped establish at St. Jude’s, detailed in the American Journal of Health-System Pharmacy ((2011;68:143-150), is the culmination of her research and clinical interests. The service relies on pharmacists to review and interpret the results of pharmacogenetic tests, which are conducted preemptively at St. Jude’s in patients likely to require one of several drugs that are metabolized by polymor-

26 Clinical

Pharmacy Practice News • November 2012

Pain Medicine

OPIOID DEBATE

‘A lot of patients [with chronic pain] can’t take [other] analgesics for one reason or other.’

continued from page 1

what it said was a lack of evidence for the safety and effectiveness of longterm opioid use for CNCP as the main reasons for the group’s action. “Unfortunately,” the petition stated, “many clinicians are under the false impression that chronic opioid therapy is an evidence-based treatment for chronic non-cancer pain and that doserelated toxicities can be avoided by slow upward titration. These misperceptions lead to overprescribing and high dose prescribing.” Pharmacists and physicians opposed to PROP’s proposed label restrictions were quick to respond. Professionals for Rational Opioid Monitoring and Pharmacotherapy (PROMPT), a multidisciplinary group of 35 physicians, pharmacists and other pain specialists, sent a letter to the FDA express-

—Jeffrey Fudin, PharmD, FCCP ing its own con ncerns about the safety of chronic opio oid use but suggesting an alternative approach a emphasizing “clinician ed ducation, proactiive risk stratificatio on n and appropriate therapeutic monitoring.” PROMPT also o endorsed the len ngthier and more h heated response from the American Acad d e my of

Commentary

Two More Pharmacists in Favor of PROMPT James B. Ray, PharmD, CPE Pharmacy Clinical Coordinator, Pain and Palliative Care University of Virginia Health System Charlottesville, Virginia Co-chair, Pharmacotherapy Special Interest Group American Pain Society

e agree with the PROMPT position and that of the American Academy of Pain Medicine, which opposes many of PROP’s goals to regulate the prescribing of opioid medications. Having said that, like the folks who created the PROP petition, I too am very concerned about the increase in prescription drug abuse and overdose deaths. But I do not see that their request to the FDA for limits on opioid prescribing (some via labeling changes) will do anything to significantly curb the misuse and abuse of these medications; rather, the PROP position further polarizes views on these difficult issues. This debate is certainly an important one, given the prevalence of chronic pain in the United States. Prescribing practitioners will probably see more patients with some type of chronic pain syndrome than any other disease in their professional career. In fact, there are more chronic pain patients in this country than patients with cardiovascular disease, cancer and AIDS combined. However, there is little to no attention being paid to training clinicians on the proper and safe use of opioids for these often complex pain patients (J Pain 2011;12:1199-1208). As poor as education on pain management is, addiction medicine training is even worse. The diseases of pain and addiction now overlap with each other more and more each day and practitioners are ill prepared to deal with patients with pain and addiction. For those already practicing, mandatory education programs on safe and appropriate prescribing should be designed and implemented. Those safe practices should include conducting a pain assessment; performing a risk stratification for opioid use; designing a treatment and monitoring plan that includes how to use abuse- and diversion-deterrent tools such as urine drug monitoring; state prescription monitoring programs to assess compliance/development of opioidrelated problems; and finally, assessment of function

(use of the four A’s) to determine if a continuation of the “trial of an opioid” is warranted. Additionally, curricula need to be overhauled in all professional health care programs regarding pain management and addiction medicine. Integration into the students’ early experience would create “muscle memory” about how they should treat pain and monitor for abuse and addiction properly once they are in practice. This is especially important in the primary care area of practice. Dr. Kolodny is right in stating, “The FDA doesn’t regulate the practice of medicine.” Why, then, is PROP asking the FDA to implement these labeling changes? If approved, I fear that the revised labeling will do little to nothing to improve the very problem PROP’s proponents hope to improve. Instead, we need to ask Congress to appropriate money to implement the Institute of Medicine’s recommendations regarding pain management and to create a larger budget within the National Institutes of Health for conducting basic and clinical research on pain and addiction. As far as what pharmacists can do in all of this, I would suggest that all pharmacists—not just those in our profession who specialize in pain—can and should play a crucial role to ensure safe and proper use of opioids. Specifically, we should be counseling each and every patient about opioids, discussing side effects, including the risk for respiratory depression (especially when opioids are combined with other central nervous system–active agents), stressing that the use of the drug is limited to them alone and that they have a responsibility to secure the medication in their home so no one else has access to it. (Studies suggest that 70% of prescription drugs that are being abused/misused come from friends or family members.) Moreover, pharmacists should partner with prescribers to advocate for useful electronic prescription monitoring programs in their individual states so that the technology can be added to other tools they already have for effective patient monitoring. Pharmacists also need to advocate for their prescribing colleagues’ right to prescribe judicious quantities of opioids—especially for acute pain problems. And pharmacists can advocate for frequent prescription “takeback” programs in their communities and work with

legislators and regulators in their respective state to remove barriers to make this easier for our patients and their families. In short, I am confident that these measures are a more effective strategy for improving the safety of opioid prescribing than the labeling changes and other heavy-handed prescribing limits sought by the PROP proposal. If you share my concerns, I urge you to make your voices heard by submitting a letter to the FDA during this open comment period (http:// www.regulations.gov/#!documentDetail;D=FDA2012-P-0818-0001), because if instituted by the FDA, these proposed label changes will only make our lives as clinicians much more difficult and will negatively impact the quality of pain care that we provide to our patients.

Sean Ustic, PharmD Clinical Coordinator Pain Management Specialist South Florida Baptist Hospital Plant City, Florida Co-chair, Pharmacotherapy Special Interest Group American Pain Society

agree with Dr. Ray: The whole culture of pain needs an overhaul. Most of us in the health care profession are taught only a brief introduction on initiating medications for the treatment of acute or chronic pain. More education on de-escalation and goal setting up front tends to help patients stay engaged in their own recovery of functionality. Opioids continue to be used because they are relatively cheap and effective but likely are not the best option for everyone with chronic noncancer pain. In addition, there aren’t many safe and effective long-term alternatives for chronic noncancer pain. If opioids are not the answer, what is? With more education, pharmacist-coordinated medication therapy management for patients with chronic pain is an opportunity that hasn’t yet been well recognized. Pharmacists trained in pain management also would be able to help maximize multimodal therapy (nonopioid options), minimize drug–drug and drug–disease state interactions, help interpret drug screens and also aid in goal setting with patients.

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Pharmacy Practice News • November 2012

Pain Medicine Pain Medicine, which called the PROP proposals “seriously flawed, potentially harmful to patients with debilitating pain conditions for whom opioid therapy is indicated, and without substantive scientific foundation.” Pharmacy Practice News talked with the principals of both PROP and PROMPT and found a depth of conviction on the issue from both sides.

Andrew Kolodny, MD, the president of PROP and the chairman of the Department of Psychiatry at Maimonides Medical Center, in New York City, spoke about a decade of rising addiction and overdose death rates “fueled by overprescribing of opioids” mostly for “people with a diagnosis of chronic noncancer pain.” “What caused this increase,” he said, “was a very effective marketing and education campaign to convince doctors that we were underutilizing opioids.” Physicians were “incorrectly” told, he said, that “we didn’t have to worry about getting patients addicted and that opioids were effective. “This increase in prescribing,” he added, “has led to this public health crisis. We think it’s now time for the FDA to communicate clearly to the medical community that long-term use of opioids for chronic noncancer pain has not been proven safe and effective.” According to Dr. Kolodny, “the best available evidence does not suggest that they’re safe and effective. In the United States, where we’re consuming a large portion of the world’s opioid supply, there’s absolutely no evidence that we’re doing any better a job of treating chronic pain than in countries where opioids are prescribed more cautiously. “In fact,” he added, “the best available epidemiologic data that’s looked at this question comes from Denmark. What they found in a very large study [[Pain 2006;125:172-179] was that people who are on opioids long-term for chronic pain were doing very poorly compared with people who were having their pain treated with nonopioid analgesics. There are other studies from the United States that have replicated that.” He added: “So I don’t believe a reduction in prescribing of opioids for chronic pain will worsen the problem of untreated chronic pain. In fact, because I don’t believe that opioids are effective for most people with chronic pain, I think it exacerbates the problem of untreated chronic pain and to some extent we’re undertreating pain by overprescribing opioids.”

PROMPT’s Dr. Fudin: More Rational Solution Needed Jeffrey Fudin, PharmD, FCCP, a diplo-

—Andrew Kolodny, MD

Incidence, %

PROP’s Dr. Kolodny: More Opioid Oversight Needed

‘We think it’s now time for the FDA to communicate clearly to the medical community that long-term use of opioids for chronic noncancer pain has not been proven safe and effective.’

33 30

22 20

14.3 9.1

8.7

7.7 0.8

Methadone

Morphine

Hydrocodone

Hydromorphone

Oxycodone

Fentanyl

Buprenorphine

Figure. Drug-related deaths involving opioids by drug type.

mate of the American Academy of Pain Management and chairman of PROMPT and an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences, in New York, offered a number of objections to PROP’s proposals. First, he said, it was “absurd” of PROP to ignore the multiplicity of therapeutic options required to treat all of the “unique disorders” that cause CNCP. Moreover, he said, “a lot of patients [with chronic pain] can’t take [other] analgesics for one reason or other.” Also, limiting opioid dosages to the equivalent of 100 mg of morphine per day disregards the variability in conversion calculations that can occur among different opioid products. He pointed to one study of accepted conversion charts that showed variations in calculations ranging “all the way from –50% to +245%.” (Shaw KC. Eastern States Residency Conference 2012:Abstract 15v). As for adverse events associated with chronic analgesic treatment, Dr. Fudin said many more are linked to nonsteroidal anti-inflammatory drugs than to opioids, including bleeding disorders, kidney dysfunction and deaths. He also said that most opioid deaths occur in patients on multiple sedating medications (including alcohol) and in those abusing multiple medications, not in patients being treated by knowledgeable pain management clinicians with opioids taken as prescribed. Moreover, he noted that the largest contributor to rising opioid mortality rates was methadone. A recent report by the Centers for Disease Control and Prevention, he said, found that although 2% of all opioid prescriptions are written for methadone, 33% of opioid-related deaths

involve the synthetic opioid ((MMWR 2012;61:493-497; Figure). “That’s huge,” Dr. Fudin said. “Methadone pharmacokinetics are very complex, and a lot of prescribers don’t have experience and should not be prescribing it.” A clear example of this, he noted, was seen in the state of Washington, where “the state’s decision to list methadone as a preferred painkiller to cut costs contributed to increasing numbers of overdoses among patients covered by Medicaid” ((JAMA 2012;8:749-750). So what is the answer to the problems that PROP is addressing? Dr. Fudin believes FDA’s risk evaluation and mitigation strategy (REMS) program for extended-release opioids “is a step in the right direction,” but regulations “should go further and make education mandatory for all people who prescribe opioids. “It doesn’t matter if [the opioids] are extended-release or not,” he continued. “[Prescribers] need to learn about risk stratification, and they need to be trained in how to do urine drug screens and how to interpret them. They also need to know that if the urine screen shows something unusual, they have to take the next step to order a qualitative confirmation or perhaps follow up with a [serum analysis], and they need to know how to evaluate those serums.” If prescribers had that knowledge, he said, “outcomes would be much better.” The PROP proposal is on the FDA docket, and the agency has until January 2013 to respond. Dr. Kolodny noted that even if the agency decided to require label changes, individual physicians would not be restricted from prescribing off-label for longer-term opioid therapy at higher doses for patients with CNCP. “The FDA doesn’t regulate the practice

of medicine. It regulates drug companies,” he said. Dr. Fudin said that although physicians would be able to prescribe off-label, the presence of label restrictions could dissuade many from doing so because of liability concerns, thus denying relief to patients needing more potent analgesics. Additionally, he said, many health insurers including Medicare and Medicaid likely would withhold payments for opioid prescriptions not adhering to label indications—a potential financial hardship for people unable to work because of painful disabilities. He cited Florida’s experience with the so-called “pill mill” legislation. The new law, he said, is causing many doctors to fear prescribing opioids and pharmacies to be unwilling to fill prescriptions, leaving many elderly patients with chronic pain syndromes not only in pain but also going through withdrawal. “If Florida represents even a small percentage of what we can expect countrywide from the PROP petition, it will be a disaster.” Dr. Kolodny said the assertion that medical insurers would withhold payments from physicians prescribing opioid therapy off-label was “just plain wrong,” adding that psychiatrists like himself “do a lot of prescribing for offlabel indications” and encounter no payment problems with Medicare and Medicaid or other insurers. He also maintained that the reluctance of many legitimate retail pharmacies in Florida and other states to fill prescriptions for opioids like oxycodone was due not to state laws seeking to curb illicit “pill mills,” but to their fear of robberies and because “they just don’t want to be caught in the middle of all this.” —Bruce Buckley

28 Clinical

Pharmacy Practice News • November 2012

Pain Medicine

Data Mining Can Improve Opioid Safety T

al made during the 90-minute webinar exploration of troublesome opioid safety issues. The panelists also offered practical strategies for improving pain management practices. 0

No Hurt

Hurts Little Bit

Hurts Little More

Hurts Even More

Hurts Whole Lot

Hurts Worst

No pain

Moderate pain

Worst possible pain

Pain Rating Scales

‘The idea that we can get you to a pain score of near zero is not really an appropriate end point.’ —Lewis S. Nelson, MD

Incidence, %

oo many opioid-related medication errors fly under the radar of voluntary reporting systems, so pharmacists need to mine other hospital data sources for a truer picture of opioid safety risks in their organizations, according to Matthew Fricker, MS, RPh, FASHP, program director at the Institute for Safe Medication Practices (ISMP). Opioid errors often lie hidden in these data, he suggested. Speaking during a recent ISMP webinar panel discussion, Mr. Fricker listed several often-overlooked information sources that could help heighten hospital-wide awareness of opioid misadventures and prompt a more rigorous push for safer practices. First, he advised, look at the hospital’s adverse reaction database because many events reported as drug reactions are actually the result of medication errors. “If we give someone 4 mg of hydromorphone IV push—particularly an opioidnaive patient with some comorbidities— we will have an adverse drug reaction, but it is really more of a medication error.” Records of pharmacist interventions, Mr. Fricker said, can be another “significant bucket” of valuable safety data. How many interventions, he asked, involve “pharmacists calling prescribers to get an opioid dose modified? Essentially what you have there are near misses or close calls that didn’t reach the patient because of some intervention upstream.” Additionally, he said, if the data are available, examine how often opioid-reversal drugs like naloxone had to be used and how many rapid response team actions were related to respiratory depression following opioid administration. Other helpful clues can be gleaned from database sources outside of your own hospital, noted Dr. Fricker and the other panelists—Lewis S. Nelson, MD,

40 30 20 10 0

Wrong Dose

Improper Patient Monitoring

Other Factors

Figure. Joint Commission Sentinel Event database (2004-2011) for opioid-related adverse drug events. a professor in the Department of Emergency Medicine at NYU Langone Medical Center, in New York City, and ISMP President Michael R. Cohen, ScD, MS, RPh, FASHP. One useful source of information is the Joint Commission’s Senti-

nel Event database, which gives breakdowns of opioid-related adverse drug events that have occurred nationally and thus are likely to be potential trouble spots for your own facility (Figure). These suggestions were among sever-

Could REMS Help Ease Fears Over Opioids?

he FDA’s most recent Risk Evaluation and Mitigation Strategy (REMS) for opioids, which covers extended-release and long-acting formulations, requires opioid product makers to develop educational programs for health care providers and nonpromotional medication guides for patients designed to reduce the risks for opioid-related medication errors and curb overprescribing. Prescriber enrollment in the educational programs related to the extended-release and long-acting opioid REMS is voluntary. A REMS introduced late last year covered fentanyl formulations but mandated education for prescribers, pharmacies, distributors and patients. The FDA has indicated that a REMS on short-acting opioids may follow in a “stepwise approach” to safer use of all products. Asked to comment on the opioid REMS, Lewis S.

Nelson, MD, one of two presenters in the ISMP webinar, cited an article in the Journal of the American Medical Association (2012;308:457-458) that he cowrote with Jeanmarie Perrone, MD, of the Department of Emergency Medicine at the Perelman School of Medicine, University of Pennsylvania, in Philadelphia. Although “prescriber and patient education alone will likely prove insufficient to assuage the concerns of patients with chronic noncancer pain, who fear the reduced availability of opioid pain relievers, and public health advocates, who fear the excessive use of these drugs,” the authors wrote, the REMS approach “may be an important component for addressing the opioid epidemic in the United States.” They also noted the importance of minimizing “the burden on physicians and the health care system by implementing a REMS that does not compromise

Managing Expectations Aggressive use of opioids for managing pain as well as the promise of a pain-free patient experience both came under fire from Dr. Nelson and Mr. Fricker. “The expectation of absolute pain control is a little bit misguided,” Dr. Nelson said. “Surgeries hurt. Injuries hurt. But the idea that we can get you to a pain score of near zero is not really an appropriate end point.” Mr. Fricker added that the desire to keep patients pain free “may be contributing to some overly aggressive prescribing of higher doses of opioids.” Promising patients that they will be pain free “is a serious mistake,” he said. “It’s a goal that you will not be able to achieve.” Instead, he suggested, “we should be saying, ‘You may be experiencing some pain, but we will respond to your pain. We will manage it. We will not allow you to continuously be in pain.’” Patient satisfaction scores, they both suggested, may be driving some practitioners and hospitals to promote more aggressive pain management practices. “A lot of people,” Mr. Fricker said, are concerned about achieving high scores on the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) or Press Ganey surveys, which tie patient satisfaction ratings to reimbursement. Dr. Nelson added that the link between patient satisfaction scores and reimbursement together with “intense competition” among medical centers are part of the reason “that we’ve put an extreme focus” on pain control. “And that’s great,” he continued. “There is no doubt that managing pain

•

see DATA MINING, page 30

care.” One risk, they wrote, was that physicians might “avoid prescribing a drug if they are unwilling or unsure of how to meet the REMS requirements.” As evidence, they pointed to a recent study which showed that 13.4% of 259 physicians would stop prescribing opioids if they were required to obtain four to eight hours of training and two hours of continuing education every two years (J Opioid Manag 2011;7:109-115). The authors indicated other concerns, including “financial motivations and creative risk-benefit messaging” in REMS programs, which, “although ostensibly independent,” are being funded by opioid product manufacturers. “Furthermore,” they wrote, ”although education is a crucial element of safety, medication guides and related warnings have generally been ineffective in educating patients about the risks associated with certain medications.” —Bruce Buckley

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30 Clinical

Pharmacy Practice News • November 2012

Pain Medicine

DATA MINING continued from page 28

is important,” but he added that opioids—and all pain medications—have adverse side effects and are not completely safe. “I’d rather explain to a patient that their pain score is slightly higher than they would like it to be than explain to a family member why a patient is dead from respiratory depression or another complication.” The potential for addiction should be another reason for taking a less aggressive approach, Dr. Nelson said. “We know that it’s rare to get addicted to pain medications through medical care, but we know it happens,” he said. “We just have to keep a focus on that as well.” A less aggressive approach to opioid reversal is also a good idea, Dr. Nelson suggested. “Naloxone is often used unnecessarily in patients with respiratory depression,” he said, when “a good bag valve mask and some exogenous oxygen” are all that is needed. “The problem with naloxone use is that people administer it too aggressively, in too high a dose and

too rapidly. What that does is throw the patient into precipitated opioid withdrawal, which is terrible.” The way to go, Dr. Nelson said, is to begin with smaller naloxone doses and titrate upward, “as long as you’re able to provide a little bit of bag valve mask respiration to tide them over.” He suggested the appropriate starting dose should be 0.04 mg, or 40 mcg, rather than the standard 0.4- to 2-mg dose. “Taking a patient with chronic pain who is getting an opioid and rapidly reversing them is not an acceptable alternative,” he said.

Pharmacist’s Role Pharmacists can play a key educational role in fostering safer opioid practices, Mr. Fricker said, noting that there is “a large knowledge deficit out there about opioids and how to use them safely.” For example, he pointed to an ISMP practitioners survey in which one question asked whether obese patients required higher or lower opioid doses. Many of them, he said, “got it wrong. They felt that obese patients would need more drug.” To help fill that knowledge gap, phar-

macists can ask to attend a surgical or other appropriate department meeting “to spread the message” about opioid problems, Mr. Fricker said. “Ask for five minutes. Just hit the highlights about what is happening with opioids in your own institution, what’s happening out there, what are we reporting in the ISMP newsletter.” Developing an educational program to help practitioners remember comorbid conditions that affect opioid requirements as well as equianalgesic potencies of various opioids is another potential opportunity, he said. Education

Statement of Ownership

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.™

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Pharmacy Practice News • November 2012

Pain Medicine may be a “low-level strategy,” he added, “but we need to start with it.” Virginia Ghafoor, PharmD, a clinical pharmacy specialist for pain management at the University of Minnesota Medical Center, in Minneapolis, said that while strengthening opioid education for prescribers is a laudable goal, it has some limitations. “Educating staff on pain management and appropriate medication therapy looks easy on paper, but in reality is very difficult,” Dr. Ghafoor said. “For physicians and other health care providers,

many of the continuing education programs offered on pain management and medication safety are based on voluntary participation, and the participants are not required to maintain credentials. Also, true competency-based training with strict requirements tied to opioid prescribing could hurt patients by making providers opt out of this practice. So, there are no easy answers to this.” As for the webinar’s cited strategy of tracking medication interventions and the use of naloxone, ‘that may provide data on ‘risk’ for respiratory depression,

but this is a retrospective approach,” Dr. Ghafoor said. “A true opioid safety plan needs to take a proactive approach to preventing medication errors before they lead to patient harm.” Dr. Ghafoor said she is particularly excited about the potential for pharmacist-led admission medication reconciliation to have “a profound influence” on opioid safety. Such programs, she noted, can document the correct drug, dose and frequency of opioid medication use—information “that is fundamental to pain management by reducing the

The science behind the molecule behind the formulation... The efficacy behind the safety behind the trust A distinctive hydrogel core...a long history of clinical excellence... over 260 million units*1 prescribed...and counting

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Millions prescribed. Millions treated.

• 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.

potential to under- or overdose the opioid.” With nearly all 50 states now having a controlled substance database program for retail oral opioid prescriptions, she added, pharmacists also can use this information to provide a more accurate assessment of the patient’s opioid exposure. By doing so, “the medication history and institutional practice guidelines for safe opioid prescribing can be incorporated into a pain management plan that is customized for the individual patient.” —Bruce Buckley

32 Clinical

Pharmacy Practice News • November 2012

Research

LIT AWARDS continued from page 25

PharmD, was applying for a fellowship position, the pair dropped in for an informal visit at the home of C. Michael White, PharmD, a professor of pharmacy practice and the head of the center, to “set the stage for the next day’s interview.” “It was 2007, and my wife was out of town and I was looking after my two very small children,” recounted Dr. White. “My cats were interested in who the

new people were so they were walking around us the whole time. I had no inkling Olivia was horribly allergic to cats until her eyes swelled and other symptoms kicked in big time. I knew then that if she was willing to risk death to be my fellow, she was serious about success and would accomplish great things!” Dr. Phung’s work, and the particular study for which she is being recognized— a Bayesian mixed treatment comparison of oral antidiabetic drugs for the prevention of type 2 diabetes—fills a significant gap that exists in light of a paucity of

(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

2.2

0.7

0.4

2.7

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

head-to-head drug trials, Dr. White said. “With a multitude of placebo-controlled trials but scant information regarding direct therapy comparisons, the use of this analytical approach can provide insights into the relative efficacy of these drugs where large-scale, head-to-head trials are under way or are unlikely to be conducted,” Dr. White pointed out. Dr. Phung’s analysis of 20 randomized controlled trials of antidiabetic drugs showed that α-glucosidase inhibitors, biguanides and thiazolidinediones sig-

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

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

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

nificantly reduced the relative risk for developing diabetes compared with control, but the latter had the greatest effectiveness in this regard ((Diabetic Med 2011;28:948-964). Dr. Phung, now an assistant professor of pharmacy practice and administration at the Western University of Health Sciences, in Pomona, Calif., said that improving patient care through research is her modus operandi. “By highlighting the existing evidence, synthesizing it and disseminating the results, I’m contributing to overall scientific knowledge which can then be applied to patient care,” she said. Given the urgent need for improved treatment and prevention of type 2 diabetes, Dr. Phung added, “I can only see my involvement in diabetes-related research growing.”

Pharmacy Practice Research Award As a pharmacy resident at Henry Ford Hospital in Detroit, Jessica Schillig, PharmD, came to be known Jessica Schillig, as a “pitbull.” PharmD “She was tough, not afraid to advocate for the patient and for the safe use of anticoagulant medications, and she wasn’t easily rattled by the occasional professional disagreement or conflict that she encountered in starting a new service,” recalled James Kalus, PharmD, BCPS, Dr. Schillig’s residency director at the time. Dr. Kalus, the senior manager of patient care services at Henry Ford and the senior author of a study examining the clinical and safety impact of the inpatient pharmacist-directed anticoagulation service (PDAS) that Dr. Schillig helped create and for which she received the Pharmacy Practice Research Award. The study included 500 internal medicine or cardiology patients receiving warfarin, randomized to drug management by either the PDAS or a physician ((J Hosp Med 2011;6:322-328). PDASinitiated and managed in-hospital warfarin treatment involved pharmacists providing patient education and a dosing schedule upon discharge, as well as including a summary of warfarin administration in the patients’ electronic medical records. “Our paper is one of only a handful to evaluate standardized pharmacistdirected inpatient management of anticoagulation therapy, and it demonstrates similar safety outcomes to traditional physician management, and even suggests improved safety with the PDAS in high-risk subpopulations,” said Dr. Schillig, who is now clinical pharmacist at LifeCare Hospitals of

Clinical 33

Pharmacy Practice News • November 2012

Research Fort Worth, Texas. The awardee’s interest in pharmacy can be traced back to a stint as a pharmacy clerk in Grafton, Ohio, during high school, where she “realized the impact and relationship that the pharmacist could have with a patient.” Her focus on pharmacist-managed inpatient anticoagulation treatment grew during a longitudinal residency rotation at Henry Ford’s outpatient anticoagulation clinic. Discussions at the time on how best to meet the Joint Commission’s National Patient Safety Goal 03.05.01, which emphasizes harm reduction among inpatients receiving anticoagulants, was the impetus for the creation of the PDAS. “Dr. Kalus approached me about developing the PDAS, and I was up for the challenge,” she said. Thanks to Dr. Schillig’s persistence and perseverance, Henry Ford’s PDAS—one of the first in the country—has expanded the range of clinical services that hospital pharmacists can offer. Clearly, her pitbull attributes serve not only herself, her hospital and her patients but also the profession as a whole.

Student Research Award The pithy Twitter name speaks volumes: @OracleofPharma. Tech-savvy, ambitious and innovative, Ronak Savla, PharmD, has Ronak Savla, always had his eye on PharmD the future. “My interest in nanotechnology started when I attended a magnet school for math, science and engineering,” Dr. Savla said from his lab at the Department of Pharmaceutics at Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, in Piscataway. “The subject seemed very futuristic.” Appropriately, the title of the abstract for which he received the Student Research Award carries a sci-fi feel: “Tumor Targeted Quantum Dot-Mucin 1 Aptamer-Doxorubicin Conjugate for Imaging and Treatment of Cancer.” The research examined the ability of a modified doxorubicin molecule to increase drug delivery directly to tumors ((J Control Release 2011;153:1622). The investigators created the modified molecule by conjugating it with a quantum dot—a nano-drug carrier— and with a DNA aptamer that binds to mutated mucin-1 receptors, which are overexpressed in many cancer cells. To further limit the drug’s release to tumors, they designed the doxorubicin-quantum dot bond to hydrolyze in mildly acidic environments, like those of lactic acid–filled tumors. “The results of our in vitro and mouse model biodistribution studies

have been promising,” said Dr. Savla. The drug showed a greater degree of cytotoxicity than the currently used form of the agent, and the decreased amount of systemic drug release should reduce drug-related toxicity, he said. Furthermore, fluorescence emitted by the quantum dot only when it is attached to the doxorubicin molecule can help clinicians monitor treatment, Dr. Salva noted. As a researcher and a student, Dr. Savla has proven himself to be “exceptional,” senior study author Tamara

Minko, PhD, told Pharmacy Practice News. “Since he joined Rutgers, Ronak has been on the Dean’s Honors list every semester and has received several scholarships and awards,” noted Dr. Minko, a professor and the chair of the Department of Pharmaceutics at Rutgers. Dr. Savla also is one of the first students in the School of Pharmacy’s newly created PharmD/PhD program, she added. With an interest in the business of pharmaceuticals and seemingly unlimited ambition, it would be no surprise if Dr. Savla also pursues a business

degree—and puts it to good use. “My goal is to start a biotech company and eventually go into venture capital, helping other companies develop their own ideas,” he said. In preparation, he is making note of therapeutic pipeline developments and sharing his insights on his blog, wtpharma.blogspot.com. As he closely tracks industry developments, you can be sure that Dr. Savla himself will be an innovator to watch out for. —David Wild

0 HP 95 AS th 1 o Bo

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Pharmacy Practice News • November 2012

Educational Review

Management of

Gastroesophageal Reflux Disease M. CHANDRA SEKAR, RPH, PHD Associate Professor

LORI ERNSTHAUSEN, PHARMD, BCPS Assistant Professor College of Pharmacy University of Findlay Findlay, Ohio

hronic gastroesophageal reflux disease (GERD) results from the e dysfunction of the lower esopha ageal

sphincter (LES), which leads to frequentt exposure of the esophagus to gastric contents, including substances such as acid and pepsin that are harmful to the esophageal epithelium.

GERD management primarily involves decreasing the acidic content of the stomach that is responsible for causing esophageal damage and improving the function of LES. Goals of GERD therapy include improving symptoms and quality of life, healing erosive esophagitis, and preventing complications, such as esophageal stricture.

Epidemiology of GERD GERD is quite prevalent, with an estimated 44% of US adults experiencing heartburn—the principal symptom resulting from acid regurgitation—at least once a month.1 Many patients use over-the-counter (OTC) medications to self-treat heartburn symptoms. Although many patients suffer from occasional indigestion and get sufficient relief from these OTC medications, others have chronic attacks of heartburn that require further medical treatment. The diagnosis of GERD is not always simple or straightforward. Getting a patient’s complete medical history is the first step. If a patient has classic or typical symptoms of heartburn and regurgitation, with no additional complications, then the diagnosis of GERD can be made with relatively high confidence. Although there is no gold standard for diagnosing GERD, because it involves alterations in acid secretion

and, therefore, pH, 24-hour pH monitoring with a probe is an accepted standard to establish or exclude the presence of the disease.2 Patients generally present to the outpatient pharmacy or clinic with symptoms of heartburn, dyspepsia, or regurgitation. However, some patients may present with atypical or complicated signs and symptoms of GERD, such as asthma, chest pain, or chronic cough that may delay the diagnosis of GERD (Table 1).3-5 Patients presenting with atypical or complicated symptoms should be referred to their health care provider immediately for further assessment and should not treat themselves with OTC medications.

Pathophysiology of GERD GERD results from repetitive acid exposure to the esophageal mucosa. The LES remains tonically contracted under normal resting conditions, but in cases of GERD it becomes “leaky,” allowing stomach contents to pass from the stomach into the esophagus. Any drug or disorder that increases LES relaxation or impairs reflexes following normal LES relaxation may worsen GERD. Other pathophysiologic conditions such as hypothyroidism, diabetes mellitus, and asthma, as well as pregnancy, may worsen the disease. Lying in a supine position or bending over after

eating, or consuming a large meal can cause increased acid secretion and increased pressure on the LES and result in symptoms of GERD.

Acid Secretion and Its Regulation Gastric acid secretion is stimulated by neuronal (acetylcholine), paracrine (histamine), and endocrine (gastrin) mechanisms. The central nervous system (CNS) predominantly stimulates acid secretion by parietal cells through the action of acetylcholine on the enteric nervous system. CNS activation occurs in response to sight, smell, taste, or anticipation of food. Acetylcholine, released in response to CNS stimulation, causes the release of histamine from enterochromaffinlike cells. Histamine, in turn, acts as a paracrine regulator, causing acid secretion. The efficacy of histamine H2 receptor antagonists in blocking acid secretion clearly demonstrates the important role histamine plays in acid secretion. Gastrin, the most potent stimulator of acid secretion, is released from antral cells via multiple mechanisms, including CNS activation, local distension, and triggering by certain chemical components of the gastric contents. On the other hand, gastric secretion is controlled via feedback regulation. Somatostatin, which is produced by the Text continues on page 36

36 Clinical

Pharmacy Practice News • November 2012

Educational Review Text continued from page 35

antral cells, inhibits acid secretion by causing feedback inhibition of gastrin release when the luminal pH falls below 3.0. In addition to the somatostatinbased feedback regulation mechanism, another mechanism whereby the epithelial layer is protected from gastric acid is via prostaglandin E2 and I2 stimulation of bicarbonate release, which neutralizes gastric acid. The epithelial layer of the mucosa also is protected by insoluble gel that coats the mucous surface.

Table 1. GERD Symptom Classification Typical Symptoms

Atypical Symptoms

Complicated Symptoms

Heartburn Hypersalivation Regurgitation

Asthma Chronic cough Chronic sore throat Dental erosions Hoarseness Laryngitis Noncardiac chest pain

Anemia Barrett’s esophagus Bleeding Choking Dysphagia Odynophagia Weight loss

GERD, gastroesophageal reflux disease Based on references 3 3-5. 5.

Nonpharmacologic Treatment All patients with GERD should (Table 3).9 Typically, OTC doses of H2 are called on to consider different employ nonpharmacologic treat- antagonists and PPIs are prescribed patient-specific factors and proment options for the management on a scheduled (once- or twice-dai- vide counseling to help patients of symptoms, regardless of wheth- ly) basis for a 2-week trial. Antacids avoid further complications. Addier pharmacologic treatment is indi- also may be used on a scheduled tionally, they should advise patients cated. For patients coming to the basis, as well, or in combination with to look for specific ingredients in clinic with their first experience of H2 antagonists or PPIs for the treat- their antacid preparations because GERD, lifestyle changes should be ment of breakthrough symptoms. manufacturers have started “brandemployed for at least 2 weeks before Patients who do not achieve relief ing” antacid products with comscheduled acid-suppressing thera- with scheduled OTC doses should pletely different compositions with py is recommended. Patients should continue therapy with either stan- the same “name.” For example, be counseled to eat smaller meals dard-dose (prescription) H2 recep- 5 mL of Mylanta Supreme (McNeil) and to avoid foods that may trigger tor antagonists for 6 to 12 weeks or contains 400 mg of calcium carbonate and 135 mg of magnesium symptoms of GERD (Table 2).6,7 The PPIs for 4 to 8 weeks. patient’s medication list also should hydroxide, but 5 mL of Mylanta Maximum Strength (McNeil) contains be evaluated for any drugs that may ANTACIDS cause relaxation of the LES or cause The mechanism of action of ant- 400 mg of aluminum hydroxide, 400 direct irritation of the stomach or acids is relatively straightforward mg of magnesium hydroxide, and 40 esophageal mucosa. Patients expe- and involves direct neutralization mg of simethicone. riencing symptoms at night may ele- of acid via interaction with a base. Although sodium bicarbonate vate the head of the bed or avoid Despite the simple mechanism, the is rapidly absorbed and effective eating meals before bedtime. Other appropriateness of any particular at neutralizing acid, excess sodinonpharmacologic lifestyle interven- antacid for the patient will be deter- um resulting from its use could be tions that may improve GERD symp- mined by the patient’s physiologic risky for a patient with cardiac and toms include weight loss, smoking status, as well as personal taste and renal failure. Additionally, belchcessation, and avoiding or decreas- formulation preferences. Because ing produced by sodium bicarboning alcohol consumption. patients usually obtain their ant- ate and calcium carbonate could acids OTC, pharmacists frequently be a problem in some patients.

Pharmacologic Treatment Patients who do not experience relief of their symptoms with lifestyle changes should continue with lifestyle modifications; however, scheduled acid-suppressing therapy with either antacids, H2 antagonists, or proton pump inhibitors (PPIs) should be considered.8 The choice of whether to begin pharmacotherapy with antacids, H2 antagonists, or PPIs depends on patient preference, previous treatment success (if any), potential for drug interactions, cost, and convenience

Table 2. Foods and Drugs That Worsen GERD Foods

Drugs

Alcohol Chocolate Citrus fruits Coffee Fatty foods Mint Onions Peppers Spicy foods

Anticholinergics Aspirin Bisphosphonates Caffeine Corticosteroids Dihydropyridine calcium channel blockers Estrogen Iron Nitrates NSAIDs Potassium chloride Progesterone Tetracycline

GERD, gastroesophageal reflux disease; NSAID, nonsteroidal anti-inflammatory drug Based on references 6 and 7 7..

Magnesium- and aluminum-containing compounds provide a better neutralizing profile and greater sustained action; these agents often are used in combination and in lower doses to avoid the side effects of diarrhea (with magnesium) and constipation (with aluminum) associated with single-ingredient products. However, in patients with renal insufficiency, increased absorption of aluminum can contribute to osteoporosis, encephalopathy, and proximal myopathy, so products containing aluminum should be used with caution in this population. Many antacid preparations also include simethicone, an antifoaming agent with a surfactant capability that decreases foaming—by reducing the surface tension of gas bubbles so that larger bubbles can be eliminated easily. Like PPIs and H2 antagonists, antacids have a pHaltering property that may alter the absorption of certain drugs when they are given concomitantly. For example, pH affects the absorption of itraconazole, ketoconazole, glipizide, glyburide, cefuroxime, digoxin, and indinavir. In contrast, drugs such as ciprofloxacin can chelate with aluminum and magnesium in the antacid. The anionic polysaccharide alginic acid is capable of forming a “viscous gum” in the presence of water. Because of this, alginate has been used in antacid preparations such as Gaviscon (GlaxoSmithKline) to create a physical barrier that protects the epithelium from acid. H2 RECEPTOR ANTAGONISTS H 2 receptor antagonists prevent acid secretion by competitively inhibiting the binding of histamine to its receptor on the basolateral side of parietal cells. Because they predominantly suppress basal acid secretion, they are more effective for the treatment of peptic ulcer disease than for the treatment of GERD. The available H2 receptor antagonists—cimetidine, famotidine, nizatidine, and ranitidine—(Table 3) are less potent than PPIs; however, they do exert much faster onset of action than PPIs and produce 70% inhibition following 24-hour Text continues on page 39

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Pharmacy Practice News • November 2012

Educational Review

Table 3. Characteristics of Available GERD Treatments Drug

Usual Dosage

Comments

Cimetidine

400a or 800a mg bid

Greater interactions with CYP450 metabolizing pathway than other H2 antagonists

Famotidine

20 or 40 mg bid

Nizatidine

150a or 300a mg bid

Ranitidine

150 or 300 mg bid

H2 antagonists

PPIs Dexlansoprazole (Dexilant, Takeda)

30 mg/d

Interaction with antiretrovirals and methotrexate

Esomeprazole (Nexium, AstraZeneca)

20 or 40 mg/d

Caution in patients with “slow metabolizer” of CYP450 pathway

Lansoprazole

30a or 60a mg/d

Interaction with antiretrovirals and methotrexate

Omeprazole

20 or 40a mg/d

Caution in patients with “slow metabolizer” of CYP450 pathway

Omeprazole with sodium bicarbonate

20 or 40a mg/d

Caution in patients with “slow metabolizer” of CYP450 pathway

Pantoprazole

40 or 80a

Less chance of interaction compared with other PPIs

Rabeprazole (Aciphex, Eisai)

20 or 40a mg/d

Increases digoxin trough levels

bid, twice daily; CYP, cytochrome P450; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor a

Unlabeled use.

proton pump, leading to the pump’s administration, thereby providing inactivation. It takes several days more rapid relief of symptoms. All of treatment with PPIs before the 4 H2 antagonists are available as maximal inhibition of acid secreboth prescription and OTC products. tion is seen. Characteristics of the Three of them—cimetidine, ranitidine, 6 available PPIs—dexlansoprazole and famotidine—also are available (Dexilant, Takeda), esomeprazole for IV and IM administration. (Nexium, AstraZeneca), lansopraThe H 2 antagonists mainly dif- zole, omeprazole, pantoprazole, and fer in their pharmacokinetics and rabeprazole (Aciphex, Eisai)—are potential for drug–drug interac- shown in Table 3. tions. They are rapidly absorbed PPIs are prodrugs that get confollowing oral administration, and verted to an active drug under acidthis absorption may be enhanced ic conditions. This activation must by food and decreased by antac- occur in the canaliculi of the pariids. Unlike PPIs, very small amounts etal cells. As food intake leads of H2 antagonists are protein bound. to acid secretion, and all the PPIs The major excretion mechanism of (except pantoprazole) inactivate H 2 antagonists involves the kid- only the active form of the proton neys; thus they necessitate dosage pump, it is advisable to take PPIs 30 adjustments in patients with renal, minutes before meals for maximum but not liver, dysfunction. effect. It is very important for pharmacists to recognize and emphaPPIS size this difference to ensure an PPIs are among the most potent optimum therapeutic outcome. The inhibitors of acid secretion, inhibit- only exception to this rule is pantoing acid secretion by 80% to 95%. prazole, which is capable of inactiTheir mechanism of action involves vating the pump in both the basal interaction with the activated and activated state. Text continued from page 36

To prevent the degradation of PPIs by acid in the gastric lumen, many formulations of PPIs are supplied in enteric-coated formulations. For patients who cannot swallow a tablet, orally disintegrating tablets and delayed-release suspensions are available. PPIs are rapidly absorbed, highly protein-bound and extensively metabolized by cytochrome P450 (CYP) enzymes. CYP2C19 and CYP3A4 are the 2 major CYP enzymes mainly involved in PPI metabolism. Asians are more likely to possess the “slow” metabolizing CYP2C19 genotype compared with Caucasians and blacks; this has been suggested to contribute to heightened efficacy and toxicity of these agents among this ethnic group.8 Although no adjustment in the once-daily dosing is required for a patient with chronic renal failure, hepatic disease substantially reduces the clearance of esomeprazole and lansoprazole, necessitating dosage adjustment. PPIs have now been used for

more than 3 decades and have demonstrated a good safety profile. The most common side effects are nausea, abdominal pain, constipation, flatulence, and diarrhea. Other less common side effects include myopathy, arthralgias, headaches, and skin rashes. Caution should be exercised when any drug with pH-dependent absorption is to be administered to a patient receiving a concomitant PPI. A simple solution, if possible, would be to administer the drugs at least 4 hours apart.

Overall Treatment Approach As mentioned previously, all patients should be counseled on lifestyle modifications to reduce the risk for and manage symptoms of GERD. Antacids, OTC H2 antagonists (taken up to twice daily), or PPIs (taken once daily) should be considered for use as patient-directed therapy in those whose symptoms persist despite lifestyle changes (Figure).3,7 Patient-directed therapy involves the use of antacids or Text continues on page 40

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Pharmacy Practice News • November 2012

Educational Review 3. Zweber A, Berardi RR. Chapter 13. Heartburn and Dyspepsia. In: Krinsky DL, Berardi RR, Ferreri SP, Hume AL, Newton GD, Rollins CJ, Tietze KJ, eds. Handbook of Nonprescription Drugs An Interactive Approach to Self-Care, 17th ed. http:// www.pharmacylibrary.com/resource/23. Accessed August 13, 2012.

Text continued from page 39

acid-suppressing therapy on an asneeded basis as symptoms arise or as GERD symptoms are anticipated. Many patients, however, still experience symptoms despite patientdirected therapy and may require prescription-strength, acid-suppressing therapy with H2 antagonists or PPIs. Longer-term prescriptionstrength therapy should be titrated to the lowest dose that provides control of the symptoms. Patients may use antacids for occasional breakthrough symptoms.10 Continuous daily administration of acid-suppressing therapy, particularly PPIs, has been shown to be more effective than patient-directed therapy; however, patient-directed therapy may be appropriate for patients with less frequent heartburn or those who can identify trigger foods.11 Promotility agents and mucosal protectants have been found to have limited roles in the treatment of GERD and are not routinely recommended in the management of GERD. Likewise, the combination of acid-suppressant therapies (H2 antagonists and PPIs) is not recommended and does not provide any additional benefit. Patients who continue to have symptoms despite optimal prescription-strength therapy should follow-up with their prescriber and may require further assessment, high-dose therapy, or surgery.12

Conclusion Appropriate management of patients with GERD requires the use of lifestyle modifications along with pharmacologic agents such as antacids, H2 antagonists, and PPIs. Nonpharmacologic therapy is the basis of management for patients with

4. Heidelbaugh JJ, Gill AS, Van Harrison R, Nostrant TT. Atypical presentations of gastroesophageal reﬂex disease. Am Fam Physician. 2008;78(4):483-488. 5. Holtmann G, Bigard M, Malfertheiner P, Pounder R. Guidance on the use of overthe-counter proton pump inhibitors for the treatment of GERD. Int J Clin Pharm. 2011;33:493-500. 6. Dent J, El-Serag HB, Wallander M, Johansson S. Epidemiology of gastrooesophageal reﬂex disease: a systematic review. Gut. 2005;54(5):710-717. 7.

Williams DB, Schade RR. Chapter 39. Gastroesophageal Reﬂex Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey ML, eds. Pharmacotherapy: A Pathophysiologic Approach, 8th ed. http://www. accesspharmacy.com/resourceToc. aspx?resourceID=669. Accessed August 13, 2012.

8. Dickson EJ, Stuart RC. Genetics of response to proton pump inhibitor therapy: clinical manifestations. Am J Pharmacogenomics. 2003;3(5):303-315.

Figure. Treatment approach for symptomatic GERD. GERD, gastroesophageal reflux disease; H2RA, histamine-2 receptor antagonist; OTC, over-the-counter; PPI, proton pump inhibitor Based on references 3 and 7.

GERD, but in most cases therapeutic lifestyle changes do not control symptoms. Pharmacists can serve to provide patient education on lifestyle interventions for symptom relief or assist patients with identifying triggers for their symptoms. The choice among pharmacologic agents and length of therapy depends on various patient- and drug-specific factors and should be reassessed periodically to determine

9. Wallace JF, Sharkey KA. Goodman & Gilman. The Pharmacological Basis of Therapeutics, 12th ed. New York, NY: McGraw-Hill; 2001. 10. Kahrilas PJ. Clinical practice. Gastro– esophageal reﬂux disease. N Engl J Med. 2008;359(16):1700-1707.

any subsequent courses of therapy.

References 1.

Sontag SJ. The medical management of reﬂux esophagitis. Role of antacids and acid inhibition. Gastroenterol Clin North Am. 1990:19(3):683-712.

2. Johnsson F, Weywadt L, Solhaug JH, Hernqvist H, Bengtsson L. One-week omeprazole treatment in the diagnosis of gastroesophageal reﬂux disease. Scand J Gastroenterol. 1998;33(1):15-20.

11. Ip S, Chung M, Moorthy D, et al. Comparative effectiveness of management strategies for gastroesophageal reﬂux disease: update. Comparative Effectiveness Review No. 29. AHRQ Publication No. 11-EHC049-1. Rockville, MD: Agency for Healthcare Research and Quality. September 2011. http:// effectivehealthcare.ahrq.gov/index.cfm/ search-for-guides-reviews-and-reports/?p ageaction=displayproduct&productid=781. Accessed September 7, 2012. 12. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reﬂex disease. Am J Gastroenterol. 2005;100(1):190-200.

Infectious Disease

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questions we have been asking” during ongoing conference calls between pharmacy directors in Massachusetts and state health officials, according to the director of a multihospital healthsystem in the northeast who asked to remain anonymous due to the sensitive nature of the discussions. The consensus, the director said, was this: If you can purchase compounded drugs from an FDA-approved and inspected facility, “that’s who you should go with; it’s really the safest bet.” The problem with the methylprednisolone implicated in the outbreak, the

source pointed out, is that it often has been in short supply from the major manufacturers. As a result, pain clinics and some health systems have had to purchase the drug from NECC and other non–FDA-approved facilities. Because those facilities are not required under current pharmacy statutes to adhere to all of the safety checks required of large commercial operators, “there’s risk involved” in partnering with such entities, he said. The extent of that risk became particularly clear in late October, when Massachusetts state health officials announced that their probe of NECC had uncovered a litany of regulatory and safety violations that further

strengthened the link between the company’s practices and the fungal infections. Floor mats in compounding areas filled with dirt and debris, standing water adjacent to a supposed “clean room” used for sterile preparations and visible black fungus in sealed vials of the steroid suspensions linked to the outbreak were among the environmental violations found, the investigators reported. The investigators also found evidence that NECC shipped compounded drugs before the sterility testing results were sent back to the company, in violation of federal safety rules governing large-scale sterile compounding. As perhaps a final note on NECC’s cul-

pability, on Oct. 26 the FDA released a form called a 483, which is issued when investigators believe they have found safety violations that may violate federal law. The form came as a result of even more concrete evidence of negligent sterile compounding practices at NECC, including signs of mold growth in at least 83 vials of methylprednisolone and a failure to act after the company was aware of “actionable” levels of bacteria and mold were present on clean room production hoods used to compound supposedly sterile medications. Those findings followed an earlier report from the Centers for Disease Control and Prevention (CDC) and the

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42 Clinical

Pharmacy Practice News • November 2012

Infectious Disease

MENINGITIS continued from page 40

FDA, which found that the Exserohilum rostratum fungus detected in the vast majority of infected patients was present in at least one of the lots of methylprednisolone recalled by NECC.

A History of Problems

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The safety problems at NECC are not an isolated occurrence. In 2002, five people in North Carolina treated with the same steroid implicated in the cur-

rent outbreak of meningitis contracted fungal infections; one of the patients died ((MMWR 2002;51:1109-1112). Concerned about other reports of problems, in 2001, the FDA tested samples of compounded products from a dozen pharmacies and found that approximately one-third of the products failed quality control tests, most having to do with potency. Given that history, why would a hospital pharmacy continue to purchase products from outside compounders? One pharmacy director who contin-

ues to occasionally outsource selected products echoed the point that ongoing drug shortages are the usual driver. Tom Van Hassel, RPh, MPA, director of pharmacy at Yuma Regional Medical Center, in Yuma, Ariz., said that in the case of the implicated methylprednisolone solutions shipped by

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NECC, “at times they were the only company that could consistently provide this product in the strengths needed by pain clinics and some hospitals.” In an ideal world, Mr. Van Hassel noted, “of course” it is always preferable to purchase drug products from established manufacturers because those products are regulated for quality control by the FDA, as opposed to compounders, where no one regulatory body fully embraces that responsibility. “But when only the compounders reliably have a short-supply medication, we really have no other recourse,” he said. Mr. Van Hassel stressed that the majority of compounders are large, well-run operations that produce millions of safe doses each year and follow strict quality control processes and procedures. “But if their error rate is 0.1%—that is, 99.9% accuracy—it means that hundreds, if not thousands, of potentially contaminated or otherwise unsafe doses are still getting into the supply chain,” he said. The lack of failsafe quality control in pharmacy compounding “is really scary,” added Mr. Van Hassel. “This is what keeps pharmacy directors up at night.”

A Better Plan for Methylprednisolone? Virginia Ghafoor, PharmD, a clinical pharmacy specialist for pain management at the University of Minnesota Medical Center (UMMC), in Minneapolis, has a suggestion for pain clinic physicians and pharmacy directors who are losing sleep over the safety of methylprednisolone purchased from outside compounding pharmacies: Stop buying from those companies unless you have a deep knowledge of how the product is prepared. Dr. Ghafoor explained that because the steroid used for epidural injection is a suspension, it is difficult to adequately remove pyrogens and other bacterial contaminants via the usual method— using a 0.2 micron filter—due to clogging and other issues. Additionally, heat sterilization, another method for ensuring sterility, “will not necessarily remove pyrogens and fungal contaminants,” she said. Given those production and safety challenges, “our pharmacy compounding experts ... decided years ago that compounding injectable steroid suspensions was risky. So when methylprednisolone is in short supply, our policy now is to always use alternative agents such as triamcinolone or betamethasone, if available. And we get those medications from one of the larger manufacturers who are regulated by the FDA, and thus who are

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NO SHORTAGE OF COMMITMENT.

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Clinical 43

Pharmacy Practice News • November 2012

Infectious Disease

Tools for Vetting Compounders Can Help, But Some Detective Work Is Needed

harmacies and pain clinics looking to partner with new compounders or check on the quality control practices of existing vendors don’t have to go it alone. In 2010, the American Society of Health-System Pharmacists published guidelines on outsourcing sterile compounding (Am J Health-Syst Pharm 2010;67:757-765) that include detailed information on how to evaluate compounders. Dozens of recommendations are included, with many focused on ways to assess whether a potential supplier has key safety procedures in place. Help also is at hand from the ASHP Foundation’s Contractor Assessment tool (http://www. ashpfoundation.org/SterileProductsTool), developed with support from PharMEDium. A pharmacy director from a health-system in the northeast, who asked to remain anonymous due to the sensitive nature of supplier relationships, said that the guidelines and assessment tool were very useful when evaluating suppliers, including PharMEDium and Ameridose. “I came away very impressed with both company’s sterile compounding capabilities and have been purchasing from them,” the source said. “So I’ve found these materials to be very helpful.” But the resources are only a partial solution. One of the recommendations in the 2010 guidelines is to obtain copies of any “significant regulatory actions” that have been brought against potential suppliers. Unfortunately, those actions are not always readily obtainable. In the case of Ameridose, a 2008 FDA inspection found that the company did not test all of its drug lots and shipped some products before receiving the results of sterility testing, according to an industry newsletter that obtained a copy of the inspection report under the Freedom of Information Act. (Several emails to the FDA requesting confirmation of those findings had not been answered at press-time.) The pharmacy director who had used the vendor assessment materials to evaluate Ameridose said that the company’s 2008 safety issues “were not something our institution was aware of.” Cynthia Reilly, BS Pharm, the ASHP’s director of practice development, acknowledged that safety violations committed by compounders are not always a matter of public record, “especially when you are seeking the actual violation information,” she said. “For example, with the TPN contamination that occurred in Alabama last year, it’s easy to locate media stories on the Web that indicated a problem existed at [the implicated manufacturing] facility. What is harder—perhaps impossible—to find in these cases is the report of the actual violation as well as reports on corrective actions and

follow-up inspections.” Still, in many cases, Ms. Reilly noted, doing a Google search can yield useful information. “Lots of the safety problems similar to the ones initially noted at NECC and other compounders may come up with an Internet search,” she said. “Certainly, if there was a violation of a state pharmacy practice act, that is going to be in the public record,” Ms. Reilly added. “But states will vary

in terms of how navigable their web sites are in listing those violations. So it sometimes may be hard to access that type of information.” That lack of transparency “is a valid concern” that is coming to light as a result of the current outbreak, she noted. As for other measures that healthsystems should take when evaluating compounders, Ms. Reilly stressed the importance of “not only doing your due diligence during the initial selection

process but also engaging in an ongoing quality-control evaluation to ensure that the compounder is still meeting the standards you were looking for when you first established a contract with them.” Using the ASHP’s 2010 guidelines on outsourcing sterile compounding can help in that process, she noted. Ms. Reilly also stressed the importance of taking a careful look at your entire health-system’s drug purchasing

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44 Clinical

Pharmacy Practice News • November 2012

Infectious Disease

MENINGITIS continued from page 42

far more likely to follow Good Manufacturing Practices.” The problem with that approach is that the larger manufacturers don’t usually offer preservative-free steroids for injections into the epidural space. “Preservatives are toxic to the central nervous system,” Mr. Van Hassel said. “And that’s been our challenge with methylprednisolone: You sometimes can only get preservative-free

versions of this drug from outside compounders that, like NECC, are not preparing their products in FDAapproved facilities.”

One Possible Fix A possible solution to that dilemma surfaced during the conference call with pharmacy directors and Massachussetts health officials. Going into the calls, the participating pharmacy directors assumed that there usually are only two choices in purchasing compounded drugs: obtaining the med-

ications from FDA-approved facilities that manipulate existing, sterile commercial preparations—PharMEDium was cited as an example—or the more risky option of buying from companies such as NECC that make their products from nonsterile raw powders, in part because those ingredients are less prone to drug shortages. But during the conference call, a third option came up: purchasing products from companies that do work with nonsterile raw ingredients, but that also adhere to rigorous quality control procedures, such as

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routine batch testing and environmental sampling and cleaning. “We are in contact with several companies that take that approach, and if what they say about their commitment to safety pans out, this may be a partial solution to this problem,” one of the directors said. One of the companies mentioned during the call was AnazaoHealth, a specialty compounding pharmacy headquartered in Tampa, Fla., that supplies local health systems with compounded pain medications that the facilities often ship to local pain clinics. David Joseph, RPh, the company’s director of pharmacy, quality and regulatory compliance, confirmed that the firm does work with original pharmaceutical ingredients. “We have to do that in this business because the drug concentrations physicians typically order for pain patients—typically those using implanted intrathecal pain pumps—are not available commercially,” Mr. Joseph said. “Also, because these medications are injected into the spinal space, they do have to be preservative-free. So it’s necessary for us to do high-risk sterile compounding to give the physicians what they want.” To ensure safety and quality, he noted, the company complies with United States Pharmacopeia (USP)

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TOOLS continued from page 43

procedures. “Your pharmacy department may be contracting with very reputable, vetted pharmacy compounders that are hitting all of the right compliance and safety targets,” she said. “But you also need to look at your offsite clinics in terms of where they are getting their products. Don’t assume that you don’t have some affiliate out there that is making independent purchasing decisions. This is really something that you have to look at across-the-board.” The importance of that 360-degree view was underscored in October, when the FDA released two large lists of NECC customers. Dozens of very well-known healthsystems appeared on those lists, including the northeastern pharmacy director’s system. “This wasn’t a surprise when the lists came out—we had already determined that five of our hospitals had purchased drugs from NECC, although none had bought methylprednisolone,” the director said. “But I was certainly surprised at the variety of products we were purchasing from them. So we are taking a hard look at our purchasing processes for all of our compounded medications.” —David Bronstein

Q & A 45

Pharmacy Practice News • November 2012

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46 Clinical

Pharmacy Practice News • November 2012

Infection Control

Core Elements of the CUSP Program

CLABSIs continued from page 1

AHRQ Director Carolyn Clancy, MD, stressed the significance of the national CUSP findings. “Forty percent is not just a number,” she said. “It means 500 lives were saved and more than 2,000 fewer patients suffered an infection. It also means we avoided an estimated $34 million in costs.”

Toolkit for Quality Improvement At the core of CUSP is a toolkit, developed by clinicians for clinicians, that provides doctors, nurses and pharmacists with the means for understanding safety problems and how to address them. “The toolkit essentially is a multipronged quality improvement program and, very importantly, it is customizable and self-paced,” Dr. Clancy said. “It includes instructor guides, presentation materials, implementation tools such as checklists, and videos that demonstrate desired behaviors.” The kit is available at www.ahrq.gov/cusptoolkit. The main checklist is based on infection prevention guidelines from the Centers for Disease Control and Prevention. These guidelines are extensive and the checklist distills them into a form that clinicians can easily use. The checklist describes measures such as using a dedicated line cart, removing unnecessary lines, performing hand hygiene, avoiding the femoral site in adult patients, using skin antisepsis with 0.5% chlorhexidine and empowering staff to stop nonemergent procedures that are violating guidelines. Institutions can modify the checklist to meet their local needs. The CUSP strategy is based on four Es: engage (understand how the project can improve outcomes), educate, execute and evaluate. “This all starts with measurement. You really have to be aware that you have a problem in the first place,” said Michael Tooke, MD, the chief medical officer at Shore Health, a two-hospital system on the eastern shore of Maryland and an affiliate of the University of Maryland Medical System. The two hospitals—Memorial Hospital in Easton and Dorchester General Hospital in Cambridge—have participated in the national CUSP project and, at press time, had not had a central line–associated bloodstream infection (CLABSI) in more than two years. Dr. Tooke noted that CUSP is much more than a checklist. “We put the checklist in place and we saw our [infection] rates drop, but they didn’t go to zero because [CUSP] is an entire process.” He added that they had to look at how a line is maintained and how different products were influencing safety, among other things. The tools in CUSP are numerous. The Staff Safety Assessment Tool gath-

• Identify five simple steps known to prevent bloodstream infections—such as hand-washing before line insertion and avoiding line placement in the groin area—and incorporate them into a checklist similar to those used by aviation crews. • Develop central-line insertion “bundles” that contain all supplies and sterile material needed for the procedure. This simplifies the procedure and ensures that all items are readily available. • Encourage nurses to speak up, and even stop the procedure, if providers deviate from the guidelines. • Train staff in the science of safety. • Foster the development of a workplace culture of safety in which caregivers feel welcome to bring up concerns—such as when physicians attempt to insert a line without first washing hands—and their ideas for how to prevent harm. • Continually measure infection rates and give feedback on results to staff and managers. Source: http://www.hopkinsmedicine.org/innovation_quality_patient_care/areas_expertise/ infections_complications/BSI.html

‘Everyone was involved and it made a huge difference. It was really working collaboratively as a team that made [our CUSP] so successful.’ —Susan Siford, PharmD, MBA ers information from front-line health care providers, asking how a provider thinks the next patient in their unit will be harmed and what they think can be done to prevent this harm. The Learn From Your Defect Tool helps rigorously analyze the various components and conditions that contribute to an adverse event. It asks questions about possible contributing factors related to patients, tasks, providers, team, training and education, information technology, local environment and institutional environment. What goes wrong in one ICU may be totally different from what goes wrong in another, Dr. Pronovost noted. “We know there are a lot of local problems.

practices are being used and serve on the committee that evaluates CUSP monthly. Pharmacists evaluate patient charts on a daily basis, identifying medications that can be converted from IV to oral formulation, which allows for the removal of unnecessary central lines. Shikha Polega, PharmD, a clinical specialist in the surgical ICU at St. Joseph Mercy Hospital, Ann Arbor, Mich., said that her pharmacy department was involved in performing a literature assessment for their CUSP and that a pharmacist sits on the program’s evaluation committee. According to Dr. Siford, the reason CUSP has been so successful is that a multidisciplinary team is involved in developing each institution’s program

‘This all starts with measurement. You really have to be aware that you have a problem in the first place.’ —Michael Tooke, MD You need to build capacity for those front-line clinicians to address all those things that could go bump in the night, and that is what this program does.”

Pharmacists Part of the Multidisciplinary CUSP Initiative Pharmacists have played a part in many of the CLABSI CUSP efforts. Susan Siford, PharmD, MBA, who works with Dr. Tooke and is the director of pharmacy services for Shore Health, said her pharmacists are involved on several levels. They serve on the multidisciplinary committee that created their CUSP, perform literature reviews to make sure best

and implementing it. “Everyone was involved and it made a huge difference,” said Dr. Siford. “It was really working collaboratively as a team that made [our CUSP] so successful.” Lindsay Ryder, PharmD, BCPS, a specialty practice pharmacist in the medical ICU at Ohio State University Wexner Medical Center, in Columbus, was not part of the national CUSP project, but her hospital has implemented a similar multidisciplinary initiative involving a checklist to slash CLABSIs. She agreed that involving health care workers at all levels—nurses, doctors, pharmacists, etc.—is key to slashing

infection rates. “We all feel a sense of accountability. It is not just one group’s job or one person’s job. The biggest reason for our success is involving all members of the team,” said Dr. Ryder. She also agreed that the biggest role that pharmacy can play in a CLABSI reduction initiative is decreasing the number of medications that are administered through a central line. Getting involved, however, is the first step for pharmacists at institutions that are starting CUSP programs. “[Pharmacists should] get in early and make sure they are part of the multidisciplinary team that drives the care,” Dr. Siford stressed.

A Growing Movement Focused On Multiple Safety Targets In addition to CUSPs focused on CLABSIs, many hospitals have rolled out CUSPs focused on different targets. Easton Memorial Hospital and Dorchester General Hospital have rolled out programs aimed at prevention of ventilator-associated pneumonia (VAP) as well as prevention of central line–associated urinary tract infections. St. Joseph Mercy Hospital has rolled out several other CUSPs: VAP prevention, tight glucose control, sepsis prevention and delirium management. “CUSP has changed the entire culture of how we implement guidelines, how we assess evidence-based medicine,” Dr. Polega said. “Because we have changed the culture of safety, people are not scared to speak up. We have created an environment and multidisciplinary rounds, so that they do speak up.” Theresa Hickman, RN, a nurse educator at Peterson Regional Medical Center, in Kerrville, Texas, which is nearing a three-year CLABSI-free mark, said that in her 32 years as a nurse, she has never seen a program as effective as CUSP. One of the defects identified at her 125-bed rural center with the CUSP Learn From Your Defect Tooll was a drug error caused by an older nurse who could not read the small print on a drug vial. “We found out that it was a common problem: The nurses were having trouble reading,” Ms. Hickman said. “So we bought a whole bunch of magnifying glasses and we didn’t have that defect happen anymore.” Those involved in the CUSP movement are confident that it will continue to spread to additional hospitals. “There is no better rocket fuel than success,” said Dr. Clancy. “When hospitals see others succeeding, it goes viral.” —Kate O’Rourke Drs. Pronovost, Clancy, Tooke, Siford, Polega and Ryder, and Ms. Hickman reported no relevant ﬁnancial conﬂicts of interest.

Clinical 47

Pharmacy Practice News • November 2012

Infectious Disease Chapter 797 guidelines on sterile compounding. Additionally, “we never release a preparation for dispensing prior to receiving the sterility report on that agent; we are very stringent in our environmental procedures, both cleaning and testing and monitoring our environment; and we have a dedicated quality manager in each division of the company whose only responsibility is to make sure all of these safety parameters are being met on a daily basis.” AnazaoHealth does not, however, compound methylprednisolone, Mr. Joseph said. “We don’t dispense large batches of either compounded or repackaged drugs for stock; it’s just not what we do,” he said. “The vast majority of our business is patient-specific compounded medications, such as morphine, hydromorphone, fentanyl, sufentanyl, plus adjunctive agents such as bipuvicaine and lidocaine.” The ASHP agrees that the issue of prescription-specific compounding is a relevant one, according to a statement it issued on the meningitis outbreak. “ASHP believes that any entity that manufactures medications without a prescription should be registered with the [FDA] as a manufacturer and subject to strict federal oversight, including routine inspections.”

acknowledged that state boards face some difficulties meeting that responsibility. Each state, he noted, might take a somewhat different approach, which can lead to varying levels of enforcement. In Arizona, he noted, the state has chosen to create its own set of rules for pharmacy compounders “that frankly are more targeted and raise far fewer compliance issues” than the USP guidelines on sterile compounding.

Clinical Picture Emerges In other developments, two articles were published online in The New England Journal of Medicine (DOI: 10.1056/NEJMoa1212292; DOI:10.1056/ NEJMra1212617), painting a detailed picture of the clinical course of the meningitis cases tied to tainted steroid injections. Much of the information was not encouraging if you are a clinician whose patient contracts the potentially

lethal infection. A difficult diagnosis to pin down, a variable incubation period and months of highly toxic therapy with voriconazole were among the treatment challenges noted. At IDWeek 2012, in San Diego, Tom M. Chiller, MD, MPHTM, the deputy chief of the CDC’s Mycotic Disease Branch, echoed some of those observations. “We know from experience with a very similar outbreak 10 years ago that the longest confirmed ... incubation period [was] 152 days,” Dr. Chiller said during a panel

•

see MENINGITIS, page 50

More Government or Less? The scope and severity of the meningitis outbreak has not gone unnoticed on Capitol Hill. U.S. Rep. Edward J. Markey, for example, said in October that he would introduce a bill to strengthen the FDA’s role in monitoring pharmacy compounding, which he called “a regulatory black hole.” It is “shocking,” Mr. Markey said, that a company such as NECC could ship at least 17,000 doses of a medication across various state lines without FDA regulation. “That’s impossible for an individual state to regulate,” he said. Some pharmacists are wary of such government intervention. Practicing in a state where more than 800 patients have been injected with the contaminated product from NECC, “I am acutely aware of the need for tighter safety controls,” UMMC’s Dr. Ghafoor said. “But I don’t think heavy-handed governmental oversight is the right answer; I would prefer that our national pharmacy organizations and State Boards of Pharmacy come up with some viable solutions, since we have lots of talented people who have a deep understanding of the safety and quality issues we all face in sterile compounding.” Mr. Van Hassel, who serves as vice president of the Arizona Board of Pharmacy, agreed that state boards of pharmacy need to play an active role in oversight, especially since they are already tasked with the lion’s share of monitoring pharmacy compounders. But he also

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48 Technology

Pharmacy Practice News • November 2012

Medication Safety

Closing the Medication Safety Loop in the ED Jamie Kelly President Entropy Research San Diego, California

n the decade between 1996 and 2006, US emergency department (ED) visits grew by 32% to nearly 120 million visits per year,1 while the total number of emergency care providers declined. Flagging supply and growing demand created a crisis of overcrowding that persists today. EDs have become akin to mini hospitals, offering emergent care, primary care, and boarding ill patients who wait for scarce inpatient beds. Amid these chaotic conditions, few safeguards have evolved to address the mounting risks to medication safety. Twice as many medication errors occur in EDs than in the inpatient setting.2 Of the approximately 110 million patients who receive ED care each year in the United States,3 5% experience adverse drug events4; 70% of these events, or 3.8 million, are thought to be preventable.5 In fact, the Institute of Medicine reported that EDs have the highest rate of preventable adverse events among

clinical environments studied.6,7 Yet, the rate at which medication errors are intercepted prior to administration is lower in EDs than in the rest of the hospital (23% vs 39%). Medication administration and prescribing most often are reported as the steps of the medication use process in which ED errors originate.2 One study found that 1 of every 2 doses prescribed in the ED involved an administration error; 14% of these errors were considered at least moderate in clinical severity.8 In response to the elevated risk, the health-system pharmacy community is seeking systematic changes to prevent medication errors in EDs, with a specific focus on the medication administration and prescribing steps.

Closing the Loop In a closed-loop medication administration system, physicians have access to patient-specific information and clinical decision support tools at the time they are ordering medication. Additionally, pharmacists can view the same information and review the orders, and nurses, at the moment of medication administration, can verify the medication order with respect to the “five rights” (patient, drug, dose, route,

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and time). A closed-loop system also ensures that each dose is documented accurately at the time of administration, thus adding information to the patient’s electronic medication administration record (eMAR) for informed subsequent clinical decision making. In current practice, the redundancies inherent in the closed-loop medication management approach do not commonly exist in EDs. One analysis of wrongdose events in EDs showed that 28.5% of the events implicated missing patient information errors (eg, weight, age, existing medication profiles, medication reconciliation process, and wrong patient identification). Dosing errors also are a good example of a risk that exists in EDs when independent double checks are not performed. A closed-loop medication safety solution for the ED has multiple components. To start, a number of no-tech solutions, such as limiting the number and variety of medications and concentrations available in EDs, can immediately improve safety.9 Also, involving clinical pharmacists in EDs has the potential to reduce errors. Although the presence of clinical pharmacists in the inpatient setting has long been recognized as resulting in safer and more effective use of medications,10 pharmacists based in the ED are relatively rare. Fewer than 7% of hospitals have ED-based pharmacists,11 despite the Joint Commission’s Medication Management standard 4.10 and an endorsement from the American Society of Health-System Pharmacists specifying the benefit of pharmacists’ prospective review of medication administration in the ED.12,13 The primary obstacle to the widespread establishment of clinical pharmacy services in the ED may be financial. No definitive scientific assessment has been published to support the cost–benefit of such programs. Staffing aside, computerized prescriber order entry (CPOE) and eMAR supported by assistive technologies such as bar-code medication administration (BCMA) provide substantial opportunities for improved medication safety. Both present significant, although not insurmountable, challenges that make it necessary to carefully weigh the merits and costs of each solution when designing a long-term plan for medication safety improvement in EDs. Recognizing that both will be required eventually, the order in which organizations introduce solutions will affect their speed to success. CPOE implementation in the ED can reduce pharmacy verification times by up to 80%, and can reduce test repetition, documentation redundancy, and

length of stay.14,15 Initially, the proposed rules of the American Recovery and Reinvestment Act of 2009 excluded ED orders in calculating CPOE usage. But after insistence from health care providers, the Final Rule for Stage 1 meaningful use specifies that more than 30% of all unique patients admitted to eligible “inpatient or emergency departments” must have at least one medication order entered using CPOE.16

eMAR and Bar Coding Since the mid-1990s, hospitals have demonstrated that eMARs with assistive technology such as BCMA can improve medication safety, enhancing the effectiveness of double checks.17,18 A 2011 ASHP survey found that 50% of hospitals used BCMA.19 As the adoption of BCMA grows, however, the literature advocating its use has been focused primarily on inpatient units and not EDs. Some long-time users of BCMA technology in the inpatient environment contend that the technology is not appropriate for use in EDs, citing numerous obstacles such as patient wristbanding and the complexity of affixing bar codes to the wide range of medication dosage forms administered to patients in EDs. Even facility issues such as inadequate wireless infrastructure, electrical sources, and a lack of physical space for scanning equipment can hinder BCMA adoption in the ED. Furthermore, ED staff members often initially do not recognize the value of scanning, creating compliance issues and pushback. Additionally, ED staff may express concern that scanning will delay the administration of urgently needed medications, impede clinical care, and lengthen ED turnaround times. Yet the greatest challenge to BCMA in EDs is the absence of an electronic health record (EHR). According to a study in 2010, 53.5% of EDs still operate without clinical information systems.20 Essential for bar-code scanning systems, software must compare the medication dose to be administered with an electronic order. In EDs, medications often are prescribed verbally and administered immediately, departing from the inpatient best-practice cycle of physician order, pharmacist review, dispensing, administration, and documentation. Circumventing the pharmacy review process interrupts the standard workflow required by BCMA systems. Although it is preferable that medications be matched to physician orders before being administered, even in the absence of a pharmacy review, BCMA

•

see SAFETY LOOP, page 50

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Fundamentals of Geriatric Pharmacotherapy: An Evidence-Based Approach

Lisa C. Hutchison, Pharm.D., MPH, FCCP,BCPS; Rebecca Sleeper-Irons, Pharm.D., FASCP, BCPS March 15, 2010 This new textbook provides thorough coverage on therapeutic and social issues affecting elderly patients. It is divided into two sections; the first section addresses general concepts about aging and the second section is organized by both organ system and disease states common in the elderly.

Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care

Daniel L. Krinsky; Rosemary R. Berardi November 5, 2011 This book provides accessible information on nonprescription drug pharmacotherapy, nutritional supplements, medical foods, nondrug and preventive measures, and complementary and alternative therapies.

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Lawrence A. Trissel, FASHP October 31, 2012 This is the premier reference for compatibility, stability, storage and preparation of parenteral drugs. The 17th edition is completely updated and peer reviewed with new monographs, new references, additional information and the latest guidelines—essential for your confidence as a professional p who makes critical decisions on a dailyy basis.

Managing Anticoagulation Patients in the Hospital: The Inpatient Anticoagulation Service

Michael Gulseth June 15, 2007 The first guide to providing systematic anticoagulation care in inpatient settings, this new resource will be welcomed by all pharmacists who practice in or are developing, implementing and maintaining an inpatient anticoagulation service.

Math Calculations for Pharmacy Technicians: A Worktext, Second Edition

Robert M. Fulcher; Eugenia M. Fulcher March 26, 2012 This book helps you learn to calculate drug dosages safely and accurately. A practical worktext format covers everything from basic math skills to reading and interpreting labels and physicians’ orders, introducing key calculation and conversion concepts and then providing hundreds of problems so you can practice and master the material.

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Shane Desselle; David Zgarrick; Greg Alston June 12, 2012 The book is filled with advice from the field’s top experts who take you through the principles applicable to all aspects of pharmacy practice, from managing money to managing personal stress. Long after you’ve completed your last course, you’ll turn to this book for answers to make your practice more professionally rewarding and personally enriching.

Understanding Pharmacology for Pharmacy Technicians

Mary Ann Stuhan August 6, 2012 Throughout this textbook, anatomy and physiology are discussed in rela-tion to various disorders and associated pharmacotherapies to give the p a acy technician pharmacy tec c a students stude ts a context co te t for o how o drugs d ugs work. o PPN1112

50 Technology

Pharmacy Practice News • November 2012

Medication Safety

SAFETY LOOP continued from page 48

at least can confirm which medication caregivers have taken from automated dispensing cabinets, providing a double check. Additionally, ED BCMA systems may provide basic drug-specific dose-range checks and warnings from embedded drug reference libraries. When interfaced with hospital information systems, BCMA systems may provide patient-specific allergy checking and weight-based dose calculations. Furthermore, ED eMARs enable pointof-care access to drug information, protocols, order sets, and standardized emergency drug preparation guidance, as well as references regarding the rate of administration or infusion, method of titration, and so on.21,22 Another benefit of BCMA is improved documentation. Scanning medications in EDs helps ensure the creation of a complete and accurate record of all medications administered to a patient during his or her hospital stay. This is invaluable to physicians when deciding to continue, discontinue, or amend medication orders. Indeed, prospective pharmacy review is the end goal, but until that is in place, a bar code–enabled eMAR provides the best possible information for retrospective review by pharmacy. Even when EDs are not seamlessly integrated with EHRs throughout the rest of the hospital, accurately printed eMARs derived from ED BCMA systems can follow patients for safer transfers and improved continuity of care. Additional safety and efficiency can be gleaned through implementation of the newest frontier of medication administration safety—integration of eMAR and BCMA with “smart” infusion pump programming or bar code– enabled IV (BCIV). In an emergent situation, the nurse relies on memory and limited notes to retrospectively document the infusions administered, a time-consuming process. However, with BCIV, the infusion data, titrations, and time stamps are captured on the pump throughout the episode as the nurse scans through each infusion. The system associates the information with

Incidence, %

100 80

70 53.5

Care Medicine and the American College of Clinical Pharmacy. Pharmacotherapy. 2000; 20(11):1400-1406.

40 20

0 Adverse drug events in EDs deemed preventable

US hospitals that still operate without clinical information systems in EDs

ED doses involved in an administration error

US hospitals with ED pharmacists

Figure. Key medication safety statistics in emergency departments. ED, emergency department

physiologic and hemodynamic data from cardiac monitors. The nurse can quickly review the synched data, revise it if necessary, and sign the electronic record, reducing post-code documentation time to just minutes.

A Step in the Right Direction Notwithstanding the potential for clinical pharmacists to someday provide prospective medication order review in the ED, the next level of safety improvement requires broader, more complicated solutions that will be accompanied by hefty price tags and complex human factors issues. Despite the special requirements of emergency care, the path to safer medication administration in the ED ultimately must take a facility through the journey of CPOE and eMAR supported by assistive technology. As briefly touched on here, these projects present a host of operational challenges for the ED and require significant financial investment. Because addressing all of them at once is implausible, decisions must be made regarding where to begin. The current states of information technology infrastructure in individual organizations will be a determining factor, but given the relative costs and user-compliance hurdles that accompany CPOE relative to eMAR with bar coding, BCMA may offer greater opportunity than CPOE for rapid safety improvement.

2006 emergency department summary. Natl Health Stat Rpt. 2008;7Aug 6:1-40. http:// www.cdc.gov/nchs/data/nhsr/nhsr007.pdf. Accessed October 15, 2012. 2. Santell JP, Hicks RW, Cousins DD. Medication errors in emergency department settings—5 year review. Presented at: American Society of HealthSystem Pharmacists Summer Meeting; June 2004; Las Vegas, NV. Abstract. 3. American Hospital Association. Hospital statistics. Chicago, IL: AHA; 2000. 4. Chin MH, Wang LC, Jin L, et al. Appropriateness of medication selection for older persons in an urban academic emergency department. Acad Emerg Med. 1999;6(12):1232-1242. 5. Brennan TA, Leape LL, Laird NM, et al. Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. N Eng J Med. 1991;324(6):370-376. 6. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human: Building a Safer Health System. Washington, DC: National Academies Press; 2000. 7. Leape LL, Brennan TA, Laird N, et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Eng J Med. 1991;324(6):377-384. 8. Gokhman R, Seybert AL, Phrampus P, Darby J, Kane-Gill SL. Medication errors during medical emergencies in a large, tertiary care, academic medical center. Resuscitation. 2012;83(4):482-487.

References

9. Cohen MR, Smetzer JL, Tuohy NR, et al. High-alert medications: safeguarding against errors. In: Cohen MR, ed. Medication errors. 2nd ed. Washington, DC: American Pharmacists Association; 2007:318-320.

1. Pitts SR, Niska RW, Xu J, Burt CW. National Hospital Ambulatory Medical Care Survey:

10. [No authors listed.] Position paper on critical care pharmacy services. Society of Critical

11. Pedersen CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: dispensing and administration—2008. Am J Health Syst Pharm. 2009;66(10):926-946. 12. Brown JN, Barnes CL, Beasley B, Cisneros R, Pound M, Herring C. Effect of pharmacists on medication errors in an emergency department. Am J Health Syst Pharm. 2008;65(4):330-333. 13. Bonkowski J, Weber R. Including emergency departments in hospitals’ bar-code-assisted medication administration system. Am J Health Syst Pharm. 2012;69(12):1018-1019. 14. Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Committee on Quality of Health Care in America, ed. Washington, DC: National Academies Press; 2001. 15. Yoon P, Steiner I, Reinhardt G. Analysis of factors influencing length of stay in the emergency department, CJEM. 2003;5 (3):155-161. 16. Department of Health and Human Services; Centers for Medicare and Medicaid Services; Medicare and Medicaid Programs; Electronic Health Record Incentive Program; Final Rule, 42. Fed Regist. 2010; Parts 412, 413, 422, et al. July 28, 2010: 44332-44334. 17. Poon EG, Cina JL Churchill W, et al. Medication dispensing errors and potential adverse drug events before and after implementing bar code technology in the pharmacy. Ann Intern Med. 2006;145(6):426-434. 18. The Joint Commission. http://www.jointcommission.org/. Accessed October 15, 2012. 19. Pedersen CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: Dispensing and administration—2011. Am J Health Syst Pharm. 2012;69(9):768-785. 20. Landman AB, Bernstein SL, Hsiao AL, Desai RA. Emergency department information system adoption in the United States. Acad Emerg Med. 2010;17(5):536-544. 21. Paparella S. Drug information resources: essential but may be error prone. J Emerg Nurs. 2010;36(3):250-252. 22. Paparella S. Weighing in on medication safety. J Emerg Nurs. 2009;35(6):553-555.

Jamie Kelly is the president of Entropy Research, Inc, a marketing ﬁrm serving the life science industry. Ms. Kelly is the co-founder of the annual unSUMMIT for Bedside Barcoding educational conference (www.unsummit.com). She may be contacted at jkelly@entropyresearch.net.

CLINICAL

Infectious Disease

MENINGITIS continued from page 47

discussion. “We need to be cautious in thinking that we’re out of the woods after a few weeks.” In the current outbreak, he noted, the incubation period so far appears to range from 4 to 42 days. As for treatment, the CDC is recom-

mending voriconazole for meningitis and septic arthritis, with a loading dose (6 mg/kg BID) to start off therapy. “But the duration clearly is a big question,” Dr. Chiller said. “For the joint infections, you have a bit of time to rule out other potential causes, unlike the CNS infections that are life-threatening.” He added that “we’re finding a fair amount

of toxicity” from the antibiotic regimen. “Hallucinations and other CNS effects from voriconazole are directly related to [drug] levels. We wanted to get high levels, but you have to observe patients and modulate the doses as necessary.” Tom Patterson, MD, a professor of medicine at the University of Texas Health Science Center in San Antonio,

offered this advice on dosing: “You want to have a therapeutic level, but you don’t want it to be toxic. Current guidance says to look for levels between 2 and 5 mcg/mL.” —David Bronstein, with additional reporting at IDWeek 2012 by Seth Kandel

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Ã&#x20AC;XLG )OXLG UHVWULFWLRQ GXULQJ WKH Â¿UVW KRXUV RI WKHUDS\ ZLWK 6$06&$ PD\ LQFUHDVH WKH OLNHOLKRRG RI RYHUO\ UDSLG FRUUHFWLRQ RI VHUXP VRGLXP DQG VKRXOG JHQHUDOO\ EH DYRLGHG Gastrointestinal Bleeding in Patients with Cirrhosis: ,Q SDWLHQWV ZLWK FLUUKRVLV WUHDWHG ZLWK WROYDSWDQ LQ K\SRQDWUHPLD WULDOV JDVWURLQWHVWLQDO EOHHGLQJ ZDV UHSRUWHG LQ RXW RI WROYDSWDQ WUHDWHG SDWLHQWV DQG RXW RI SODFHER WUHDWHG SDWLHQWV 6$06&$ VKRXOG EH XVHG LQ FLUUKRWLF SDWLHQWV RQO\ ZKHQ WKH QHHG WR WUHDW RXWZHLJKV WKLV ULVN Dehydration and Hypovolemia: 6$06&$ WKHUDS\ LQGXFHV FRSLRXV DTXDUHVLV ZKLFK LV QRUPDOO\ SDUWLDOO\ RIIVHW E\ Ã&#x20AC;XLG LQWDNH 'HK\GUDWLRQ DQG K\SRYROHPLD FDQ RFFXU HVSHFLDOO\ LQ SRWHQWLDOO\ YROXPH GHSOHWHG SDWLHQWV UHFHLYLQJ GLXUHWLFV RU WKRVH ZKR DUH Ã&#x20AC;XLG UHVWULFWHG ,Q PXOWLSOH GRVH SODFHER FRQWUROOHG WULDOV LQ ZKLFK K\SRQDWUHPLF SDWLHQWV ZHUH WUHDWHG ZLWK WROYDSWDQ WKH LQFLGHQFH RI GHK\GUDWLRQ ZDV IRU WROYDSWDQ DQG IRU SODFHER WUHDWHG SDWLHQWV ,Q SDWLHQWV UHFHLYLQJ 6$06&$ ZKR GHYHORS PHGLFDOO\ VLJQLÂ¿FDQW VLJQV RU V\PSWRPV RI K\SRYROHPLD LQWHUUXSW RU GLVFRQWLQXH 6$06&$ WKHUDS\ DQG SURYLGH VXSSRUWLYH FDUH ZLWK FDUHIXO PDQDJHPHQW RI YLWDO VLJQV Ã&#x20AC;XLG EDODQFH DQG HOHFWURO\WHV )OXLG UHVWULFWLRQ GXULQJ WKHUDS\ ZLWK 6$06&$ PD\ LQFUHDVH WKH ULVN RI GHK\GUDWLRQ DQG K\SRYROHPLD 3DWLHQWV UHFHLYLQJ 6$06&$ VKRXOG FRQWLQXH LQJHVWLRQ RI Ã&#x20AC;XLG in response to thirst. Co-administration with Hypertonic Saline: 7KHUH LV QR H[SHULHQFH ZLWK FRQFRPLWDQW XVH RI 6$06&$ DQG K\SHUWRQLF VDOLQH &RQFRPLWDQW XVH ZLWK K\SHUWRQLF VDOLQH LV QRW UHFRPPHQGHG Drug Interactions: Other Drugs Affecting Exposure to Tolvaptan: CYP 3A Inhibitors: 7ROYDSWDQ LV D VXEVWUDWH RI &<3 $ &<3 $ LQKLELWRUV FDQ OHDG WR D PDUNHG LQFUHDVH LQ WROYDSWDQ concentrations [see Dosage and Administration (2.3), Drug Interactions (7.1)] 'R QRW XVH 6$06&$ ZLWK VWURQJ LQKLELWRUV RI &<3 $ [see Contraindications (4.4)] DQG DYRLG FRQFRPLWDQW XVH ZLWK PRGHUDWH &<3 $ LQKLELWRUV CYP 3A Inducers: $YRLG FR DGPLQLVWUDWLRQ RI &<3 $ LQGXFHUV H J ULIDPSLQ ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH 6W -RKQÂ¶V :RUW ZLWK 6$06&$ DV WKLV FDQ OHDG WR D UHGXFWLRQ LQ WKH SODVPD FRQFHQWUDWLRQ RI WROYDSWDQ DQG GHFUHDVHG HIIHFWLYHQHVV RI 6$06&$ WUHDWPHQW ,I FR DGPLQLVWHUHG ZLWK &<3 $ LQGXFHUV WKH GRVH RI 6$06&$ PD\ QHHG WR EH increased [see Dosage and Administration (2.3), Drug Interactions (7.1)]. P-gp Inhibitors: 7KH GRVH RI 6$06&$ PD\ KDYH WR EH UHGXFHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK 3 JS LQKLELWRUV H J cyclosporine [see Dosage and Administration (2.3), Drug Interactions (7.1)]. Hyperkalemia or Drugs that Increase Serum Potassium: 7UHDWPHQW ZLWK WROYDSWDQ LV DVVRFLDWHG ZLWK DQ DFXWH UHGXFWLRQ RI WKH H[WUDFHOOXODU Ã&#x20AC;XLG YROXPH ZKLFK FRXOG UHVXOW LQ LQFUHDVHG VHUXP SRWDVVLXP 6HUXP SRWDVVLXP OHYHOV VKRXOG EH PRQLWRUHG DIWHU LQLWLDWLRQ RI WROYDSWDQ WUHDWPHQW LQ SDWLHQWV ZLWK D VHUXP SRWDVVLXP ! P(T / DV ZHOO DV WKRVH ZKR DUH UHFHLYLQJ GUXJV NQRZQ WR LQFUHDVH VHUXP SRWDVVLXP OHYHOV ADVERSE REACTIONS: Clinical Trials Experience: %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQV UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHÃ&#x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Â&#x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able 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term

Tolvaptan 15 mg/day-60 mg/day (N = 223) n (%) ( )

Placebo (N = 220) n (%)

Gastrointestinal Disorders 'U\ PRXWK

Constipation

General Disorders and Administration Site Conditions a 7KLUVW

Asthenia

Pyrexia

Metabolism and Nutrition Disorders b +\SHUJO\FHPLD

Anorexia c Renal and Urinary Disorders

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SAMSCAÂ® (tolvaptan) RU SROODNLXULD WROYDSWDQ SODFHER 7KH IROORZLQJ DGYHUVH UHDFWLRQV RFFXUUHG LQ RI K\SRQDWUHPLF SDWLHQWV WUHDWHG ZLWK 6$06&$ DQG DW D UDWH JUHDWHU WKDQ SODFHER LQ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV 1 WROYDSWDQ 1 SODFHER RU LQ RI SDWLHQWV LQ DQ XQFRQWUROOHG WULDO RI SDWLHQWV ZLWK K\SRQDWUHPLD 1 DQG DUH QRW PHQWLRQHG HOVHZKHUH LQ WKH ODEHO Blood and Lymphatic System 'LVRUGHUV 'LVVHPLQDWHG LQWUDYDVFXODU FRDJXODWLRQ &DUGLDF 'LVRUGHUV ,QWUDFDUGLDF WKURPEXV YHQWULFXODU Â¿EULOODWLRQ Investigations: Prothrombin time prolonged; Gastrointestinal Disorders: Ischemic colitis; Metabolism and Nutrition Disorders: Diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis; Nervous System: Cerebrovascular accident; Renal and Urinary Disorders: Urethral hemorrhage; Reproductive System and Breast Disorders (female): Vaginal hemorrhage; Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure; Vascular disorder: Deep vein thrombosis. DRUG INTERACTIONS: Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP 3A Inhibitors: 6$06&$ LV PHWDEROL]HG SULPDULO\ E\ &<3 $ .HWRFRQD]ROH LV D VWURQJ LQKLELWRU RI &<3 $ DQG DOVR DQ LQKLELWRU RI 3 JS &R DGPLQLVWUDWLRQ RI 6$06&$ DQG NHWRFRQD]ROH PJ GDLO\ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PJ NHWRFRQD]ROH GDLO\ RU ZLWK RWKHU VWURQJ &<3 $ LQKLELWRUV H J FODULWKURP\FLQ LWUDFRQD]ROH WHOLWKURP\FLQ VDTXLQDYLU QHOÂ¿QDYLU ULWRQDYLU DQG QHID]RGRQH DW WKH KLJKHVW ODEHOHG GRVH ZRXOG EH H[SHFWHG WR FDXVH DQ HYHQ JUHDWHU LQFUHDVH LQ WROYDSWDQ H[SRVXUH 7KXV 6$06&$ DQG VWURQJ &<3 $ LQKLELWRUV VKRXOG QRW EH FR DGPLQLVWHUHG [see Dosage and Administration (2.3) and Contraindications (4.4)]. Moderate CYP 3A Inhibitors: 7KH LPSDFW RI PRGHUDWH &<3 $ LQKLELWRUV H J HU\WKURP\FLQ Ã&#x20AC;XFRQD]ROH DSUHSLWDQW GLOWLD]HP DQG YHUDSDPLO RQ WKH H[SRVXUH WR FR DGPLQLVWHUHG WROYDSWDQ KDV QRW EHHQ DVVHVVHG $ VXEVWDQWLDO LQFUHDVH LQ WKH H[SRVXUH WR WROYDSWDQ ZRXOG EH H[SHFWHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK PRGHUDWH &<3 $ LQKLELWRUV &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PRGHUDWH &<3 $ LQKLELWRUV VKRXOG WKHUHIRUH JHQHUDOO\ EH DYRLGHG [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Grapefruit Juice: &R DGPLQLVWUDWLRQ RI JUDSHIUXLW MXLFH DQG 6$06&$ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. P-gp Inhibitors: 5HGXFWLRQ LQ WKH GRVH RI 6$06&$ PD\ EH UHTXLUHG LQ SDWLHQWV FRQFRPLWDQWO\ WUHDWHG ZLWK 3 JS LQKLELWRUV VXFK DV H J F\FORVSRULQH EDVHG RQ FOLQLFDO UHVSRQVH [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. Rifampin and Other CYP 3A Inducers: 5LIDPSLQ LV DQ LQGXFHU RI &<3 $ DQG 3 JS &R DGPLQLVWUDWLRQ RII ULIDPSLQ DQG 6$06&$ UHGXFHV H[SRVXUH WR WROYDSWDQ E\ 7KHUHIRUH WKH H[SHFWHG FOLQLFDO HIIHFWV RI 6$06&$ LQ WKH SUHVHQFH RI ULIDPSLQ DQG RWKHU LQGXFHUV H J ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH DQG 6W -RKQÂ¶V :RUW PD\ QRW EH REVHUYHG DW WKH XVXDO GRVH OHYHOV RI 6$06&$ 7KH GRVH RI 6$06&$ PD\ KDYH WR EH LQFUHDVHG [Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide: &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ GLJR[LQ IXURVHPLGH DQG K\GURFKORURWKLD]LGH ZLWK 6$06&$ KDV QR FOLQLFDOO\ UHOHYDQW LPSDFW RQ WKH H[SRVXUH WR WROYDSWDQ Effects of Tolvaptan on Other Drugs: Digoxin: 'LJR[LQ LV D 3 JS VXEVWUDWH DQG 6$06&$ LV D 3 JS LQKLELWRU &R DGPLQLVWUDWLRQ RI 6$06&$ DQG GLJR[LQ UHVXOWV LQ D IROG LQFUHDVH LQ WKH H[SRVXUH WR GLJR[LQ Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide: &R DGPLQLVWUDWLRQ RI WROYDSWDQ GRHV QRW DSSHDU WR DOWHU WKH SKDUPDFRNLQHWLFV RI ZDUIDULQ IXURVHPLGH K\GURFKORURWKLD]LGH RU DPLRGDURQH RU LWV DFWLYH PHWDEROLWH GHVHWK\ODPLRGDURQH WR D FOLQLFDOO\ VLJQLÂ¿FDQW GHJUHH Lovastatin: 6$06&$ LV D ZHDN LQKLELWRU RI &<3 $ &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ DQG 6$06&$ LQFUHDVHV WKH H[SRVXUH WR ORYDVWDWLQ DQG LWV DFWLYH PHWDEROLWH ORYDVWDWLQ È&#x2022; K\GUR[\DFLG E\ IDFWRUV RI DQG UHVSHFWLYHO\ 7KLV LV QRW D FOLQLFDOO\ UHOHYDQW change. 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Nursing: $GYLVH SDWLHQWV QRW WR EUHDVWIHHG DQ LQIDQW LI WKH\ DUH WDNLQJ 6$06&$ >VHH 8VH ,Q 6SHFLÂ¿F 3RSXODWLRQV @ )RU PRUH LQIRUPDWLRQ DERXW 6$06&$ FDOO RU JR WR ZZZ VDPVFD FRP 0DQXIDFWXUHG E\ 2WVXND 3KDUPDFHXWLFDO &R /WG 7RN\R -DSDQ 'LVWULEXWHG DQG PDUNHWHG E\ 2WVXND $PHULFD 3KDUPDFHXWLFDO ,QF 5RFNYLOOH 0' SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

UNMET NEED. FILL IT.

FREE VVATER V2

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Order SAMSCA® (tolvaptan)

15 mg

30 mg

NDC: 59148-020-50

NDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic and euvolemic hyponatremia

100 %

of physicians surveyed (N=57) would recommend SAMSCA to a colleague 1 In this same survey (patient cases; N=150), physicians were satisﬁed or very satisﬁed with SAMSCA 90% of the time1

Indication and important limitations • SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA. It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients

Important safety information SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients. • Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors • Co-administration with hypertonic saline is not recommended • Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium Commonly observed adverse reactions: (SAMSCA vs placebo) thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%). Reference: 1. Market Rx 2010.

For more information about SAMSCA, visit samsca.com or call 1-877-726-7220.

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. Samsca is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

March 2012

0712A-4220K

NOVEMBER 2012 Brought to You by

REPORT Pharmacy Experience With IVIg:

Perspectives on the Commitment To Use Privigen I

ntravenous immunoglobulin (IVIg) products are FDA approved for first-line treatment for patients who have immunoglobulin deficiencies due to inherited disease, such as primary immunodeficiency (PID).1,2 Some IVIg products have received approval for therapeutic use in other conditions, including immune thrombocytopenic purpura (ITP) and several autoimmune-related neurologic diseases.1,3-5 Additional uses for immunoglobulin have led to a marked increase in the overall use of this agent in the United States (Table 1).1,4,6-8 In the 1990s and 2000s, the increasing uses of IVIg products, combined with limited plasma donor

availability and suitability, production problems, and national and international manufacturing requirements (eg, product lot should be prepared from a pool of at least 1,000 donors and contain at least 90% intact IgG, etc.),9,10 resulted in significant shortages of the supply of IVIg.7 Isolation and preparation of IVIg by manufacturers is a relatively labor-intensive process: Immunoglobulins are isolated from the plasma of human donors, who are carefully selected and screened, and donated plasma then is pooled and chemically processed and purified.11 Furthermore, a number of viral inactivation and removal methods are used as part of the manufacturing

Faculty Russell C. Horne, PharmD, MBA Director of Pharmacy University Medical Center Health System Lubbock, Texas

Timothy Reilly, PharmD

Les Schloesser, MS, RPh

Clinical Assistant Professor Ernest Mario School of Pharmacy at Rutgers New Brunswick, New Jersey

Director of Pharmacy HackensackUMC Mountainside Montclair, New Jersey

Please see important safety information for Immune Globulin (Human) 10% Liquid, Privigen速 on page 8, black box warning on page 2, and attached full prescribing information. Supported by

REPORT

Warning: Acute Renal Dysfunction/Failure • Use of Immune Globulin Intravenous (IVIG) products, particularly those containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death. Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Immune Globulin Intravenous (Human), 10% Liquid, Privigen does not contain sucrose. • For patients at risk of renal dysfunction or failure, administer Privigen at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]).

process.12 Shortages—often due to the temporary closing of manufacturing plants as IVIg makers faced inspections based on changing standards and updated production methods as a result11—caused a host of adverse effects, such as the inability to adequately plan treatment within outpatient infusion centers. These shortages also may have resulted in worse outcomes for patients who required but may not have received IVIg products; in some cases, physicians have reported that these shortages resulted in patient deaths.13 Fortunately, over the past decade, the FDA has approved the use of several different IVIg formulations from various manufacturers, greatly decreasing the risk for future product shortages. Over the next few years, even more IVIg formulations may be introduced into the marketplace. Variations in these formulations mean that a medical institution now can choose the specific IVIg product that best suits the needs of its patient populations, pharmacy and clinical operations, and institutional economics. With this evolving, competitive marketplace for IVIg products, it is even more important for an institution to identify a trusted product with an established reputation when determining its formulary agents. One of these formulations is Privigen (CSL Behring), the first and only ready-to-use, sterile, 10% liquid IVIg stabilized with proline.12 This special report examines, through the perspective of directors of pharmacy, the experience of the continued use of Privigen by several institutions after switching from another IVIg product, and provides an overview of the physical and chemical characteristics of Privigen.

Discussions With Pharmacists and Directors of Pharmacy on Maintaining Their Institutions’ Use of Privigen Experience With Privigen at HackensackUMC Mountainside (Montclair, New Jersey) Les Schloesser, MS, RPh, is director of pharmacy at HackensackUMC Mountainside in Montclair, New Jersey, where he has the overall responsibility for purchasing and day-to-day operations of the department. His institution is licensed for 350 inpatient beds and uses IVIg both in its inpatient population and its outpatient infusion center. Mr. Schloesser noted that his institution, like other institutions, is seeing increased use of

IVIg for its patients. “We use IVIg for ITP and for patients with immunodeficiencies, but we’re also seeing tremendous growth in the use of IVIg for [other] conditions,” he said. Mr. Schloesser noted that product supply is a major concern. He recalled a period of IVIg shortage at his institution that occurred roughly a decade ago. “Availability of IVIg is a big issue. Years ago, we had shortages, and it was very difficult. It got to the point that doctors were very careful about ordering the drug as well as giving it [to patients] even when they ordered it. I think a lot of people who might have benefited from IVIg probably didn’t get it because of these shortages,” he said. “You can see today, with the shortages in critical chemotherapy medications, that history can repeat itself. So, although the days of IVIg shortages seem to be behind us, it’s something that still weighs on my mind. Although pricing considerations play a big part in why we adopted Privigen as our formulary IVIg agent, supply considerations also were very important.”

Privigen PromiseTM Recognizing the hazards and anxiety associated with potential shortages, the manufacturer of Privigen offers a guarantee through the end of 2016. Mr. Schloesser explained, “Privigen also comes with a manufacturer commitment to an ongoing supply—called the Privigen Promise. When signing a contract for Privigen, you state the amount of drug that you need, and the onus is on the manufacturer to guarantee the supply. This sort of commitment from a manufacturer—well, in this day and age, you don’t find that very often. And that is what we’re seeing, I haven’t had a problem getting Privigen at all.” In addition to the steady supply of Privigen, Mr. Schloesser also suggested that the speed at which he can get additional product works well with his institution’s business model. “The time from when we order the product when more is needed to when we actually have it in hand has been excellent,” he said. “This is important in that my institution is a for-profit hospital, and in this day and age of budget constraints and decreasing reimbursements, you don’t want to keep inventory on your shelves unless you have to.” “I’m a big proponent of ‘just-in-time’ inventory. We stock what we need for our scheduled patients—we use anywhere from 400 to 600 g per month—and I keep an extra 80 to 100 g

REPORT

Table 1. Selected Uses of IVIg Hematology/Oncology and Immunology FDA-approved

Selected non– FDA-approved uses

Neurology

PIDs (including XLA, CVID, SCID, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and others) ITP Bone marrow transplantation (prevention of GVHD or infections) Pediatric HIV infection

CIDP Multifocal motorneuropathy

Secondary immunodeficiencies (MM, et al.) Immune hemolytic anemia Immune neutropenia Parvovirus B19-associated aplasia

Dermatomyositis and inflammatory myopathies Guillain-Barré syndrome Lambert-Eaton syndrome Multiple sclerosis Myasthenia gravis Stiff person syndrome

Dermatology

Other Kawasaki disease

Atopic dermatitis Blistering diseases Dermatomyositis Immune urticaria Pyoderma gangrenosum Scleromyxedema Toxic epidermal necrolysis

Autoimmune uveitis Mucous membrane pemphigoid Streptococcal toxic shock syndrome SLE Vasculitis

CIDP, chronic inflammatory demyelinating polyneuropathy; CVID, common variable immunodeficiency; GVHD, graft-versus-host disease; ITP, immune thrombocytopenic purpura; IVIg, intravenous immunoglobulins; MM, multiple myeloma; PID, primary immunodeficiency; SCID, severe combined immunodeficiency; SLE, systemic lupus erythematosus; XLA, X-linked agammaglobulinemia a

FDA-approved indications vary among the different IVIg products. Privigen is indicated only for primary humoral immunodeficiencies and for chronic ITP.

Adapted from references 1 and 4.

as an emergency for unforeseen circumstances. But you never know when you’re going to need more, especially on the inpatient side,” Mr. Schloesser added. “What’s really important is, if I need more quickly, I can order it from our vendor and get it in a day or an even shorter time if it’s an emergency. When we were using IVIg products other than Privigen, this wasn’t possible. It suggests to me that the manufacturer of Privigen is doing a great job extracting the product.” At his institution, Mr. Schloesser noted that he and his colleagues have been very happy with their ongoing use of Privigen. “Privigen works for most of our patients,” he added. “Most tolerate the drug without a problem.” In clinical trials, adverse reactions observed in more than 5% of subjects given Privigen were headache, pain, nausea, fatigue, chills, vomiting, joint swelling/effusion, pyrexia, and urticaria.12 Mr. Schloesser explained further that the physical and chemical properties of Privigen make it conducive to easy use and less waste at his institution. “The days of our institution using a lyophilized product thankfully are over. The reconstitution

process for lyophilized product was [challenging]. It required a lot of time from our pharmacy technicians, and it slowed down the turnover of chairs in our outpatient infusion center because, to avoid wasting product in the case of no-show, we wouldn’t start reconstituting the product until the patient arrived,” he explained. “Privigen is a ready-to-use liquid, and so we can get the product to the nurses immediately. It enhances our infusion center chair turnover, and there’s no danger of wasting product. The fact that it comes in different vial sizes also is helpful in terms of reducing waste.” Another advantage that Mr. Schloesser noted is the ability to store Privigen at room temperature. “Also, the fact that Privigen does not need refrigeration is very important. Say, for example, your refrigerator in the pharmacy supplying the outpatient infusion center goes down on the weekend—you won’t know until Monday morning. With other IVIg formulations that need refrigeration, you really have a hard time figuring out if the product is still usable,” he said. “With Privigen, you don’t have to worry about that. Even aside from the rare risk for technical

REPORT

failure, refrigerator space is at a premium both in the inpatient pharmacy and in the infusion center pharmacy, so the fact that Privigen does not require refrigeration makes it much easier from a pharmacy operations standpoint.” When asked about the future of IVIg at his institution, Mr. Schloesser concluded, “I don’t anticipate switching from Privigen to another IVIg formulation. I get representatives from other companies for IVIg coming in here all the time—if they had a compelling argument for any clinical advantage over Privigen, we’d [review] it—but to date, they don’t.”

Medical Center Experience With Privigen (New Jersey) Timothy Reilly, PharmD, is clinical assistant professor at the Ernest Mario School of Pharmacy at Rutgers in New Brunswick, New Jersey, and a New Jersey-area medical center clinical pharmacist. Dr. Reilly relates that he has extensive experience working with IVIg products as a pharmacist. Dr. Reilly lauded the advantages that come with the increasing variety of available IVIg formulations. “Now, we are afforded the opportunity to choose a specific IVIg formulation that has the right balance of properties that is most closely applicable across our entire patient population in need of IVIg,” he said. “We were previously using 2 different IVIg products (1 lyophilized product and 1 low immunoglobulin A [IgA] product), and we found that Privigen could replace both of them. That’s because it’s a 10% premixed liquid product with low IgA content and because it’s sucrose-free. What’s more, it doesn’t require refrigeration, and it offered us significant cost savings over [our previous low IgA–content IVIg],” Dr. Reilly said. Privigen contains less than 25 mcg/mL IgA. “The fact that we can use Privigen alone instead of 2 different IVIg products created some significant institutional efficiencies. It simplifies things. Also, when we were using 2 different IVIg products, we had a difficult time getting our information technology department to support us because they had to program in 2 different computerized order sets and nursing flow instructions with different infusion protocols, and so on. Now, with Privigen, we only need 1 computerized order set, and the details are the same for all our patients. The physicians, nurses, and our pharmacists all are very happy about that.” Dr. Reilly also has firsthand experience with IVIg shortages. “When I became a pharmacist in the early 2000s, we were confronted with all the IVIg product shortages. Even now, when you look at the FDA Web site, there are probably more than 100 drug shortages—20 of which are critical for us at any given time,14 so drug shortages are always on my mind. With the Privigen Promise program, the fact that we know we’ll have a steady supply [through 2016] is a real relief, and in practice, the supply of Privigen has been excellent.” Dr. Reilly commented regarding the customer service he received from the manufacturer and its employees. “I have called in requests for information, and they have been very helpful with getting us the information we need. One of things

that our staff members were concerned about was the precise detail surrounding how the IVIg manufacturers obtain their product,” he added. “Their representative provided that information for us right away. And it’s great because the supplier has its own plasma-collection division, which reassured us that the supplier has made a commitment to getting good-quality donors, which translates into good-quality product. Whereas, my impression of suppliers that outsource the plasma collection is that the organization collecting the IVIg may not always have a vested interest in maintaining appropriate donors or providing quality products.” “Not having to use a lyophilized product also has made a significant impact. In the pharmacy, we don’t have to spend all our time reconstituting the product. From the nursing standpoint, they like [the fact that they] can get the product quicker—that’s a big consideration when you’re sitting 5 feet away from the patient, and they’re anxious to get started,” he noted. “The nurses also [prefer that they] don’t have to give a test dose of Privigen, like we did with our previous IVIg product. Certainly, both of these factors have made a difference in terms of decreasing our per-patient infusion chair time. So, we find that with Privigen, our patient and employee satisfaction has increased dramatically and that it’s cost-effective.”

Experience With Privigen at University Medical Center Health System (Lubbock, Texas) Russell C. Horne, PharmD, MBA, is director of pharmacy at University Medical Center (UMC) Health System in Lubbock, Texas. The UMC Health System is affiliated with Texas Tech University School of Medicine and currently operates a hospital with more than 400 beds as well as an outpatient infusion center. Dr. Horne’s current role also is supplemented by his previous role with a home-infusion provider prior to joining the UMC system. Dr. Horne said that his hospital adopted Privigen as its formulary IVIg both in inpatient and outpatient infusion center settings several years ago. Dr. Horne described several important reasons for his hospital’s adoption and continued use of Privigen: sufficient and consistently reliable supply and the clinical characteristics of the product. Supply is an important concern when selecting an IVIg product, Dr. Horne said. “In today’s world, you’ve got to worry about drug shortages, and you have to ask yourself, ‘Does this company have the capacity to manufacture what you need, or are they going to call you in a week and say there’s no more drug available?’” he said. “Our previous IVIg vendor was a smaller company, and it didn’t demonstrate that it had the same capacity to supply us with IVIg. The manufacturer of Privigen demonstrated to us their capacity for production, and it impressed on me that they would be able to continue to supply it. And, in fact, with Privigen, we have had absolutely no problem with drug supply at all.” Dr. Horne appreciated several aspects of customer service from the manufacturer and company representatives for Privigen when ordering supply for his institution. “The company

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Table 2. Interviewed Faculty-Described Advantages to Privigen Privigen Properties

Corresponding Advantages According to Interviewed Faculty

Supplied as a premixed liquid

No need for laborious reconstitution steps • Lower resource utilization and less error • Increased patient satisfaction • Increased chair turnover at outpatient infusion center

Supplied as a 10% protein solution

Ability to minimize volume administration to at-risk patients (eg, CHF, renal dysfunction)

Sucrose-free

Obviates risk for sucrose-induced nephropathy

Low IgA content (≤25 mcg/mL)

Theoretical lower risk for sensitization of anaphylactic reactions

Stability at RT for 36 mo

No need for refrigeration • Reduces costs and resource use • Allows procurement of larger amounts at any one time • Eliminates risk for waste due to improper storage (eg, erroneously storing a product that requires refrigeration at RT)

Supply guarantee (Privigen PromiseTM program)

Continuity of patient care Facilitates planning for outpatient infusion center administration

Other

Competitive pricing Customer service

CHF, congestive heart failure; IgA, immunoglobulin A; IVIg, intravenous immunoglobulin; RT, room temperature Adapted from reference 12.

seemed sincerely invested in getting our institution what we needed. I initially told the Privigen representative that we needed 400 g of IVIg per month. Then, at the last minute, my purchaser came in and said we need 500 g per month. I remember calling the Privigen representative and bracing myself for him to say ‘It’s too late,’ as that had been the kind of experience that we had with our previous IVIg vendor. Instead, the representative from Privigen said ‘That’s absolutely no problem; I’ll take care of it for you.’ You could tell he was in it for the long term.” Once Dr. Horne recognized that his institution would be able to obtain the amount of Privigen needed for his patient population, he consulted with his clinical pharmacy manager. “We combed through all the data and determined it was an appropriate therapeutic interchange for our patient population,” he said. “Some of the factors that came up in our discussion were that [Privigen] was a ready-to-use, 10% solution, and that it did not contain sucrose.” Investigators have corroborated Dr. Horne’s observations regarding the use of proline as a stabilizing agent. In their review of the use of proline, Hagan and colleagues reported that the initial increase in plasma proline levels following administration of Privigen was rapidly cleared and returned to

baseline levels within 24 hours.15 Also, this increase in proline levels was not associated with any adverse effects.15 “Another important advantage was the fact that you don’t have to refrigerate Privigen. We like that a lot,” Dr. Horne said. “It means that it’s easier to store. Refrigerator space is limited, and refrigerators are expensive. We have much more space for storage outside our refrigerators.” Dr. Horne also stated that, since switching to Privigen, his institution has been satisfied with results from using the product in clinical situations. “In addition to the vendor demonstrating its ability to reliably supply Privigen, patients in our clinical population have been able to tolerate appropriate infusion rates without significant infusion reactions, and our staff has been very happy with it,” he said. “Often, we can hang the product in its original container without transferring it to a sterile bag.” Adverse reactions observed in more than 5% of subjects with PID and chronic ITP in clinical studies were headache, vomiting, chills, nausea, and pyrexia, among others.12 Other members of a network of hospital providers reported similar experiences, according to Dr. Horne. “We’re a member of the Safety Net Hospitals for Pharmaceutical Access organization, and we have an electronic forum [where] all the

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Table 3. Features of IVIg Products That Are Considerations for Patients With Certain Risk Factors Risk Factor

Sodium Content

Renal dysfunction

Heart disease

Sugar Content

Diabetes mellitus, prediabetes

Osmolality/ Osmolarity

Volume Load

IgA

Elderly

Neonatal, pediatric

Thromboembolic risk

IgA deficiency

X X X

IgA, immunoglobulin A Adapted from reference 18.

800-plus hospitals that belong to this organization can participate,” he said. “I remember looking at some of the information from hospitals that were using Privigen, and they were unanimous in saying that they were doing very well with its terms of use and its supply from the vendor. That was very reassuring.” Additionally, he summarized his considerations when choosing an IVIg product. “When choosing a preferred formulary product for your institution, you have to balance out all the characteristics and efficiencies of a drug: patient safety, clinical effectiveness, operational efficacy, and potential adverse events. Once you’ve made that determination, you also have to consider whether the price and the vendor’s ability to supply the product are adequate. To my knowledge, no other company has a supply guarantee like Privigen’s manufacturer. At this point, I really can’t imagine switching to another IVIg product.”

Clinical Characteristics of Privigen The FDA approved the use of Privigen for patients with primary humoral immunodeficiency and chronic ITP in July 2007.12 Privigen is supplied in 5-, 10-, and 20-g vials,12 and the manufacturing process for Privigen includes 3 steps to reduce the risk for virus transmission. Two of these are dedicated virus clearance steps: pH 4.0 incubation to inactivate enveloped viruses and virus filtration to remove, by size exclusion, both enveloped and nonenveloped viruses as small as approximately 20 nanometers.12 Additionally, a depth-filtration step contributes to the virus-reduction capacity. Several of the production steps have been shown to decrease

transmissible spongiform encephalopathy (TSE) infectivity (a model of prion transmission). These TSE reduction steps include octanoic acid fractionation, depth filtration, and virus filtration.12 Privigen has several chemical and physical properties that distinguish it from other available IVIg formulations. First, Privigen is a premixed, ready-to-use liquid formulation. In contrast to earlier products, which were supplied as lyophilized powders and required reconstitution, Privigen can be used directly from its vials or transferred to a sterile bag for immediate administration.16 Second, Privigen is supplied as a 10% solution. Third, Privigen has IgA content of 25 mcg/mL or less, and includes proline as its stabilizer. The corresponding benefit to proline is that Privigen does not use sucrose as a stabilizer, thus limiting the risk for sucrose-induced nephrotoxicity that can occur with other IVIg products that use sucrose.12 Proline also has been shown to reduce the amount of dimers, fragments, and aggregates that can form in immunoglobulin solutions. Finally, whereas other IVIg products require refrigeration to ensure stability, proline enables room temperature storage for up to 36 months.12 A paper authored by Scott M. Mark, PharmD, MS, MEd, MPH, MBA, in a recent issue of Hospital Pharmacy discussed Privigen’s properties and their effect on cost and convenience, as previously highlighted by Dr. Reilly. In his review, Dr. Mark noted that absence of sucrose, the 10% solution concentration, and the low IgA content could reduce costs by minimizing adverse events. Along with these qualities, availability as a premixed, ready-to-use solution and the ability to store it at room temperature possibly could reduce costs by

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decreasing preparation time and by requiring less refrigeration resources, respectively.17 CSL Behring, makers of Privigen, research, develop, manufacture, and market biotherapies that are used to treat serious and rare conditions. For more than 100 years, CSL Behring has fractionated plasma products providing the first nanofiltered human normal immunoglobulin for IV administration in the United States, first FDA-approved subcutaneous immunoglobulin treatment, and the first proline-stabilized IVIg.

Conclusion IVIg products are not interchangeable—there are important product differences, and this makes matching the right product with the right patient extremely important. There are multiple IVIg formulations on the market, each with different specific physical and chemical properties that do impact and influence

patient safety and satisfaction, resource utilization, and overall costs of care. The benefits of Privigen include its quick preparation for patient administration, according to the interviewed faculty, its availability as a 10% solution, its low IgA content, the absence of sucrose, and its stability up to 3 years at room temperature (Table 2).12 Review of institutional experience with Privigen through discussions with expert pharmacists reveals that most have stayed with this formulation as a result of its ease of use with a diverse population of patients who need IVIg therapy and that the use of a single formulation with this favorable profile has resulted in multiple efficiencies throughout their clinical departments (Table 318 ). Furthermore, the Privigen Promise program affords important assurances for a reliable, ongoing supply of IVIg in quantities necessary to optimize patient outcomes.

References 1. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006;117(4 suppl):S525-S553. 2. Kirch W, Stangel M, Pittrow D, et al. Immunoglobulins for primary or secondary immunodeficiency or for immunomodulation in neurological autoimmune diseases: insights from the prospective SIGNS registry. J Pub Health. 2012;20(3):289-296. 3. Harkins C, Hammond-Tooke G, Faed J. Intravenous immunoglobulin therapy for neurological disorders. N Z Med J. 2009; 122(1305):41-46. 4. Jolles S, Sewell WAC, Misbah SA. Clinical uses of intravenous immunoglobulin. Clin Exp Immunol. 2005;142(1):1-11. 5. Qin YH, Zhou TB, Su LN, Lei FY, Zhao YJ, Huang WF. The efficacy of different dose intravenous immunoglobulin in treating acute idiopathic thrombocytopenic purpura: a meta-analysis of 13 randomized controlled trials. Blood Coagul Fibrinolysis. 2010;21(8):713-721. 6. Goddard EA. Intravenous immunoglobulin. Curr Allerg Clin Immunol. 2008;21(1):26-31.

10. Appropriate uses of human immunoglobulin in clinical practice: memorandum from an IUIS/WHO meeting. Bull World Health Organ. 1982;60(1):43-47. 11. Chapel HM. Safety and availability of immunoglobulin replacement therapy in relation to potentially transmissable agents. IUIS Committee on Primary Immunodeficiency Disease. International Union of Immunological Societies. Clin Exp Immunol. 1999;118(suppl1):29-34. 12. Privigen [prescribing information]. Bern, Switzerland: CSL Behring AG; 2012. 13. Drug Topics. Witnesses tell of deaths due to IVIG shortage. http://drugtopics.modernmedicine.com/drugtopics/Health+ System+News/Witnesses-tell-of-deaths-due-to-IVIG-shortage/ ArticleStandard/Article/detail/382516. Accessed August 22, 2012. 14. U.S. Food and Drug Administration. Current Drug Shortages. www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm. Accessed August 22, 2012. 15. Hagan JB, Wasserman RL, Baggish JS, et al. Safety of L-proline as a stabilizer for immunoglobulin products. Expert Rev Clin Immunol. 2012;8(2):169-178.

7. Bayry J, Kazatchkine MD, Kaveri SV. Shortage of human intravenous immunoglobulin—reasons and possible solutions. Nat Clin Pract Neurol. 2007;3(3):120-121.

16. Kallenberg CG. A 10% ready-to-use intravenous human immunoglobulin offers potential economic advantages over a lyophilized product in the treatment of primary immunodeficiency. Clin Exp Immunol. 2007;150(3):437-441.

8. Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. 2008;28(4): 765-778, viii.

17. Mark SM. Comparison of intravenous immunoglobulin formulations: product, formulary, and cost considerations. Hosp Pharm. 2011;46(9):668–676.

9. Knezevic-Maramica I, Kruskall MS. Intravenous immune globulins: an update for clinicians. Transfusion. 2003;43(10):1460-1480.

18. Siegel J. The product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005;25(11 Pt 2):78S-84S.

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Important Safety Information Immune Globulin Intravenous (Human), 10% Liquid, PrivigenÂŽ, is indicated as replacement therapy for patients with primary immunodeficiency (PI) associated with defects in humoral immunity, including but not limited to common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. Privigen is also indicated to raise platelet counts in patients with chronic immune thrombocytopenic purpura (ITP). WARNING: Use of Immune Globulin Intravenous (IVIg) products, particularly those containing sucrose, have been associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death. Privigen does not contain sucrose. Administer Privigen at minimum rate practicable in patients at risk of renal dysfunction or acute renal failure. At-risk patients include those with preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia; over 65 years of age; or receiving known nephrotoxic drugs. See full prescribing information for complete boxed warning. Privigen is contraindicated in patients with history of anaphylactic or severe systemic reaction to human immune globulin, in patients with hyperprolinemia, and in IgA-deficient patients with antibodies to IgA and history of hypersensitivity. Monitor patient vital signs throughout infusion of Privigen. In cases of severe hypersensitivity or anaphylactic reactions, discontinue administration and institute appropriate medical treatment. In patients at risk for developing renal failure, monitor urine output and renal function, including blood urea nitrogen and serum creatinine. Thrombotic events have occurred in patients with risk factors; consider baseline assessment of blood viscosity for those at risk of hyperviscosity.

Patients could experience increased serum viscosity, hyperproteinemia or hyponatremia; infrequently, aseptic meningitis syndrome (AMS) may occur (most often with high doses and/ or rapid IVIg infusion). Hemolysis that is either intravascular or due to enhanced red blood cell sequestration can develop subsequent to treatment with Privigen. Closely monitor patients for hemolysis and hemolytic anemia. Risk factors for hemolysis include non-O blood group, underlying inflammation, and high doses. Carefully consider relative risks and benefits before prescribing highdose regimen for chronic ITP in patients at increased risk of thrombosis, hemolysis, acute kidney injury or volume overload. Monitor patients for pulmonary adverse reactions and signs of transfusion-related acute lung injury (TRALI). Privigen is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. In clinical studies of patients being treated with Privigen for PI, the most serious adverse reaction was hypersensitivity (one subject). Adverse reactions observed in >5% of subjects with PI were headache, pain, nausea, fatigue, chills, vomiting, joint swelling/effusion, pyrexia, and urticaria. In clinical studies of patients being treated with Privigen for chronic ITP, the most serious adverse reactions were AMS (one subject) and hemolysis (eight subjects). Adverse reactions seen in >5% of subjects with chronic ITP were headache, pyrexia/hyperthermia, positive DAT, anemia, vomiting, nausea, increases in conjugated and unconjugated bilirubin, hyperbilirubinemia, and increased blood lactate dehydrogenase. Treatment with Privigen might interfere with a patientâ&#x20AC;&#x2122;s response to live virus vaccines and could lead to misinterpretation of serologic testing. For more information about Privigen, please see full prescribing information.

Disclosures: Drs. Horne and Reilly reported no relevant financial conflicts of interest. Mr. Schloesser reported that he is an advisory board member for CSL Behring and Daiichi Sankyo.

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Disclaimer: This monograph is designed to be a summary of information. While detailed, it is not an exhaustive clinical review. McMahon Publishing 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.