The November 2010 Digital Edition of Pharmacy Practice News by McMahon Group

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The Pharmacist’s News Source Edition Hematology/Oncology Pharmacy

Volume 377 • Number 11 • November 2010

Printer-friendly versions available online

Strength in Numbers

Studies: Teamwork Yields Best Results For Chronic Illness

in this issue Ongoing Drug Shortages Place Up Front

Patients, Hospitals at Risk: ISMP

Awards ASHP literature award winners profiled.

Clinical

Medication Safety

see COLLABORATION, page 32

Infectious Disease

Students help remove unused drugs from community.

Research News Hormone therapy slows metastatic prostate cancer.

Hemonc Pharmacy Pediatric center offers its oncology informatics tips.

Operations & Mgmt

Leadership in Action Communication, empathy and emotional intelligence.

Technology Automation, education help boost vaccinations.

Educational Reviews

Treatment Options in HIV

Dollars and Sense Of Anticoagulation: Pharmacists Crucial

Managing IV Iron Antimicrobial Stewardship

PPN Embraces Bar Codes

Austin, Texas—Handing over the management of outpatient anticoagulation therapy to pharmacists is known to help physicians maximize valuable time and patient outcomes. Now, a study recently presented at the annual meeting of the American College of Clinical Pharmacy suggests that implementing such a service also may significantly reduce health care costs. Researchers counted nearly $700,000 in savings for 175 patients who used the University of Pittsburgh Medical Center’s

Look for smart phone– enabled 2D bar codes in this issue to access Web-exclusive content.

see DOLLARS, page 40

ospital drug shortages have become a national al crisis, straining pharmacy resources and d threatening patient safety, according to o a Medication Safety Alert recently released eased by the Institute for Safe Medication tion Practices (ISMP). The ISMP P report, based on a July to September ber survey of more than 1,800 health care practitioners—68% 8% of them pharmacists—painted ts—painted an alarming picture of pharmacy directors and others scrambling to find d substitutes for widely dely used surgical and d critical care injectable able drugs and certain antibiotics. that have become come unavailIn some cases, survey respondents able withoutt warning or noted, patients died as a result of not explanation. getting the best available drug in a Among the he key timely manner. drugs and categoThe respondents expressed grave ries reported ed in concerns about their inability to get critically short information about the cause of the supply were proposhortages or how long the shortages fol, neuromuscular uscular would last. They reported that they blocking agents, nts, morhad difficulties obtaining suitable phine, epinephrine, phrine heparin, chemotherapy agents, fosphenytoin see DRUG SHORTAGES, page 12

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$700,000 in savings documented

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McMahon Publishing

Austin, Texas—By closely collaborating with physicians and other clinicians, pharmacists can more effectively treat and stabilize chronic conditions and potentially save some money in the process, according to findings from several research abstracts presented at the annual meeting of the American College of Clinical Pharmacy (ACCP). In three of the studies, researchers evaluated a mix of medical conditions and collaboration strategies, including both pharmacy-led clinics and pharmacists practicing as part of larger teams. In one study, a heart failure disease management program resulted in a reduction of 53% in 30-day hospital readmissions. In

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For directions, see Editor’s Note, page 3

WWW.CMEZONE.COM

Clinical and Pharmacoeconomic Evaluation of Thrombin-Containing Products in the Hospital Setting See insert after page 20.

FDA Heeds Advisory Panel, OKs Pradaxa for Stroke in AF Patients

he FDA has approved r roved dabigatran etexilatee to reduce the risk for stroke o oke and systemic emboluss in patients with atrial fibrillation (AF). The decision follows an n FDA advisory committee’s e ee’s unanimous vote to approve ove dabigatran dabigatran, which has been widely touted as a long overdue alternative to warfarin, in part

because the new oral be e direct thrombin inhibid ttor does not require anticoagulation moniaan toring. But obviating the tor ri need for f such testing could drawbacks, sevhave serious see with expertise eral pharmacists pharrm in anticoagulation therapy told anticoa Pharmacy Practice News.

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see PRADAXA, page 44

New Products New temperature monitoring software from Isensix See page

Medi-Dose/EPS introduces LiquiDose Flag and Receipt Labels See page

Introducing Teva’s New and Improved Product Labeling NDC#s are prominently placed in top left corner

Lot number is imprinted for easier tracking

TALLman lettering, used when appropriate, helps reduce dispensing errors

Bar Coded with a scannable Standard RSS bar code

Strength is highlighted in color for better visibility. Products with multiple strengths are distinguished by different colors.

Manufacturing location of product

Expiration Date

For up-to-date information on all of our products, including many latex-free and preservative-free injectables, visit www.tevausa.com

8430 A

19 Hughes • Irvine, California 92618 800.729.9991 • www.tevausa.com

Up Front 3

Pharmacy Practice News • November 2010

Editor’s Note

Thanks for Trying 2D Bar Codes—and for Reading PPN F

or years, we’ve been publishing articles on the benefits that accrue to hospitals that employ bar coding. Improved patient safety, better patient identification and more consistent charge capture were just a few of the advantages cited. But we never thought Pharmacy Practice News—and our readers—could also take advantage of the scanning technology. Well, we were wrong. Scattered throughout this issue are several two-dimensional (2D) bar codes, also known as matrix codes, that connect you to additional information about the articles you’re perusing. The technology is based on Microsoft’s “Tag” mobile bar code system, which apparently is taking off far faster than hospital adoption of bar codes: according to a recent Microsoft press release, more than 2 billion tags—scannable via smart phones—have been printed for various applications since the system launched in January 2009. They’re showing up in consumer packaged goods, interactive gift cards, publishing and more. For details on how to scan the 2D bar codes in this issue, see the box below. By giving it a try, you’ll gain access to a wide range of additional content, including PDFs of educational reviews, bonus coverage of the American College of Clinical Pharmacy annual meeting and background documents from the FDA, ISMP and ASHP. Let us know what you think of this technology. Was it easy to use? Was the information accessed worth your time? What other value-added content would you like us to offer via the 2D bar codes in future issues? The goal of this initiative is to make PPN a smarter read. If smart phones can help in that endeavor—and bring us a bit farther into the digital age—then all the better. So we thank you for participating.

2-D Bar Codes in PPN 1. Get the FREE Microsoft Tag Reader application through your smart phone browser by going to http://gettag.mobi and follow the steps to download. (There may be a charge from your wireless provider for the data services.) 2. Open the Tag Reader and find the PPN bar code image in this publication. 3. Let the Tag Reader focus on the bar code image to instantly access related materials and/or Web sites.

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=UN_ZNPf =bOYVPNaV\[ =bOYVPNaV\[ =bOYVPNaV\[ =_NPaVPR ;Rd` . / 0

Figure 1. Average Page Exposures—Health-System Pharmacy Directors.

Figure 2. High Readers—Total Health-System Pharmacy (Directors, Staff and Clinical Pharmacists).

Source: ©Kantar Media Pharmacy Readership Study (2010), Table 115

Source: ©Kantar Media Pharmacy Readership Study (2010), Table 217

We’re No. 1 We’d also like to thank you for our latest readership scores from Kantar Media, an independent research firm that measures readership of health-system pharmacy publications. According to the company’s June 2010 survey, PPN ranked No. 1 in 10 major categories. In several of those categories, the gap between PPN and the second-ranked publication was significant: for example, we’re eight points higher in Average Page Exposures among pharmacy directors (Figure 1), and seven points higher in High Readers among pharmacy directors, staff and clinical pharmacists combined (Figure 2). We could not have achieved such high scores without your loyalty, so our humble thanks. A shout-out is also due to our editorial advisory board for keeping PPN focused on key trends in pharmacy practice. For those of you attending the ASHP Midyear Clinical Meeting, please don’t hesitate to drop by our booth (#257); I’d love to hear what else we can do to meet your information needs. If you’re not attending, I welcome your input by other means. And I promise not to include a 2D bar code for that: a phone call (212-957-5300, x212) is always welcome!

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, MAX Graphics

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

Volume 37 • Number 11 • November 2010 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN Robert Barkin, PharmD, Chicago, IL Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY BIOTECHNOLOGY Indu Lew, PharmD, Livingston, NJ CARDIOLOGY

INTERNAL MEDICINE Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP Des Moines, IA NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

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Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Kate O’Rourke, Contributing Editors

McMAHON PUBLISHING

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Robin B. Weisberg, Manager, Copyediting Services

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CNS/PSYCHIATRY

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4 Up Front

Pharmacy Practice News • November 2010

Capsules

good month/ Medical volunteerism, after the U.S. Department of Health and Human Services (HHS) launched a national Web site to make volunteering in an emergency faster and easier for health professionals. The new site (www.phe.gov/esarvhp) provides a single point of entry for potential volunteers, quickly connecting them to each state’s medical volunteer program. According to the HHS, the new process can shave hours off the time volunteers used to wait to have their credentials verified.

bad month for ...

—David Bronstein

The family medicine cabinet, after Johns Hopkins researchers reported that seven of the top 10 drugs abused by teens in a national survey were either prescribed or purchased over the counter. Pain relievers were the main culprits that parents should be taking out of those cabinets, with oxycodone and hydrocodone the most often abused, according to the survey. Nearly 6% of high school seniors reported taking oxycodone, and nearly 10% said they took hydrocodone, researchers reported at the American Academy of Pediatrics annual meeting.

Patients with pancreatic cancer, after a new study showed that progression-free survival (PFS) more than doubled in patients with advanced pancreatic neuroendocrine tumors who were treated with everolimus (Affinitor, Novartis). Patients given the mTOR inhibitor and supportive care had a median PFS of 11 months, versus 4.6 months in patients given supportive care plus placebo, investigators reported at the European Society for Medical Oncology (ESMO) in Milan (abstract LBA 9).

Excelsior Medical Corporation, after the company had to issue a class 1 recall of its saline flush syringes due to the potential for leakage and contamination. The disposable 6-cc prefilled syringes contain 5 mL of 0.9% sodium chloride and are used to flush venous access devices and IV tubing. The recall includes product code numbers EO100-50, 10056-1000, 10056-240, 14056-240, 910056-1000 and S5.

Medication reconciliation, after a panel of stakeholders in hospital pharmacy and research published a consensus paper on “key principles and necessary first steps” for improving compliance with the Joint Commission’s requirement (J Hosp Med 2010;5:477-485). In 2005, the Joint Commission classified medication reconciliation as National Patient Safety Goal (NPSG) No. 8, which states that a detailed list of a patient’s drug regimen must be obtained before he or she is allowed to transition to different areas of care. Because of perennially poor compliance, the NPSG goal remains a voluntary target.

Weight-loss drugs, after Abbott Laboratories voluntarily recalled sibutramine (Meridia) from the U.S. market due to an increased risk for heart attack and strokes. The FDA asked for the withdrawal after reviewing data from the SCOUT (Sibutramine Cardiovascular Outcomes) postmarketing trial, which showed a 16% increase in cardiovascular events and deaths in patients treated with the drug versus placebo. Later last month, the FDA rejected approving phentermine/ topiramate (Qnexa, Vivus) due to safety concerns.

FDA Alert

by the

More Details on Alaris PC Unit Recall C

numbers

arefusion Corp. has issued new details regarding its Aug. 24 recall of Alaris PC Units (model 8015), which are used in some of the company’s programmable infusion pump systems. According to Carefusion, the FDA has now classified the action as a class 1 recall, which is used in situations where “there is reasonable probability” that the use of a violative product could lead “to serious adverse health consequences or death.” In the recall, which affected approximately 17,000 units, Carefusion notified customers that under certain wireless networking conditions, affected PC units could experience an intermittent communications error, which freezes the PC screen. The error may result in a delay of therapy and inability to make programming changes to current infusions, according to a MedWatch Alert posted on the FDA’s Web site. If the communications error occurs

during infusion, the infusion continues on all channels, as originally programmed, but cannot be modified. When this error occurs, stopping the infusion to make any modification or programming changes causes the PC unit to shut down, resulting in a delay or interruption in therapy, according to the alert. Such a shutdown “could lead to serious injury and/or death,” the alert stated. The devices included in the recall were made or serviced between December 2008 and September 2009 and distributed through June 2010. The corrective action will require a hardware update to all affected units. Although the FDA stated that CareFusion does not require that the devices be returned, the agency stressed that if users experience the communications error and screen problems, “they are to remove the device from service and contact the Carefusion Recall Center [888-562-6018] immediately.”

Scan for FDA MedWatch alert; see p. 3 for instructions

From the American College of Clinical Pharmacy annual meeting, Austin, Texas

11.43|

The time, in minutes, saved when pharmacists on a new “Brain Attack Team” in the emergency department of a New Jersey hospital helped speed the delivery of tissue plasminogen activator to patients with ischemic stroke (abstract 268).

30|

The percentage of patients hospitalized with heart failure (HF) who were misdiagnosed as having pneumonia and wrongly given antibiotics. The finding underscores the fact that HF often can mimic the lung infection, resulting in inappropriate antibiotic use (abstract 124).

31|

The percentage of patients hospitalized with severe Clostridium difficile infections who were given vancomycin, the recommended treatment for advanced cases. Most of the remaining patients were given metronidazole, which is usually reserved for patients with milder disease (abstract 155).

56|

The percentage of medication errors in HIV patients caused by prescribing errors. Dispensing errors caused 28.4% of the drug mishaps, followed by administration errors, at 15.5% (abstract 160).

137,000|

The projected dollars saved annually by a pharmacist-driven protocol that helped ensure the appropriate use of albumin in patients hospitalized with liver cirrhosis. Proper use increased from 18.7% pre-protocol to 31.6% post-protocol (abstract 254).

Up Front 7

Pharmacy Practice News • November 2010

Events

Patient Care, Medication Safety Featured at 2010 Midyear C

ritical hospital drug shortages, Risk Evaluation and Mitigation Strategies (REMS) and national health care reform are just three of the issues at center stage as the American Society of HealthSystem Pharmacists (ASHP) prepares to raise the curtain on its 45th Midyear Clinical Meeting and Exhibition Dec. 5-9 in Anaheim, Calif. More than 20,000 hospital pharmacists, pharmacy leaders and others are expected to turn out for the five-day event featuring a keynote presentation by ABC-TV journalist and co-anchor Bob Woodruff and his wife, Lee. Mr. Woodruff, who was severely wounded by a roadside bomb while on assignment in Iraq in 2006, will talk about his experiences throughout his recovery. The meeting also features a “Spotlight on Health Care Reform” talk by Mark McClellan, MD, PhD, former administrator of the Centers for Medicare & Medicaid Services. Anchoring pharmacy’s largest meeting will be several hundred hours of educational and networking sessions on a broad range of clinical, technology and pocketbook issues including gaining reimbursement for pharmacist services, developing collaborative antibiotic stewardship programs, improving medication safety and advancing health information technology at all practice levels. “We have more hours of educational sessions than ever,” said JoAnn Harris, RPh, MBA, director of ASHP’s Educational Services Division. The emphasis will be on practical solutions. “We want people to learn something at the meeting that they can bring home and use, either in their departments to improve efficiency or to directly help patients,” Ms. Harris said.

Show Me the Money An example is Tuesday’s two-part Learning Community on “Building Ambulatory Services: Convincing Your Institution to Charge for Pharmacist Services.” Leading the sessions will be Amy L. Stump, PharmD, BCPS, clinical assistant professor of pharmacy practice at the University of Wyoming School of Pharmacy and clinical pharmacist at the University of Wyoming Family Medicine Residency Program at Cheyenne. “Reimbursement for services is one of the biggest challenges that a lot of pharmacists face,” Dr. Stump said, and she promised that presenters would be offering “positive examples” of successful billing strategies, as well as discussing the barriers they have had to overcome. The three-hour morning session will open with a review of the most common reimbursement methods,

along with strategies for approaching upper management about setting up billing systems. In the afternoon, she said, pharmacists will offer three case vignettes focusing on successful billing practices at a university medical

center–based diabetes clinic that recently transitioned into a medical home as well as a comparison of anticoagulation clinics in community and university hospital settings. The afternoon also will feature pharmacist-facilitators who have successfully billed for services. Dr. Stump said today’s tough economic climate had made the reimbursement issue more relevant to pharmacists than ever. Many administrators “used to be OK with pharmacists justifying their existence based on how many dollars they saved. Now you have to be able to justify your existence based on how many dollars you are bringing in the door.”

Spotlight on Drug Shortages Hospital drug shortages will be in the spotlight at several networking sessions and a Tuesday afternoon program, “Identifying Strategies to Minimize the Impact of Drug Shortages.” The financial impact will be the main focus of the latter session, noted co-presenter Kavish J. Choudhary, PharmD, MS, manager of pharmacy support services at the University of Utah Hospitals and Clinics in Salt Lake City. “Shortages are increasing,” said Dr. Choudhary, “and the reality is that they are here to stay.” He said the presenters would offer different perspectives on the shortages, including the challenges

faced by a major group purchasing organization; operational strategies, with an emphasis on technology and automation; and specific moves that one hospital pharmacy department made to minimize the impact of drug shortages. “I’ve been at this institution for a little over a year now,” said Dr. Choudhary, “and we have really refined how we do things. We had a pretty good system in place prior to my coming here, but now we’ve actually documented it.” Noting that shortages often seem to occur at 5 p.m. on Fridays, he said, “We have a response plan in place. We know who to contact and what our back-up measures are so we don’t have to scramble and catch everyone by surprise.” Dr. Choudhary said his department also works with the University of Utah Drug Information Service to anticipate shortages and to take steps to avoid critical outages, such as forward buying when possible, vigorously managing shelf and dispensing cabinet supplies and having contingency plans for when alternative products need to be ordered. Following that session will be an open forum on the shortages that will give pharmacists an opportunity to talk about their experiences and learn about ASHP’s efforts in that area. The session will be coordinated by staff from ASHP’s Practice Development Division and experts in the field. (For more details on the drug shortage, see article, page 1.)

REMS Case Studies A three-hour Tuesday morning session will concentrate on the REMS required by the FDA for certain medications. “This won’t be a tutorial,” said session leader JoAnn Stubbings, RPh, manager of research and public policy for the Ambulatory Care Pharmacy Department at the University of Illinois at Chicago

Come See us at Booth #257 Be sure to pick up one of our Special Projects and Publications At the ASHP meeting, we’re giving away free copies of a wide variety of medical education resources, covering immune globulins, iron supplementation in oncologic and other disorders, and more.

Scan for ASHP Midyear schedule; see p. 3 for instructions

College of Pharmacy. “We’ll have a brief overview, just so everybody is on the same page. The most important thing right now is to hear what other health systems are doing [about] REMS.” To that end, she said pharmacists from four different health systems will be presenting REMS case studies. “It’s going to be a very fast-moving session.” “We would like pharmacy to embrace REMS,” Ms. Stubbings added. “It’s not perfect and we will talk about that. But there are many opportunities for pharmacists to be involved in the REMS process and especially in medication safety.” In addition to the regular educational sessions, the meeting will have blocks of time given over to the interests of special pharmacy groups, including new practitioners, students, federal pharmacists and pharmacists practicing in small and rural hospitals. Sunday’s Federal Forum 2010, for example, will focus on women’s health issues in the military and public health sectors, according to Retired U.S. Army Col. Mike Heath, RPh, MBA, consultant, who is coordinating the forum. Last year’s theme, he noted, was “Treating the Wounds of War: Excellence in Pharmaceutical Care for America’s Heroes.” Army Capt. Sam Brown, who was severely wounded in Afghanistan, was the featured speaker. “He brought the house down,” Col. Heath said. “It went over so well that we decided that whatever we did this year, we would include another live patient describing his or her personal health care experiences in the federal sector.” At press time, the service member had not yet been selected, but, he added, “We will be trying to put a face to the issue of women’s health.” —Bruce Buckley

8 Up Front

Pharmacy Practice News • November 2010

Awards

Innovative Researchers Honored for Contributions A pioneer in critical care pharmacy and a trend-setting ED pharmacist are among winners

rnold Schwarzenegger became a weightlifter to impress his father. Mark Zuckerberg founded Facebook to impress girls and get into one of Harvard’s elite clubs. And Joseph F. Dasta, MSc, became the “father of critical care pharmacy” because it beat manual labor. Mr. Dasta, now a professor emeritus at The Ohio State University College of Pharmacy in Columbus and adjunct professor at the University of Texas at Austin College of Pharmacy, is among the five pharmacists recognized this year by the ASHP (American Society of Health-System Pharmacists) Foundation’s literature awards. Honored for sustained contributions to the literature of pharmacy practice, he has come far from his blue-collar roots in the northern panhandle of West Virginia. “It was a steel-mill city,” Mr. Dasta recently recalled of his hometown. “A lot of my high school friends stayed and worked in the mill.” His father worked for a company that provided shipping and trucks to the local steel mill. No one in the family had ever gone to college, but after a couple of summers during high school toiling for the same company that employed his father, “I quickly figured out that heavy labor was not my cup of tea,” he said. “My goal was to go to college and leave the area for brighter horizons.” He did just that, starting at a local teacher’s college, West Liberty State College. During his freshman year, he found himself wondering where his chosen major—biology—might lead him. “I went to a filing cabinet they had at the college listing careers,” he said. “Under ‘P’ for pharmacy, I thought, hmm, that sounds interesting. The combination of science and chemistry and working with patients intrigued me, more so than just plain old biology.” Mr. Dasta’s interest in clinical work only increased when he attended West Virginia University School of Pharmacy in Morgantown. After one summer interning at a chain drugstore and another at a hospital, “I knew I didn’t want to work in retail pharmacy,” he said. “I didn’t feel I would know enough about the patients. This was in the early 1970s, before computers were popular. In the hospital, I could go up to the nursing unit and read about the patients.” After graduating in 1974, he obtained a master’s degree and residency in hospital pharmacy at The Ohio State University, which promptly became his first and career-long employer. Assigned to give a lecture to pharmacy students about lung medications, he realized he wanted more than book learning. He introduced him-

‘There really weren’t any training programs in pharmacy specifically for critical care. I had to teach myself and work with physicians to learn how different those patients are.’ —Joseph F. Dasta, MSc

self to the hospital’s pulmonologist and asked if he could join him on rounds. “We’ve never had a pharmacist round with us before,” the pulmonologist said, “but it sounds like a good idea.” He ended up not only rounding, but also becoming the hospital’s first clinical pharmacist specializing in pulmonary medicine. At the time, with sustainedrelease theophylline tablets just hitting the market for chronic obstructive pulmonary disease, Mr. Dasta published the first study to compare it with the conventional-release tablets. He then made a move that would change not only his career but also that of his profession, moving into critical care pharmacy and setting up one of the first critical care residencies in the country. “Very few pharmacists practiced in the ICU at that time,” he said. “I had some role models, but there really weren’t any training programs in pharmacy specifically for critical care. I had to teach myself and work with physicians to learn how different those patients are.” When he stumbled upon the journal Critical Care Medicine and learned of the Society of Critical Care Medicine (SCCM), he called the group’s executive offices and asked if a pharmacist could join. Asked to describe what exactly he did, Mr. Dasta explained to the person on the phone, “I teach and practice and go on rounds with the physicians and respiratory specialists.” “Oh, you’re part of the team,” he was told. “Of course you can join.” In 1982, he published the first paper ever to identify the ICU as an important area for pharmacist contributions (Drug Intell Clin Pharm 1982;16:398-399). In 1985, he co-edited the first textbook devoted to the subject, Practice of Critical Care Pharmacy. By then, he had already graduated his first resident in the university’s new critical care pharmacy program: Judith Jacobi, PharmD, who has since gone on to become the first pharmacist to assume the presidency of SCCM.

“Professor Dasta is one of my most influential mentors, and one of the things I have tried to emulate is his ability to make opportunities for others,” Dr. Jacobi told Pharmacy Practice News. “This is reflected in his many publications with a host of coauthors. He has a wealth of ideas and has posed some very fundamental and important questions regarding pharmacy practice and the use of drugs, but has shared the process and taught many additional research and publication skills at the same time. He truly is the father of critical care pharmacy.”

attended the SCCM meetings. Now the pharmacy section has over a thousand members, and we have our first pharmacist as president.” If his only goal was to avoid manual labor in the steel mill, it appears that he nonetheless took a bit of steel with him to build a new area of practice of which all pharmacists can be proud.

New Model Recognized For ED Pharmacy The honoree for the next ASHP Foundation award faced down a “Twilight Zone” scenario that would have scared off Edgar Allan Poe. Imagine, if you will, a Veterans Affairs (VA) health care system serving some 32,000 patients in its emergency department (ED) each year, 40% of them receiving three or more medications during their visit, in a setting so crowded that many are treated in the hallways. Now stand back or you’ll get splattered as some fresh-faced, specially dedicated pharmacists seek to make things better, not just during sunny weekday mornings but all through the long, dark night, by implementing a comprehensive, 24-hour ED pharmacy program.

‘Since we implemented this [ED pharmacy] program, all the other major hospital systems in San Diego County have visited the VA to see how we do it.’ —Helen K. Park, PharmD, FCPhA In the early 2000s, Mr. Dasta grew interested in the pharmacoeconomics of ICU drugs. “Very little had been written about it,” he said. The fact that he had no training in the subject didn’t stop him. A fellow professor, Dr. Dev Pathak, taught him what he needed to know. Mr. Dasta went on to publish a series of studies that, together, showed how optimal pharmacotherapy can lower some of the high costs associated with critical care by avoiding unnecessary or inappropriate therapy. After retiring from Ohio State in 2007, he moved to the warmer climes of Round Rock, Texas, where he lives with his wife of 37 years, Desma. Their daughter, Dana, works for ASHP Advantage. He remains closely involved with SCCM, serving as a member of two guidelines committees, does some consulting and plays a little golf and his guitar. Commenting on his literature award from the ASHP Foundation, he said, “Certainly, I’m thrilled. I still remember when just half a dozen pharmacists

But wait; take your fingers from over your eyes. Not only did the pharmacists at the VA in San Diego survive, but they also thrived, documenting 9,568 interventions in the first six months of the operation for an estimated cost savings of $845,592—and in the process winning this year’s ASHP Foundation award for innovation in pharmacy practice. “Since we implemented this program, all the other major hospital systems in San Diego County have visited the VA to see how we do it,” said Helen K. Park, PharmD, FCPhA, director of inpatient pharmacy. “They have all now started similar pharmacy programs in their own emergency departments, which is great.” Dr. Park added that other VA hospitals across the country also have instituted ED pharmacy programs, “and we have hosted visits from various VA facilities that are planning or in the midst of implementing them.”

•

see ASHP HONORS, page 10

10 Up Front

Pharmacy Practice News • November 2010

Awards

ASHP HONORS continued from page 8

As described last year in the American Journal of Health-Systems Pharmacy (2009;66:1943-1947), Dr. Park’s team sought to track and reconcile medications, document doses administered, manage the formulary and even prospectively review medication orders. They faced the challenge not only of where the four pharmacists hired for the program would work within the ED’s close quarters, but also of how they would integrate new VA-designed software for tracking medications prescribed there for outpatients. (It involved a lot of meetings, a great deal of team building with the existing ED staff and buying some new laptops.) Luckily, help in the initial six-month planning stage came from ASHP’s 2007 Patient Care Impact Program, which focused that year on introducing emergency pharmacy into a health system. The study documented 29 interventions to prevent drug interactions, nine cases

PharmD, BCPS, whose paper caught the attention not only of the FDA, but also of the ASHP Foundation, which has awarded him this year’s Drug Therapy Research Award. Soon after the FDA released its early communication, representatives of both the agency and Eli Lilly and Company (which sells the drug under the trade name Xigris) published separate letters to the editor on Dr. Gentry’s paper in Critical Care Medicine. Perhaps not surprisingly, the drug company defended clinicians’ decisions to use the drug even in patients whose baseline bleeding risks would have excluded them from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial, on which the drug’s approval had been based; likewise, the agency defended its classification of many of those baseline bleeding risks as “warnings” rather than contraindications. Nonetheless, a teleconference with Dr. Gentry, his coauthors and the FDA followed, and his team is now conducting follow-up

‘The tendency is to try something that’s going to win the Nobel Prize. You have to think about what you can really accomplish given the time, resources and patient population available to you.’ —Chris A. Gentry, PharmD, BCPS

of drug allergies prevented or managed, 198 dosages or frequencies adjusted, 57 untreated diagnoses brought to physicians’ attention, 265 adverse drug events prevented or managed, 75 prescriptions flagged as not indicated and 45 duplications of therapy avoided. Team members who co-authored the award-winning paper with Dr. Park were Victoria E. Aldridge, PharmD, director of clinical pharmacy specialists; Mark Bounthavong, PharmD, pharmacoeconomics clinical specialist; and Anthony P. Morreale, PharmD, MBA, BCPS, national director, clinical pharmacy services and healthcare delivery services research.

Drotrecogin Alfa Study Stokes Controversy, Earns Award Early on a cold morning in February 2009, the clinical specialist in infectious diseases at the Oklahoma City VA Medical Center’s pharmacy service sat down at his desk to read an “early communication” from the FDA regarding the risk for bleeding in sepsis patients receiving drotrecogin alfa (activated), citing the very study he had published on the drug a month earlier. “It was an interesting period there for a few months,” recalled Chris A. Gentry,

studies to better assess the morbidity and mortality associated with the drug in sepsis patients with baseline bleeding risks. The study and its aftermath grew out of a simple question: What would happen to the modest 6% absolute mortality difference seen in PROWESS if it had included patients with baseline bleeding risks, as is now commonplace in clinical practice? “That’s what prompted our study,” said Dr. Gentry, who also serves as his pharmacy service’s clinical coordinator. “We saw patients getting this drug with bleeding precautions. Because these patients are so sick, the thinking in clinical practice has been to throw the kitchen sink at them.” His study (Crit Care Med 2009;37:1925) involved 73 patients who received drotrecogin alfa. Serious bleeding events occurred in seven of 20 (35%) with any baseline bleeding precaution, versus only two of 53 patients (3.8%) without (P<0.0001). More patients with a baseline bleeding precaution also died compared with patients without any bleeding precautions (65% vs. 24.5%, P≤0.0015). An accompanying editorial recommended that clinicians consider limiting the drug to patients

Up Front 11

Pharmacy Practice News • November 2010

Awards without any baseline bleeding risk. Dr. Gentry urged health-system pharmacists to take seriously their own ideas for research studies but offered this caveat: “You have to pick and choose the projects that you have a realistic chance of doing correctly between your time constraints and resources. The tendency is to try something that’s going to win the Nobel Prize. You have to think about what you can really accomplish given the time, resources and patient population available to you.”

Collaborating With Community Physicians To Lower Blood Pressure

that used a physician–pharmacist alliance to improve blood pressure control,” Dr. Carter said. The study recognized by the ASHP Foundation was a prospective, controlled clinical trial with six clinics randomized to either a control group or an intervention group (Arch Intern Med 2009;169:1996-2002). Just over 400 patients with uncontrolled hypertension received either the standard care of the clinic physicians or care supported by clinical pharmacists who made drug therapy recommendations to physicians based on national

How far beyond the walls of a health system can clinical pharmacists go to bring improved medical care to patients? This year’s winner of the ASHP Foundation’s Pharmacy Practice Research Award decided to find out.

discontinued, the study found, significant benefits over placebo persisted, although they were somewhat diminished compared with those seen during the intervention period. “It’s a big honor to get the literature award for this paper,” Dr. Carter said. “But a lot of us were involved in the project. I feel honored to be able to represent our research team.” Even non-pharmacists on his team are sold on the benefits that clinical pharmacists can bring to patient care. “There can be a lot of clinical inertia

The commitment to

•

see ASHP HONORS, page 70

ZOSYN ( p i p e ra c i l l i n /

‘Eleven studies were funded under this [NIH grant for providing outpatient services], but ours was the only one that used a physician–pharmacist alliance to improve blood pressure control.’

tazobactam) continues with Pﬁzer Injectables

—Barry L. Carter, PharmD “Our research team has been studying physician–pharmacist collaborations for many years,” said Barry L. Carter, PharmD, who serves jointly as a professor in the Department of Pharmacy Practice and Science at the University of Iowa’s College of Pharmacy, as well as professor and associate head for research in the university’s Department of Family Medicine at its College of Medicine. Although prior studies had demonstrated that blood pressure control could be improved when clinical pharmacists collaborate with physicians, Dr. Carter sought to document those benefits outside the bounds of a hospital, in community-based medical offices, by using intention-to-treat principles and controlling for as many covariables as possible. His group was awarded two grants from the National Institutes of Health to study the question, including one in response to a Request for Applications (RFA) seeking proposals on how to improve cardiovascular guideline adherence. “Eleven studies were funded under this RFA, but ours was the only one

guidelines. Research nurses performed blood pressure (BP) measurements and 24-hour BP monitoring. At six months, the study found that BP was controlled according to national guidelines in 29.9% of patients in the control group and in 63.9% of patients in the intervention group (adjusted odds ratio, 3.2; 95% confidence interval [CI], 2.0-5.1; P<0.001). Earlier this year, his group published a study assessing what happened to the patients’ BP control after the physician– pharmacist collaboration ended. Even 18 months after the intervention was

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12 Clinical

Pharmacy Practice News • November 2010

Medication Safety

DRUG SHORTAGES continued from page 1

substitutes and experienced a significant financial impact, often because alternatives are more costly and take more time to prepare and administer. Many voiced questions about why critical medications that are in short supply often can be found in secondary distribution channels at much higher cost. “The magnitude of this problem is unbelievable,” said Tom Van Hassel, RPh, MPA, director of pharmacy at Yuma Regional Medical Center in Yuma, Ariz. “It is consuming my pharmacy resources to try to locate and come up with alternatives for these items, all of them in my top 20 list of drugs that are used.”

He noted that the drugs reported in short supply “are used so commonly that virtually every patient coming into the hospital is affected. “We’ve always had drug shortages that come and go,” Mr. Van Hassel continued, “but it is now an everyday occurrence. It has a huge impact on patient safety because we’re forcing doctors and nurses to use drugs that they are not used to. We’re forcing them to use [alternatives] from different vendors so the containers are different, the labeling is different, the size of vials is different.”

Morphine Shortages Pose Risk As an example, Mr. Van Hassel said, the Yuma Regional Medical Center pharmacy “used to send nurses a 2-mg

‘The ISMP report regarding drug shortages is the most comprehensive and timely summary of what is no less than a health care crisis. Because it is primarily a hospital pharmacy issue and not a drugstore problem, it is not on the public radar screen.’ —Michael Rubino, RPh, FASHP

ISMP’s Allen Vaida, PharmD, On Impact of Drug Shortage

llen Vaida, PharmD, executive vice president of ISMP, told Pharmacy Practice News that respondents to the group’s survey on drug shortages described severe shortfalls, not only of propofol but also neuromuscular blocking agents such as succinylcholine and vecuronium, and noted that the unfamiliarity with alternatives was frequently mentioned as the cause of dosing errors. In one case, he said, a wrong dose was calculated for vecuronium because “they were using a protocol for pancuronium.” In other cases, Dr. Vaida said, respondents noted that the use of phenytoin in place of fosphenytoin, which was in short supply, had caused adverse events, including thrombophlebitis in a pediatric patient and an arrhythmia in a surgical patient caused by too rapid administration of an older anticonvulsant. He said many respondents also mentioned the financial impact of the shortages. In addition to having to purchase more costly alternatives, he said, pharmacists have been forced to spend more time tracking down the status of missing drugs. Dr. Vaida said he had just spoken to a pharmacy director, who told him that he had spent an entire morning “trying to make sure people were notified” about changes prompted by missing medications. In addition, Dr. Vaida said, many hospital pharmacies have found that their efforts to avoid look-alike medication errors by buying from different manufacturers are being stymied by unexpected product outages. “With the shortage, all bets are off,” he said. “You have to get whatever is available. Now you may be going back to a manufacturer’s product that you had purposely switched from because it looked like another product. But you really don’t have a choice.” Dr. Vaida said ISMP was trying to get a stakeholder summit together with the American Society of Health-System Pharmacists and other organizations, including the American Society of Anesthesiologists, the FDA and manufacturers. The purpose, he said, is to try to find solutions because “the shortage is real. It’s affecting patient safety and it’s affecting hospitals financially.” —B.B.

syringe of morphine for a 2-mg dose. Now they get a 10- or 15-mg vial that they have to draw a 2-mg dose out of and waste the rest. The potential for adverse events, for overdoses and underdoses, is huge.” Michael Rubino, RPh, FASHP, director of pharmacy at Hartford Hospital, in Hartford, Conn., said “the ISMP report regarding drug shortages is the most comprehensive and timely summary of what is no less than a health care crisis,” adding that “because it is primarily a hospital pharmacy issue and not a drugstore problem, it is not on the public radar screen.” Mr. Rubino noted that the FDA “has very little authority with manufacturers to reduce drug shortages, improve information regarding the shortages or require adequate inventory levels of critical drugs.” He said that his pharmacy department, along with 1,850 other caregivers, participated in the ISMP survey, in which over 1,100 errors were reported as a result of drug shortages. “It is our obligation to discuss this crisis with our federal legislators to put pressure on the executive branch to give the FDA authority to help resolve [this problem]. Hospital pharmacists can start by discussing the issue with the government affairs people in their organization and bringing the issue to the state hospital association that represents health systems at the state government level as well. We need to act now.”

Letters to President Obama And FDA Mr. Van Hassel told Pharmacy Practice News that several months ago, he sent letters to President Obama and to the FDA’s Center for Drug Evaluation and Research, in which he said “it was time for them to get off their horse and become involved and get this

resolved because it is adversely affecting health care.” He received a response from the FDA’s Drug Shortages Team dated July 23 that stated, “we share your concerns regarding the large number of shortages currently occurring” and noted that many of the shortages involve “older sterile injectables that are commonly used.” The letter also stated that the medications often are made by a limited number of firms, some of which discontinue the medications “because they may not be as profitable as new agents .... With only three or fewer firms making many of these drugs, when one firm runs into problems or delays, it’s difficult for the remaining firms to increase production.” Propofol is a case study in how manufacturing problems can contribute to chronic drug shortages. The sedative agent has been mired in a year-long supply shortage stemming from manufacturing issues at the plants of two of its makers, Teva Pharmaceuticals and Hospira. Teva announced in May that it would no longer make the drug, citing low profitability. APP Pharmaceuticals, maker of Diprivan brand propofol, has been unaffected by production issues but has been unable to meet demand for the medication. Respondents to the ISMP survey cited concerns over the continuing propofol shortages, pointing out that the supply problems were causing potentially serious adverse outcomes. As an example, the ISMP cited one case of “unintended intraoperative awareness” that occurred when a patient was given too little propofol based on weight in an attempt to conserve supplies. Another patient received a 20-fold overdose of dexmedetomidine, an alternative to propofol, when the drug dose was misprogrammed in a “smart” infusion pump. According to the ISMP report, dexmedetomidine

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see DRUG SHORTAGES, page 14

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IMPORTANT PRECEDEX SAFETY INFORMATION Clinically signiﬁcant episodes of bradycardia, sinus arrest and hypotension have been associated with Precedex infusion and may necessitate medical intervention. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex. Please see the brief summary of Prescribing Information on adjacent page.

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For step-by-step instructions on how to start using Precedex and what to expect, please visit us at www.Precedex.com. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex.2 Clinically signiﬁcant episodes of bradycardia and sinus arrest have occurred in young, healthy volunteers with high vagal tone or with different routes of administration such as rapid intravenous or bolus administration.2 Transient hypertension has been observed primarily during the administration of the loading dose. Treatment has generally not been necessary, although a reduction in loading dose infusion rate may be desirable.2

Hypotension and bradycardia can occur and may necessitate medical intervention such as —Decreasing or stopping Precedex infusion —Increasing rate of IV ﬂuid administration —Elevating lower extremities —Administering pressor agents such as atropine, ephedrine or glycopyrrolate2 Use with caution in patients with advanced heart block or severe ventricular dysfunction.2 The most common adverse effects (incidence >2%) are hypotension, bradycardia and dry mouth.2

Please see the brief summary of Prescribing Information on adjacent page. References: 1. Based on increases in weight of active ingredient sold (either mcg or mg). IMS Health National Sales Perspective 2Q 2009. US nonretail market, all channels injectables. 2. Precedex [package insert]. Lake Forest, IL: Hospira, Inc; 2008. 3. Kamibayashi T, Maze M. Clinical uses of B2-adrenergic agonists. Anesthesiology. 2000;93:1345-1349. 4. Data on file. Hospira, Inc. Hospira, Inc. 275 North Field Drive, Lake Forest, IL 60045 P10-2830 Aug., 10. Printed in the USA.

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14 Clinical

Pharmacy Practice News • November 2010

Medication Safety

DRUG SHORTAGES continued from page 12

was not in the pump’s drug “library” of preset dosage limits because it had never been used at the hospital before the propofol shortage.

The ISMP report did not disclose whether the two cases involving propofol resulted in patient harm. But other drug shortages proved fatal, the report noted. In several cases, shortages of amikacin and acy-

Scan for ISMP Medication Safety Alert!; see p. 3 for instructions

clovir contributed to patient deaths from infections that respond only to those two agents. “Alternative antibiotics and antiviral[s] were of little help in these situations,” the report stated.

Table. Near Misses, Errors and Adverse Outcomes Associated With Drug Shortages Propofol Inadequate sedation with benzodiazepines led to agitation and self-extubation; one patient bit through her tongue. Prolonged hospitalization from intractable postoperative nausea and vomiting has occurred with alternative sedation agents.

Foreign Supplies Present A Double-Edged Sword

Respiratory spasms and airway obstruction required conversion to general anesthesia when alternative agents were used for sedation.

One potential solution is to allow companies from other countries to ship drugs that are in short supply into the United States. In the case of propofol, the FDA has been allowing the importation of a European version of the sedative, Propoven, from APP’s German parent company, Fresenius Kabi. But some clinicians are concerned that relying too heavily on foreign suppliers can bring its own safety issues.

Neuromuscular Blocking Agents Pancuronium was administered to a patient with renal failure, resulting in excessive and prolonged paralysis and tachycardia. Two patients developed possible rocuronium-induced pulmonary hypertension when preferred agents, cisatracurium and vecuronium, were unavailable. Early self-extubation occurred due to shorter duration of therapy with alternative neuromuscular blocking agents. Morphine IV HYDROmorphone was prescribed at the intended dose for morphine and administered, resulting in the deaths of two patients. 10 mg (10 mg/mL) of morphine was administered instead of 1 mg (1 mg/mL); patient required naloxone and was transferred to critical care. Patient was switched from morphine 6 mg IV to HYDROmorphone without changing the dose; patient received several 6-mg doses, which required naloxone administration and increased hospital length of stay. EPINEPHrine Patient died from a 10-fold overdose of EPINEPHrine administered when a nurse drew 10 mL of a 1:1,000 solution, assuming the vial contained a 1:10,000 solution. An EPINEPHrine 1:1,000 (1 mg/mL) ampul was removed from an automated dispensing cabinet; the nurse administered the entire ampul IV along with other IV medications but should have administered 0.3 mg IM; patient developed tachycardia and elevated troponin levels necessitating transfer to another hospital. Heparin A pharmacy-prepared heparin infusion containing 25,000 units/500 mL (50 units/mL) was accidentally dispensed to the NICU and administered for 2 hours instead of the intended pharmacy-prepared solution containing 0.5 units/mL. IV heparin was administered instead of magnesium during a code because the 10,000 units/mL heparin vials purchased to replace the 5,000 units/mL vials looked like the magnesium vials. Fosphenytoin Phenytoin dispensed instead of fosphenytoin was administered IV into a peripheral vein too rapidly, which resulted in severe thrombophlebitis in a pediatric patient. Phenytoin, which was reintroduced into the OR because of the fosphenytoin shortage, was administered IV too rapidly during surgery, which resulted in an arrhythmia and cardiac arrest. Chemotherapy Substituting XELODA (capecitabine) for leucovorin has resulted in serious gastrointestinal toxicity in many patients. Chemotherapy treatments were delayed in a patient with a high potential for remission amid attempts to find a source of the needed drug. Antibiotics Inability to treat with amikacin in a patient with established resistance caused readmission due to treatment failure with ineffective alternatives. A patient with viral meningitis had to be transported by helicopter from one hospital to another because IV acyclovir was not available, which increased the patient’s hospital length of stay. Source: Adapted from ISMP Medication Safety Alert! Special Issue: Drug Shortages: National Survey Reveals High Level of Frustration, Low Level of Safety (September 23, 2010 Issue).

‘We’ve always had drug shortages that come and go. But it is now an everyday occurrence. It has a huge impact on patient safety because we’re forcing doctors and nurses to use drugs that they are not used to.’ —Tom Van Hassel, RPh, MPA

“We already have examples of subpotent antibiotics entering the market from [foreign suppliers],” said Robert P. Rapp, PharmD, FCCP, professor of pharmacy and surgery emeritus at the University of Kentucky Medical Center, in Lexington. In cases involving other drugs, such as heparin, he noted, products from foreign suppliers have been contaminated with impurities that can be lethal. “Does anybody know who is minding the store with all of this?” Dr. Rapp asked. “Shortages yes, but that may be the tip of the iceberg.” Allen Vaida, PharmD, executive vice president of ISMP, acknowledged the seriousness of the drug shortage problem. “It has gotten worse and worse,” he said, “and no one is seeing any end in sight.” —Bruce Buckley

16 Clinical

Pharmacy Practice News • November 2010

Medication Safety

Students Help Public To Just Say No to Unused Medications Austin, Texas—A pharmacy school in northwestern Ohio and local law enforcement officials have teamed up to develop a drop-off service for unused medications. The initiative helped remove potentially dangerous drugs from the environment and also gave students a taste of community outreach—and a valuable lesson in medication safety. In the course of just three drop-off days, the pharmacy students collected

193,989 capsules and tablets. Nearly two-thirds of the unused medications were prescription drugs, including controlled substances, according to John Stanovich, RPh, assistant dean at the College of Pharmacy at the University of Findlay, and a co-investigator of a study analyzing the program’s initial impact. Non-controlled prescription medications were the most common drugs brought to the drop-off sites, totaling 57.5% over the span of the program.

The breakdown of the collection also included 6.2% in controlled prescription medications and 36.3% in overthe-counter drugs. The total estimated value, based on average wholesale price, was nearly $300,000, the investigators reported at the annual meeting of the American College of Clinical Pharmacy (abstract 164). Students and faculty at The University of Findlay College of Pharmacy got involved in the collection effort after

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Flebogamma® 5% DIF is indicated for replacement therapy in primary (inherited) humoral immunodeficiency disorders. DOSAGE AND ADMINISTRATION The usual dose of Flebogamma® 5% DIF for replacement therapy in primary humoral immunodeficiency diseases is 300 to 600 mg/kg body weight administered every 3 to 4 weeks. An in-line filter with a pore size of 15 to 20 microns is recommended for the infusion. Antibacterial filters (0.2 micron) may also be used. Discard unused contents and administration devices after use. The infusion of Flebogamma® 5% DIF should be initiated at a rate of 0.01 mL/kg body weight/minute (0.5 mg/kg/minute). If, during the first 30 minutes, the patient does not experience any discomfort, the rate may be gradually increased to a maximum of 0.10 mL/kg/minute (5 mg/kg/minute). For patients judged to be at risk for developing renal dysfunction or considered to be at increased risk of thombotic/thromboembolic events, it may be prudent to limit the infusion rate to a maximum rate less than 0.06 mL/kg body weight/minute (3 mg/ kg/minute). Reduction in dose, concentration, and/or rate of infusion in patients at risk of acute renal failure, which includes patients over 65, has been proposed in the literature in order to reduce the risk of acute renal failure. CONTRAINDICATIONS Flebogamma® 5% DIF should not be administered to individuals with a history of severe or anaphylactic reactions to blood or blood-derived products. Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Anaphylaxis can occur using Flebogamma® 5% DIF even though it contains low amounts of IgA (typically < 50 μg/mL). Such patients should only receive intravenous immune globulin with utmost caution and in a setting where supportive care is available for treating life-threatening reactions. If patients are known to be intolerant to any component of Flebogamma® 5% DIF, such as sorbitol (i.e., intolerance to fructose), they should not receive the product. WARNINGS Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Flebogamma® 5% DIF does not contain sucrose. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure. Flebogamma® 5% DIF is made from human plasma. As with all plasma derived products, the risk of transmission of infectious agents, including viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The risk that such products will transmit an infectious agent has been greatly reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Biologicals at 888-GRIFOLS (888-474-3657). All patients, but especially individuals receiving Flebogamma® 5% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at risk for the development of inflammatory reactions characterized by fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations may reduce the risk of these types of events. Appropriate supportive care, including immediate access to epinephrine injection, should be available for the management of acute anaphylactic reactions.

they were approached by local officials, including law enforcement and health authorities, who were concerned about prescription abuse and potential hazards to the water supply from drugs being disposed of improperly. The ongoing partnership, with more collection days in the works, is striving to both capture and categorize unused and potentially harmful medications. “Everyone wants to collect this medication and everybody wants to weigh

PRECAUTIONS General: Any vial that has been entered should be used promptly. Partially used vials should be discarded and not saved for future use because the solution contains no preservative. Do not use if turbid. Solution that has been frozen should not be used. Ensure that patients are not volume-depleted before the initiation of the infusion of IGIV. Renal Function: Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing Flebogamma® 5% DIF at a maximum rate less than 0.06 mL/kg (3 mg/kg) body weight/minute. Aseptic Meningitis Syndrome: An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic milliliter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high-dose (e.g., > 1.0 g/kg body weight) and/or rapid-infusion IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. Hemolysis: Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration [See ADVERSE REACTIONS]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis [See PRECAUTIONS: Laboratory Tests]. Thrombotic Events: Thrombotic events have been reported in association with IGIV (See ADVERSE REACTIONS). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [See PRECAUTIONS: Laboratory Tests]. Transfusion-Related Acute Lung Injury (TRALI): There have been reports of non-cardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1 to 6 hours after transfusion. Patients with TRALI may be managed by using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum [See PRECAUTIONS: Laboratory Tests]. Information For Patients: Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians. It is recommended that the lot number of the vials used be recorded when Flebogamma® 5% DIF is administered. Laboratory Tests: Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF in patients judged to have a potential increased risk for developing acute renal failure and again at appropriate intervals thereafter.

Clinical 17

Pharmacy Practice News • November 2010

Medication Safety it,” Mr. Stanovich said. “It’s like, ‘so what’s in there?’ The difference is that we’re collecting the data that we think is important to really get to the heart of the problem here, to develop educational programs.”

‘Take-back’ Programs Gaining Traction Prescription take-back programs have become increasingly popular, amid concerns about the potential risks of unused drugs piling up in medicine cabinets at home or being flushed down the toilet. Several entities, including The Ameri-

‘We’re collecting the data that we think is important to really get to the heart of the problem here, to develop educational programs.’

—John Stanovich, RPh

can Pharmacists Association (APhA) and the Pharmaceutical Research and Manufacturers of America, have launched a campaign called SMARxT Disposal (www.smarxtdisposal.net) to educate the public about safe disposal alternatives. Also this October, Presi-

Following infusion of Flebogamma® 5% DIF, there may be a transitory rise of various antibody titers that may result in misleading positive results in serological testing. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum. Pregnancy Category C: Animal reproduction studies have not been performed with Flebogamma® 5% DIF. It is also not known whether Flebogamma® 5% DIF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Flebogamma® 5% DIF should be given to a pregnant woman only if clearly needed. Drug Interactions: Antibodies in Flebogamma® 5% DIF may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration. Pediatric Use: The above mentioned clinical trial with Flebogamma® 5% DIF enrolled only a very limited number of children (0) and adolescents (3) with primary humoral immune deficiency, a number insufficient to fully characterize and establish the efficacy and safety in pediatric patients. Geriatric Use: Subjects over 65 are at increased risk of renal failure with IGIV treatment. For these subjects, and for any other subjects at risk of renal failure, the infusion rate of Flebogamma® 5% DIF should be limited to < 0.06 mL/kg/min (3 mg/kg/min). Adverse Reactions Increases of creatinine and blood urea nitrogen (BUN) have been observed as soon as 1 to 2 days following infusion of IGIV. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment. Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, proximal tubular nephropathy, and osmotic nephrosis. Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate [See DOSAGE AND ADMINISTRATION] must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Adverse reactions may occur more frequently when a high infusion rate is used, the treatment is the initial exposure to immunoglobulin, the immunoglobulin product has been changed to that of a different manufacturer, or there has been a long interval (more than 8 weeks) since the previous infusion. Slowing or stopping an infusion usually results in the prompt disappearance of symptoms. Post-Marketing: The following adverse reactions have been identified and reported during the postapproval use of IGIV products. Respiratory

Cardiovascular Neurological Integumentary Hematologic General/Body as a Whole Musculoskeletal Gastrointestinal

Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiac arrest, thromboembolism, vascular collapse, hypotension Coma, loss of consciousness, seizures, tremor Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, bullous dermatitis Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test Pyrexia, rigors Back pain Hepatic dysfunction, abdominal pain

Because post-marketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently. Adverse events were reported in a study of 46 individuals with primary humoral immunodeficiency diseases receiving infusions every 3 to 4 weeks of 300 to 600 mg/kg body weight. Forty-three (94%) subjects experienced at least 1 adverse event

dent Obama signed the Secure and Responsible Drug Disposal Act, which will make it easier for local groups to launch their own collection initiatives. Still, performing medication inventory remains relatively

irrespective of the relationship with the product, and these subjects reported a total of 595 adverse events. None of the 46 subjects who participated in this study discontinued the study prematurely due to an adverse experience related to the study drug. One subject had treatment-emergent bronchiectasis, mild, ongoing, after infusion #10; and one subject had recurrent moderate leukopenia after the 7th and 12th infusions. No adverse events occurred with an incidence of > 2% on a per infusion basis. Table 1. Adverse Events Occurring with an Incidence of > 15% Adverse Event

Number of AEs

Combined Bronchitis Cough and productive cough Diarrhea NOSa Headache NOS and sinus headache Nasal congestion Injection site reaction NOS Pyrexia Arthralgia Sinusitis NOS Pharyngitis Upper respiratory tract infection Wheezing and asthma aggravated

19 10 14 46 11 13 27 11 38 9 24 24

Number of Subjects with AEs 14 10 9 16 7 7 17 7 20 8 15 10

Percent of Subjects with AEs 30 22 20 35 15 15 37 15 44 17 33 22

a. NOS = not otherwise specified The total number of AEs (regardless of attribution) reported whose onset was within 72 hours after the end of an infusion of Flebogamma® 5% DIF was 216. There were a total of 709 infusions, resulting in a rate of 0.305 (95% confidence interval 0.225 to 0.412) temporally associated AEs per infusion. There were 144 infusions (20.1%, 1-sided 95% upper bound confidence interval = 24.4%) associated with 1 or more AEs that began within 72 hours after the completion of an infusion. Table 2. Summary of Infusions with Mild, Moderate, and Severe TreatmentRelated Adverse Events Severity of AE Mild Moderate Severe

No. Infusions 58 25 1

Adjusted % a with AE 7.9 3.6 0.1

Confidence Intervalb 10.4 4.9 0.3

a. Adjusted % = average of the % of infusions with a treatment-related adverse event for each individual subject. b. The 95% upper bound for the adjusted % of infusions for which at least 1 treatmentrelated adverse event was reported was derived by using the t-statistic. The number and percent of subjects with treatment-emergent rises in AST or ALT are in Table 3. Table 3. Number (%) of Subjects with Treatment-Emergent Rises in AST or ALT (N = 46) Laboratory Test AST ALT

Assessment Criteria Above 3x the ULNa Above 3x the ULN

n 3 1

% 6.5 2.2

a. ULN = upper limit of normal. None of these subjects had a concomitant treatment-emergent rise in total bilirubin. Reported adverse reactions with Flebogamma® 5% DIF and other IGIV products include: headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing, rash, arthralgia, and edema, often beginning within 60 minutes of the start of the infusion. Rarely, Immune Globulin Intravenous (Human) can induce a severe fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with IGIV. In the case of shock, the current standard medical treatment for shock should be implemented. Manufactured by INSTITUTO GRIFOLS, S.A. Barcelona - Spain U.S. License No. 1181 Distributed by GRIFOLS BIOLOGICALS INC. Los Angeles - CA 90032 Phone: 888-GRIFOLS (888-474-3657)

uncommon, said Mitchel Rothholz, RPh, MBA, the APhA’s chief of staff. “I think it’s great that they did the inventory to see what people are disposing,” he said, regarding the Findlay effort. “At some point, that would be helpful in looking at and evaluating policies related to medication coverage and usage.” In northwestern Ohio, propoxyphene and hydrocodone were the two controlled substances that were most frequently brought in, the researchers said. Some medication bags contained surprises, including a veteran who contributed 1,290 cyclosporine capsules that he reported having tried— and failed—to cancel through mail order. Another individual handed in 3,350 capsules of the pancreatic enzyme substitute, pancrelipase. One of the pharmacy school’s goals is to track in more detail the source of a drug, including why the individual is dropping it off, and some demographic information from those willing to share that information. Trends in insurance coverage practices, specifically 90-day drug supplies, may play a role in the accumulation of medications, according to Mr. Rothholz and Mr. Stanovich. If the individual’s medication is changed or the dosage is adjusted, a substantial quantity of pills may be left over, Mr. Stanovich said. “Most of the medication that came in was in unopened full containers,” he said. The amount of medications that was collected in one day would have filled three 55-gallon drums, the researchers said. So they removed the medicines from their containers, thus eliminating patients’ personal information, and sorted them into three five-gallon buckets. The prescription medications were given to law enforcement officials, and the nonprescription medications were handed to local environmental authorities. As a result of the partnership’s work, a county task force has been established to start looking at strategies to reduce prescription medication abuse, including reducing the amount sitting in local homes. This kind of inventory effort could be replicated anywhere, and pharmacy students can benefit from it, said Laura Perry, PharmD, BCPS, assistant professor of pharmacy practice at The University of Findlay and another research team member. “I think it’s eye-opening for [students] to see all of these medications come in. And it makes them aware of how to dispose of medications.” —Charlotte Huff

18 Clinical

Pharmacy Practice News • November 2010

Educational Review

Treatment Options in HIV Scan for PDF of this review; see p. 3 for instructions

PAUL E. SAX, MD Clinical Director, HIV Program Division of Infectious Diseases Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

COMMENTARY BETTY J. DONG, PHARMD, FASHP, FCCP Professor of Clinical Pharmacy and Family and Community Medicine University of California Schools of Pharmacy and Medicine San Francisco, California

n the past year, the US Department of Health and Human Services (DHHS) and the International AIDS Society-USA (IAS-USA) both issued substantial revisions

to their HIV treatment guidelines. Tables 1-4 present the major recommendations from these updated guidelines. The accompanying text reviews some of the major changes in the guidelines, and important areas where they agree and where they differ.

When To Initiate ART In their revised guidelines, both the DHHS and the IAS-USA place a greater emphasis on the potential benefits of earlier initiation of antiretroviral therapy (ART). Both recommend beginning treatment for all individuals who have symptoms of HIV infection or who have CD4 cell counts less than 500 cells/mm3, even if the patient is asymptomatic. For patients with CD4 cell counts greater than 500 cells/mm3, the DHHS panel was split on whether treatment should be started, with 50% recommending therapy and the other 50% considering it optional. Concomitant conditions that would warrant ART regardless of CD4 cell counts include pregnancy, HIVassociated nephropathy, and hepatitis B infection when such therapy is indicated. The IAS-USA panel lists these conditions as well as additional considerations, including HIV RNA greater than 100,000 copies/mL, a rapid decline in the CD4 cell count (ie, >100 cells/year), active hepatitis

C infection, high risk for cardiovascular disease (CVD), symptomatic primary infection, and risk for secondary HIV transmission (eg, in a serodiscordant couple). The rationale behind this move to treat a greater proportion of people with HIV, regardless of disease stage, is based on accumulating evidence of the benefits of earlier initiation of HIV treatment and, conversely, the potential long-term and irreversible harm that accrues in the presence of uncontrolled viral replication and CD4 depletion. Key cohort studies such as NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) and ART-CC (Antiretroviral Cohort Collaboration) established that HIV treatment should be started before the CD4 cell count falls below 350 cells/mm3, and possibly even prior to that.1,2 HIV replication is now known to be associated with increased immune activation and inflammation, both of which may lead to increased risk for non–AIDS-related

complications.1,2 Furthermore, the risk for these complications—in particular CVD and non-AIDS malignancies— appears to be increased in patients with lower CD4 cell counts.3 Because the majority of HIV-related deaths in patients on suppressive ART are not related to opportunistic infections or HIV-related malignancies, it follows that the best way to prevent these non-AIDS complications is to preserve the CD4 cell count at as high a level as possible. Observational studies have demonstrated a strong decrease in the risk for sexual transmission of HIV with ART.4,5 These data have led to mathematical models proposing an eventual elimination of the HIV epidemic if all infected patients were to start therapy.6 Although this model necessarily has several limitations and will be difficult to put into practice for logistical reasons, some communities in which a greater proportion of the population is receiving ART already are reporting a decline in new HIV diagnoses.7

What Treatment To Start The recommendation to start ART earlier would never have been possible unless HIV treatment had become safer and less likely to induce optionlimiting resistance. Indeed, it was the unanticipated toxicity of ART, specifically high rates of metabolic and morphologic complications, that plagued earlier attempts at aggressive HIV treatment. Importantly, the most toxic of these early agents (in particular stavudine, didanosine, indinavir, and nelfinavir) no longer are used widely in the developed world, and, thus, these complications have become quite rare. Longitudinal studies of the more recent treatment era also have reported unprecedented levels of virologic suppression among patients on therapy, with results from clinical practice now comparable with those reported in HIV clinical trials.8,9 Not surprisingly, these rates of treatment success have been accompanied by a dramatic drop Text continues on page 21

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20 Clinical

Pharmacy Practice News • November 2010

Educational Review

Table 1. Overview of Current Antiretroviral Agents Drug Name (Brand Name, Manufacturer)

Formulation

Recommended Adult Dosing

Food Effect

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Abacavir sulfate [ABC] (Ziagen, GlaxoSmithKline)

300-mg tablets 20-mg/mL oral solution

300 mg bid or 600 mg qd

None

Abacavir sulfate/lamivudine (Epzicom, GlaxoSmithKline)

600/300-mg tablets

1 tablet qd

None

Abacavir sulfate/lamivudine/ zidovudine (Trizivir, GlaxoSmithKline)

300/150/300-mg tablets

1 tablet bid

None

Didanosine [ddl] (Videx/Videx EC, Bristol-Myers Squibb Oncology/Immunology)

125-, 200-, 250-, 400-mg enteric-coated capsules

Delayed-release capsule: <60 kg: 250 mg once daily ≥60 kg: 400 mg once daily With tenofovir TDF: <60 kg: 200 mg/d qd ≥60 kg: 250 mg/d qd Note: Preferred oral solution dosing is bid; total daily dose divided

Should be administered on an empty stomach at least 30 min before or 2 h after meal

200-mg capsules

1 capsule qd

None

10-mg/mL oral solution

240 mg (24 mL) PO qd

Lamivudine [3TC] (Epivir, GlaxoSmithKline)

150-, 300-mg tablets 10-mg/mL oral solution

150 mg bid or 300 mg qd

None

Lamivudine/zidovudine (Combivir, GlaxoSmithKline)

150/300-mg tablets

1 tablet bid

None

Stavudine [d4T] (Zerit, Bristol-Myers Squibb Oncology/Immunology)

15-, 20-, 30-, 40-mg capsules 1-mg/mL oral solution

<60 kg: 30 mg bid ≥60 kg: 40 mg bid Note: WHO recommends 30 mg bid dosing regardless of body weight

None

Tenofovir disoproxil fumarate [TDF] (Viread, Gilead Sciences)

300-mg tablets

1 tablet qd

None

Tenofovir disoproxil fumarate/ emtricitabine (Truvada, Gilead Sciences)

300/200-mg tablets

1 tablet qd

None

Zidovudine [ZDV] (Retrovir, GlaxoSmithKline)

100-mg capsules 300-mg tablets 10-mg/mL oral solution 10-mg/mL IV solution

200 mg tid or 300 mg bid

None

10 mg/mL oral solution

Emtricitabine [FTC] (Emtriva, Gilead Sciences)

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)a Delavirdine mesylate [DLV] (Rescriptor, Pfizer)

100-, 200-mg tablets

400 mg tid (100-mg tablets can be dispersed in water; 200-mg tablets should be taken intact)

Separate dosing from antacids by 1 h with or without food

Efavirenz [EFV] (Sustiva, Bristol-Myers Squibb)

50-, 200-mg capsules 600-mg tablets

600 mg qd (at bedtime)

Take on empty stomach at bedtime to reduce side effects

Etravirine [ETV] (Intelence, Tibotec)

100-mg tablets

200 mg bid

Take after full meal

Nevirapine [NVP] (Viramune, Boehringer Ingelheim)

200-mg tablets 50 mg/5-mL oral suspension

200 mg qd x 2 wk, then 200 mg bid

None

Clinical 21

Pharmacy Practice News • November 2010

Educational Review

Table 1. Overview of Current Antiretroviral Agents Drug Name (Brand Name, Manufacturer)

Formulation

Recommended Adult Dosing

Food Effect

Atazanavir sulfate [ATV] (Reyataz, Bristol-Myers Squibb)

100-, 150-, 200-, 300-mg capsules

ART treatment-naïve patients only: Take with food 400 mg qd or 300 mg + 100 mg of RTV, qd Treatment-experienced patients or with TDF: 300 mg + 100 mg of RTV, qd Treatment-naïve patients in combination with EFV: 400 mg + 100 mg of RTV, qd

Darunavir ethanolate [DRV] (Prezista, Tibotec)

75-, 150-, 400-, 600-mg tablet

Treatment-experienced patients: 600 mg bid + 100 mg RTV bid Treatment-naïve patients: 800 mg qd + RTV 100 mg qd

Fosamprenavir [FPV] (Lexiva, GlaxoSmithKline/Vertex)

700-mg tablets

Treatment-naïve patients: None 1,400 mg bid or 700 mg bid + 100 mg RTV bid or 1,400 mg qd + 200 mg or 100 mg RTV PI-experienced: 700 mg bid + 100 mg RTV bid Coadministration with EFV (unboosted FPV not recommended): 700 mg + 100 mg RTV bid or 1,400 mg + 300 mg RTV qd

Indinavir sulfate [IDV] (Crixivan, Merck)

100-, 200-, 333-, 400-mg capsules

800 mg q8h or 800 mg + 100 mg or 200 mg RTV bid

Unboosted: Take 1 h before or 2 h after meals; may take with skim milk or low-fat meal Boosted: Take with or without food Separate dosing from ddl by 1 h

Lopinavir/ritonavir [LPR/r] (Kaletra, Abbott)

200/50-mg tablet 400/100-mg per 5 mL oral solution

2 tablets bid or 5-mL bid or 4 tablets qd or 10-mL qd Note: Once-daily dosing recommended ONLY for treatment-naïve patients. Not for use in combination with EFV, NVP, FPV, or NFV. Treatment-experienced patients and in combination with EFV or NVP: 3 tablets bid or 6.7-mL oral solution bid

Take with food

Nelfinavir mesylate [NFV] (Viracept, Pfizer)

250-, 625-mg tablets 50-mg/g oral powder

750 mg tid or 1,250 mg bid

Take with food to improve absorption; can also be dissolved in water

Ritonavir [RTV] (Norvir, Abbott)

100-mg capsules 80-mg/mL oral solution

600 mg bid (when used as only PI) 100-400 mg per day in 1 to 2 divided doses as pharmacokinetic booster for other PIs

Take with food or up to 2 h after a meal to improve tolerability

Saquinavir mesylate [SQV-HGC] (Invirase, Roche)

200-mg HGC 500-mg tablets

1,000 mg with 100 mg RTV bid (Unboosted SQV is not recommended)

Take within 2 h of full meal

Tipranavir [TPV-SGC] (Aptivus, Boehringer Ingelheim)

250-mg SGC

500 mg + 200 mg RTV bid (Unboosted TPV is not recommended)

Take with food

Protease Inhibitors (PIs)

Text continued from page 18

in the incidence of both treatment failure and drug resistance. Furthermore, the increased number of options for treatment-experienced patients has translated into rates of virologic suppression that are comparable to those observed in patients who are beginning their first regimen.10 For treatment-naïve patients, both the DHHS and IAS-USA guidelines

recommend regimens consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a third active drug from a different class. Rather than listing individual components, the DHHS guidelines now list entire regimens as “preferred,” “alternative,” or “acceptable.” It was agreed that this change was warranted, given the increased trial data on specific regimens over the past several years. Preferred first-line

Take with food

regimens all include tenofovir (TDF) and emtricitabine (FTC); the third active drug can be efavirenz (EFV), atazanavir (ATV)/ritonavir (r), darunavir (DRV)/r, or raltegravir (RAL). There are several regimens listed as alternatives that may, in certain patients, be the optimal choice. The IAS-USA continues to list regimens by components (dual NRTI component plus a “key third drug”).

TDF/FTC is the recommended dual NRTI component, with abacavir-lamivudine (ABC/3TC) listed as alternative. The key third agents are the same as in the DHHS guidelines (EFV, ritonavir-boosted ATV or DRV, or RAL); alternative third drugs are lopinavir/r, fosamprenavir/r, and maraviroc. One subtle difference between the 2 guidelines is a broader range of alternative Text continues on page 22

22 Clinical

Pharmacy Practice News • November 2010

Educational Review Text continued from page 21

or acceptable choices in the DHHS guidelines. In addition to the “alternative” therapies listed by the IAS-USA, the 2009 DHHS guidelines “alternative” and “acceptable” regimens include zidovudine/3TC, didanosine plus 3TC, nevirapine, unboosted ATV, and saquinavir/r.

Future Directions During the past year, data on several promising investigational agents were presented that are likely to influence treatment in the near future. These include studies of rilpivirine (TMC278, Tibotec)11 and the integrase inhibitor elvitegravir (Gilead Sciences)—both of which are to be developed into single-pill, once-daily tablets coformulated with TDF/FTC.12 Also exciting are the early data on the integrase inhibitor S/GSK1349572.13 After this group of drugs is developed, however, there is a relative dearth of investigational agents, which highlights the importance of selecting a

durably suppressive antiretroviral regimen with the goal of avoiding drug resistance.

References 1.

Hunt PW, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008;197(1):126-133.

2. Kuller LH, Tracy R, Belloso W, et al. Inﬂammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008; 5(10): e203. 3. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ. 2009;338:a3172. 4. Donnell D, Baeten JM, Kiarie J, et al; Partners in Prevention HSV/HIV Transmission Study Team. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet. 2010;375(9731):2092-2098. 5. Sullivan S, Kayitenkore K, Chomba E, et al. Reduction of HIV transmission risk and high risk sex while prescribed ART: Results from Discordant Couples in Rwanda and Zambia [Abstract 52bLB]. Presented at: 16th Conference on Retroviruses and

Opportunistic Infections; February 8-11, 2009; Montreal, Canada. 6. Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009;373(9657):48-57. 7. Montaner JS, Lima VD, Barrios R, et al. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet. 2010;376(9740):532-539. 8. Gill VS, Lima VD, Zhang W, et al. Improved virological outcomes in British Columbia concomitant with decreasing incidence of HIV type 1 drug resistance detection. Clin Infect Dis. 2010;50(1):98-105. 9. Elzi L, Marzolini C, Furrer H, et al; Swiss HIV Cohort Study. Treatment modiﬁcation in human immunodeﬁciency virusinfected individuals starting combination antiretroviral therapy between 2005 and 2008. Arch Intern Med. 2010;170(1):57-65. 10. Yazdanpanah Y, Fagard C, Descamps D, et al; and the ANRS 139 TRIO Trial Group. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO Trial. Clin Infect Dis. 2009;49(9):1441-1449.

11. Cohen C, Molina JM, Cahn P, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing TMC278 versus efavirenz in treatment-naive, HIV-1-infected patients. XVIII International AIDS Conference; July 18-23, 2010; Vienna. Abstract THLBB206. 12. Cohen C, Shamblaw D, Ruane P, et al. Singletablet, fixed-dose regimen of elvitegravir/ emtricitabine/tenofovir disoproxil fumarate/ GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, CA. Abstract 58LB. 13. Arribas J, Lazzarin A, Raffi F, et al. Oncedaily S/GSK1349572 as part of combination therapy in antiretroviral naïve adults: rapid and potent antiviral responses in the interim 16-week analysis from SPRING-1 (ING112276). XVIII International AIDS Conference; July 18-23, 2010; Vienna. Abstract THLBB205. 14. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009; 1-161. Available at http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf. Accessed October 28, 2010. Review continues on page 24

Table 1. Overview of Current Antiretroviral Agents Drug Name (Brand Name, Manufacturer)

Formulation

Recommended Adult Dosing

Food Effect

Fusion Inhibitors Enfuvirtide [T-20] (Fuzeon, Roche/Trimeris)

Injectable (lyophilized 90 mg (1 mL) sc bid; administered powder): each single-use subcutaneously into upper arm, vial contains 108 mg of anterior thigh, or abdomen enfuvirtide to be reconstituted with 1.1 mL of sterile water for delivery of approximately 90 mg/mL

None

150-, 300-mg tablets

150 mg bid when administered with strong CYP3A inhibitors 300 mg bid when administered with T20, TPV, RTV, NVP, and weak CYP3A inhibitors 600 mg bid when administered with CYP3A inducers (eg, EFV, ETR, rifampin) and without CYP3A inhibitors

None

400-mg tablets

1 tablet bid

Take with or without food

600/200/300-mg tablets

1 tablet qd

Take on an empty stomach Dosing at bedtime may improve tolerability of nervous system symptoms

CCR5 Co-receptor Antagonist Maraviroc (Selzentry, Pfizer)

Integrase Strand Transfer Inhibitors Raltegravir (Isentress, Merck) Combination Regimens Efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla, Gilead Sciences/ Bristol-Meyers Squibb)

bid, twice daily; IV, intravenous; PO, orally; qd, every day; sc, subcutaneous; tid, 3 times daily; WHO, World Health Organization a

During clinical trials, NNRTIs were discontinued because of rash in 7% of NVP-treated patients, 4.3% of patients taking delavirdine, and 1.7% of patients taking efavirenz, and 2% of ETR-treated patients. Rare cases of Stevens-Johnson syndrome have been reported with the use of all 3 NNRTIs, the highest incidence seen with nevirapine use.

Cases of worsening glycemic control in patients with preexisting diabetes and cases of new-onset diabetes, including diabetic ketoacidosis, have been reported with the use of all PIs. Patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risk for cardiovascular events and pancreatitis. Interventions can include dietary modification, lipid-lowering modification, lipid-lowering agents, or discontinuation of PIs.

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24 Clinical

Pharmacy Practice News 窶｢ November 2010

Educational Review Review continued from page 22

Table 2. Indications for Initiation of Antiretroviral Therapy in Chronically HIV-1窶的nfected Patients From the DHHS and IAS-USA Guidelines Clinical Condition and/or CD4+ Count

Ratinga

Recommendation

Symptomatic HIV disease

Initiate treatment regardless of CD4+ cell count

Pregnant women

HIV-1 RNA >100,000 copies/mL

AII 3

Rapid decline in CD4 cell count, >100 cells/mm per year

AII

Acute hepatitis B coinfection

BII

Acute hepatitis C coinfection

AII

Active or high risk for cardiovascular disease

BII

HIV-associated neuropathy

BII

Symptomatic primary HIV infection

BII

High risk for secondary HIV transmission (eg, serodiscordant couples)

BII

Asymptomatic (CD4 cell count <500 cells/mm3)

ART is recommended

AII

CD4 cell count <350 cells/mm

AII

CD4 cell count 350-500 cells/mm

Asymptomatic (CD4 cell count >500 cells/mm )

CIII

ART should be considered unless patient is an elite controller (HIV-1 <50 copies/mL) or has stable CD4 cell count and low level viremia in the absence of ART.b Optimal time to initiate therapy is not well defined. Individual patient scenarios and comorbidities should be taken into consideration.c

ART, antiretroviral therapy; DHHS, Department of Health and Human Services; IAS-USA, International AIDS Society-USA a

Rating of recommendations: A, strong; B, moderate; C, optional. Rating of evidence: I, data from randomized controlled trials; II, data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III, expert opinion.

Recommendations from the IAS-USA guidelines.

Recommendation from the DHHS guidelines.

Table 3. DHHS Antiretroviral Regimens Recommended for Treatment-Naﾃｯve Patients Regimen

Preferred Regimen

Alternate Regimen

Acceptable Regimen

NNRTI-based (1 NNRTI + 2 NRTIs)

Efavirenza + tenofovir + emtricitabineb

Efavirenz + (abacavirc or zidovudine) + lamivudineb Nevirapined + zidovudine + lamivudineb

Efavirenz + didanosine + (lamivudine or emtricitabine)e

PI-based (1 PI + 2 NRTIs)

Atazanavir/rf + tenofovir + emtricitabine Darunavir/r (qd) + tenofovir + emtricitabine

Atazanavir/rg + (abacavir or zidovudine) + lamivudineb Fosamprenavir/r (qd or bid) + (abacavir or zidovudine) + lamivudineb Fosamprenavir/r (qd or bid) + tenofovir + emtricitabineb Lopinavir/rh (qd or bid) + (abacavir or zidovudine) + lamivudineb Lopinavir/r (qd or bid) + tenofovir + emtricitabineb Saquinavir/r + tenofovir + emtricitabineb

Atazanavir + (abacavir or zidovudine) + lamivudineb

INSTI-based (1 INSTI + 2 NRTIs)

Raltegravir + tenofovir + emtricitabine

bid, twice daily; DHHS, Department of Health and Human Services; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; qd, every day; r, ritonavir boosted a

Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or in those not using effective and consistent contraception.

Lamivudine may substitute for emtricitabine or vice versa.

Abacavir should not be used in patients who test positive for HLA-B*5701 and should be used with caution in patients at high risk for cardiovascular disease or with pretreatment HIV-RNA >100,000 copies/mL.

Nevirapine should not be used in patients with moderate to severe hepatic impairment. It should not be used in women with pre-ARV CD4+ >250 cells/mm3 or men with pre-ARV CD4+ >400 cells/mm3.

This regimen has only been studied in small clinical trials.

Atazanavir/r should not be used in patients who require >20 mg omeprazole per day.

Atazanavir/r is generally preferred over atazanavir. Unboosted atazanavir may be used when ritonavir boosting is not possible.

Lopinavir/r qd is not recommended for pregnant women. Adapted from reference 14.

Review continues on page 26

26 Clinical

Pharmacy Practice News • November 2010

Educational Review Commentary

Review continued from page 24

Betty J. Dong, PharmD, FASHP, FCCP, AAHIVE Professor of Clinical Pharmacy and Family and Community Medicine University of California Schools of Pharmacy and Medicine San Francisco, California

“Test and treat,” one of the suggested HIV management strategies considered in the current antiretroviral guidelines, repres-

sents a major shift in the care of infected patients since the beginning of the HIV epidemic in the 1980s. First touted in 2002, this strategy calls for starting antiretroviral therapy in everyone who tests positive for the virus as a means to eliminate HIV. This strategy deviates from the more conservative method of starting treatment only when the patient’s number of CD4 cells falls below

Premixed Injection in either 4.8% Dextrose or 0.86% Sodium Chloride 5% Dextrose or 0.83% Sodium Chloride Brief Summary of Prescribing Information Cardene I.V. Premixed Injection in 4.8% Dextrose 20 mg in 200 mL (0.1 mg/mL) Each mL contains 0.1 mg nicardipine hydrochloride, 48 mg dextrose hydrous, USP, 0.0192 mg citric acid, anhydrous, USP, and 1.92 mg sorbitol, NF. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7. Cardene I.V. Premixed Injection in 0.86% Sodium Chloride 20 mg in 200 mL (0.1 mg/mL)

birth weights, neonatal survival, and neonatal weight gain were noted. There are no adequate and well-controlled studies in pregnant women. Cardene® I.V. should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. NURSING MOTHERS: Studies in rats have shown significant concentrations of nicardipine in maternal milk. Therefore, use in nursing mothers is not recommended. PEDIATRIC USE: Safety and efficacy in patients under the age of 18 have not been established. USE IN THE ELDERLY: In clinical studies, no significant difference was observed in the antihypertensive effect of Cardene® I.V. in patients ≥65 years compared to other adult patients. Clinical studies of nicardipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. ADVERSE EXPERIENCES: 244 patients participated in two multicenter double-blind, placebo-controlled trials of Cardene® I.V. Adverse effects were generally not serious and most were expected effects of vasodilation. Some adverse effects required dosage adjustments. Therapy was discontinued in approximately 12% of patients due mainly to hypotension, headache, and tachycardia. The following numbers represent percentage of patients with adverse experiences during the double-blind portion of controlled trials with Cardene® I.V. (n=144) versus Placebo (n=100), respectively.

Each mL contains 0.1 mg nicardipine hydrochloride, 8.6 mg sodium chloride, USP, 0.0192 mg citric acid, anhydrous, USP, and 1.92 mg sorbitol, NF. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7. Cardene® I.V. Premixed Injection in 5% Dextrose 40 mg in 200 mL (0.2 mg/mL) Each mL contains 0.2 mg nicardipine hydrochloride, 50 mg dextrose hydrous, USP, and 0.0384 mg citric acid, anhydrous, USP. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7. Cardene® I.V. Premixed Injection in 0.83% Sodium Chloride 40 mg in 200 mL (0.2 mg/mL) Each mL contains 0.2 mg nicardipine hydrochloride, 8.3 mg sodium chloride, USP, 0.0384 mg citric acid, anhydrous, USP, and 3.84 mg sorbitol, NF. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7. INDICATION AND USAGE: For the short-term treatment of hypertension when oral therapy is not feasible or desirable. For prolonged control of blood pressure, patients should be transferred to oral medication as soon as their clinical condition permits. CONTRAINDICATIONS: Cardene® I.V. is contraindicated in patients with known hypersensitivity. Cardene® I.V. is also contraindicated in patients with advanced aortic stenosis because part of the effect of Cardene® I.V. is secondary to reduced afterload. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance. WARNINGS: BETA-BLOCKER WITHDRAWAL: Nicardipine is not a beta-blocker and provides no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of dose of beta-blocker. RAPID DECREASES IN BLOOD PRESSURE: No clinical events have been reported suggestive of a too rapid decrease in blood pressure with Cardene® I.V. However, as with any antihypertensive agent, blood pressure lowering should be accomplished over as long a time as is compatible with patient’s clinical status. USE IN PATIENTS WITH ANGINA: Induction or exacerbation of angina has been seen in less than 1% of coronary artery disease patients treated with Cardene® I.V. Increased frequency, duration, or severity of angina has been seen with chronic oral Cardene® therapy. USE IN PATIENTS WITH CONGESTIVE HEART FAILURE: Cardene® I.V. reduced afterload without impairing myocardial contractility in preliminary hemodynamic studies of CHF patients. However, in vitro and in some patients, a negative inotropic effect has been observed. Exercise caution when using Cardene® I.V., particularly in combination with a beta-blocker, in patients with CHF or significant left ventricular dysfunction. USE IN PATIENTS WITH PHEOCHROMOCYTOMA: Limited clinical experience exists in these patients; therefore, exercise caution when administering Cardene® I.V. PERIPHERAL VEIN INFUSION SITE: To minimize the risk of peripheral venous irritation, it is recommended that the site of infusion of Cardene® I.V. be changed every 12 hours. PRECAUTIONS: GENERAL: Blood Pressure: Cardene® I.V. decreases peripheral resistance; monitoring of blood pressure during administration is required. Cardene® I.V., like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is advised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. Use in Patients with Impaired Hepatic Function: Nicardipine is metabolized in the liver; exercise caution in patients with impaired liver function or reduced hepatic blood flow; consider use of lower dosages. Nicardipine administered intravenously has been reported to increase hepatic venous pressure gradient by 4 mmHg in cirrhotic patients at high doses (5 mg/20 min). Use Cardene® I.V. with caution in patients with portal hypertension. Use in Patients with Impaired Renal Function: When Cardene® I.V. was given to mild to moderate hypertensive patients with moderate renal impairment, a significantly lower systemic clearance and higher AUC was observed. These results are consistent with those seen after oral administration of nicardipine. Careful dose titration is advised when treating renally impaired patients. DRUG INTERACTIONS: Since Cardene® I.V. may be administered to patients already being treated with other medications, including other antihypertensive agents, careful monitoring of these patients is necessary to detect and promptly treat any undesired effects from concomitant administration. Beta-Blockers: In most patients, Cardene® I.V. can safely be used with beta-blockers. However, exercise caution when using this combination in CHF patients (see WARNINGS). Cimetidine: Cimetidine has been shown to increase nicardipine plasma concentrations following Cardene® capsule administration; carefully monitor concomitant use. Data with other histamine-2 antagonists are not available. Digoxin: Studies have shown that Cardene® capsules usually do not alter digoxin plasma concentrations; however, as a precaution, evaluate digoxin levels when initiating concomitant Cardene® I.V. therapy. Fentanyl anesthesia: Hypotension has been reported during fentanyl anesthesia with concomitant use of a betablocker and a calcium channel blocker. Even though such interactions were not seen during clinical studies with Cardene® I.V. (nicardipine hydrochloride), an increased volume of circulating fluids might be required if such an interaction were to occur. Cyclosporine: Concomitant use of Cardene® capsules and cyclosporine results in elevated plasma cyclosporine levels. Monitor cyclosporine plasma levels closely and reduce its dose accordingly. In vitro interaction: The plasma protein binding of nicardipine was not altered when therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine, or naproxen were added to human plasma in vitro. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Rats treated with nicardipine in the diet (at doses of 5, 15, or 45 mg/kg/day) for two years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and three-month rat studies have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine (T4) levels, with resultant increase in plasma levels of thyroid stimulating hormone (TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid. In rats on an iodine deficient diet, nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementation. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100 mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes. There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for one year and no evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man. There was no evidence of a mutagenic potential in genotoxicity tests conducted in microbes, mice and hamsters. No fertility impairment was seen in male or female rats administered oral nicardipine doses as high as 100 mg/kg/day (50 times the 40 mg TID maximum recommended human dose [MRHD] in man, assuming a patient weight of 60 kg). PREGNANCY CATEGORY C: Cardene® I.V. administered at doses up to 5 mg/kg/day and up to 0.5 mg/kg/day to pregnant rats and rabbits, respectively, produced no embryotoxicity or teratogenicity. Embryotoxicity, but not teratogenicity, was seen at 10 mg/kg/day in rats and at 1 mg/kg/day in rabbits. Nicardipine was embryocidal at oral doses of 150 mg/kg/day, given during organogenesis, to pregnant white rabbits but not at 50 mg/kg/day (25 times MRHD). No adverse effects on the fetus were observed when albino rabbits were treated, during organogenesis, with up to 100 mg/kg/day of nicardipine. Pregnant rats receiving oral doses up to 100 mg/kg/day (50 times MRHD) showed no evidence of embryolethality or teratogenicity. However, dystocia and reductions in

350 cells/mm3. When this aggressive strategy was first proposed, it failed to gain widespread support because the antiretroviral agents (ARVs) available at that time were hampered by limited efficacy and excessive toxicity. But as anti-HIV agents improved, health officials again began calling for a more aggressive approach. This approach is reflected in current antiviral treat-

Percent of Patients with Adverse Experiences During the Double-Blind Portion of Controlled Trials Cardene® (n=144)

Placebo (n=100)

14.6 0.7 0.7 0.7

2.0 0.0 0.0 0.0

Cardiovascular Hypotension Tachycardia ECG abnormality Postural hypotension Ventricular extrasystoles Extrasystoles Hemopericardium Hypertension Supraventricular tachycardia Syncope Vasodilation Ventricular tachycardia

5.6 3.5 1.4 1.4 1.4 0.7 0.7 0.7 0.7 0.7 0.7 0.7

1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

Digestive Nausea/vomiting

4.9

1.0

Injection Site Injection site reaction Injection site pain

1.4 0.7

0.0 0.0

Metabolic and Nutritional Hypokalemia

0.7

0.0

Nervous Dizziness Hypesthesia Intracranial hemorrhage Paresthesia

1.4 0.7 0.7 0.7

0.0 0.0 0.0 0.0

Respiratory Dyspnea

0.7

0.0

Skin and Appendages Sweating

1.4

0.0

Urogenital Polyuria Hematuria

1.4 0.7

0.0 0.0

Adverse Experience Body as a Whole Headache Asthenia Abdominal pain Chest pain

RARE EVENTS: The following events have been reported in clinical trials or in the literature with intravenous use of nicardipine. Body as a Whole: fever, neck pain. Cardiovascular: angina pectoris, atrioventricular block, ST segment depression, inverted T wave, deep vein thrombophlebitis. Digestive: dyspepsia. Hemic and Lymphatic: thrombocytopenia. Metabolic and Nutritional: hypophosphatemia, peripheral edema. Nervous: confusion, hypertonia. Respiratory: respiratory disorder. Special Senses: conjunctivitis, ear disorder, tinnitus. Urogenital: urinary frequency. Sinus node dysfunction and myocardial infarction, possibly due to disease progression, have been seen in patients on chronic oral nicardipine therapy. OVERDOSAGE: Several overdosages with orally administered nicardipine have been reported. One adult patient allegedly ingested 600 mg of nicardipine (standard [immediate release] capsules), and another patient, 2160 mg of the sustained release formulation of nicardipine. Symptoms included marked hypotension, bradycardia, palpitations, ﬂushing, drowsiness, confusion and slurred speech. All symptoms resolved without sequelae. An overdosage occurred in a one-year-old child who ingested half of the powder in a 30 mg nicardipine standard capsule. The child remained asymptomatic. Based on results obtained in laboratory animals, lethal overdose may cause systemic hypotension, bradycardia (following initial tachycardia) and progressive atrioventricular conduction block. Reversible hepatic function abnormalities and sporadic focal hepatic necrosis were noted in some animal species receiving very large doses of nicardipine. For treatment of overdosage, standard measures including monitoring of cardiac and respiratory functions should be implemented. The patient should be positioned so as to avoid cerebral anoxia. Frequent blood pressure determinations are essential. Vasopressors are clinically indicated for patients exhibiting profound hypotension. Intravenous calcium gluconate may help reverse the effects of calcium entry blockade. DOSAGE AND ADMINISTRATION: DOSAGE MUST BE INDIVIDUALIZED depending on severity of hypertension and patient response. Monitor blood pressure during and after the infusion; avoid too rapid or excessive reductions in systolic or diastolic blood pressure. Cardene I.V. Premixed Injection is supplied as a single-use, ready-to-use, iso-osmotic solution for intravenous administration in a 200 mL GALAXY container with 20 mg (0.1 mg/mL) nicardipine hydrochloride in either dextrose or sodium chloride, or with 40 mg (0.2 mg/mL) nicardipine hydrochloride in either dextrose or sodium chloride. Cardene I.V. Premixed Injection should not be combined with any product in the same intravenous line or premixed container. Protect from light; store in carton until ready to use. Protect from freezing. Avoid excessive heat.

See package insert for full prescribing information. For questions of a medical nature, or to report an adverse event, please call 1-877-207-5802. Cardene® I.V. is a registered trademark of EKR Therapeutics, Inc. Manufactured by: Baxter Healthcare Corporation Deerﬁeld, IL 60015 USA Marketed by: EKR Therapeutics, Inc. Bedminster, NJ 07921 USA Issued July 2009 CAR09-240

ment guidelines from the U.S. Department of Health and Human Services (DHHS) and the International AIDS Society (IAS)-USA, which propose starting antiretroviral therapy (ART) in all patients with ongoing viral replication, even in those with CD4 counts exceeding 500 cells/mm3. In fact, the IAS panel states that there is no CD4 count at which starting ARV therapy is contraindicated. These aggressive recommendations to consider treatment of all HIV-positive patients are based on accumulating observational data that clearly show that any viral replication (eg, detectable plasma HIV RNA level) is undesirable, and causes inflammation as well as an increase in non– AIDS-related morbidity (eg, cardiovascular disorders, liver failure, kidney disease, cancers) and mortality. Treatment of patients early in the course of the disease also appears to provide a public health benefit by reducing HIV transmission and new infections. But there are still several caveats associated with early, aggressive ART: • Lifelong adherence is necessary to maintain complete viral suppression and CD4 recovery and to prevent the development of drug resistance, which can lead to treatment failure. • If HIV resistance develops during ART, that resistance can be transmitted to others. • Cross-resistance among ARVs can occur during treatment failures, restricting viable future treatment options. • Although current ARVs are more effective and better tolerated than previous ARVs, are available in fixeddose combinations, and can be administered once daily, drug toxicity and adhering to prescribed regimens can still be problematic. This is particularly the case in patients with significant barriers to compliance (eg, psychiatric illness and/or substance abuse, unstable living conditions, financial issues). Given these concerns, it is perhaps not surprising that only about 50% of the DHHS panel supported the aggressive

Clinical 27

Pharmacy Practice News • November 2010

Educational Review

Dual NRTI Component

Table 4. Recommended Components for the Initial Antiretroviral Regimen From the IAS-USA Recommended

Alternative

Tenofovir/emtricitabine

Abacavir/lamivudine

Available as fixed-dose combination alone and with efavirenz Once daily Low genetic barrier to resistance (emtricitabine) Renal dysfunction, decreased bone mineral density associated with tenofovir influence choice

Available as fixed-dose combination Once daily Weaker antiviral efficacy in treatment-naÏve patients with baseline HIV-1 RNA >100,000 copies/mL than tenofovir/emtricitabine Low genetic barrier (lamivudine) Need to screen for HLA-B*5701a to reduce risk for abacavir hypersensitivity Abacavir may be associated with increased cardiovascular risk

Recommended

Alternative

Key Third Agent

Efavirenz

Lopinavir/r

NNRTI class Available in fixed-dose combination with tenofovir/emtricitabine, which has become standard-of-care comparator regimen in most clinical trials Low genetic barrier Major psychiatric illness, first trimester of pregnancy, or intention to become pregnant influences choice

PI/r class Extensive clinical experience Comparator PI/r in many trials Only PI co-formulated with ritonavir (heat stable) Can be given once daily in naïve patients Potential for hyperlipidemia and gastrointestinal adverse effects influences choice

Atazanavir/ra

Fosamprenavir

PI/r class Once daily Widely prescribed when PI/r is chosen for initial therapy Leaves options for future regimens Less lipidogenic potential than lopinavir/r Hyperbilirubinemia, need for acid-reducing agents, and risk for nephrolithiasis influence choice

PI/r class Profile similar to lopinavir/r May be useful when other initial PI/r not tolerated

Darunavir/r

Maraviroc

PI/r class Once daily in treatment-naïve patients Limited experience in treatment-naïve patients, presence of other options in most naïve patients, and efficacy in patients with treatment experience, and multidrug-resistant virus influence choice

CCR5 antagonist class Targets host protein (viral co-receptor) Need to perform viral tropism assay before use Limited clinical experience in treatment-naïve patients Strategically, may be more useful in treatment-experienced patients or when primary (transmitted) drug resistance is present but viral population should be exclusively receptor 5

Recommended

Alternative

Raltegravir

INSTI class Twice daily Rapid decline in HIV-1 RNA slope after initiation Low genetic barrier Limited experience in naïve patients, presence of other options in most naïve patients, and efficacy in treatment-experienced patients with multidrug-resistant virus influence choice

No alternative regimen

CCR5, CC chemokine receptor 5; IAS-USA, International AIDS Society-USA; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside or nucleotide analogue reverse transcriptase inhibitor; PI, protease inhibitor; /r, ritonavir boosted. a

Based on extensive clinical experience.

Based on antiviral efficacy and tolerability comparable to that of key third agents but more limited experience in treatment-naïve patients.

test-and-treat approach to HIV management. Nevertheless, the San Francisco Health Department and one of my teaching hospitals, San Francisco General Hospital, recently adopted the DHHS and IAS guidelines that ARVs should be offered to all HIV-infected persons regardless of CD4 count and viral load

unless there is a reason to defer therapy. Others have not done so. All pharmacists should be aware of these new ART recommendations and the rationale to offer ART early. Additionally, pharmacists should be able to: • Counsel patients about the risks and benefits of early ART, including the benefits of reducing HIV

transmission. • Refer those individuals not in care to HIV care. • Implement strategies to improve adherence to therapy. • Be alert to the potential for fatal and nonfatal drug interactions as more patients receive treatment. • Ensure that hospital formularies have newer ARVs available for

early therapy. ART should be offered to all HIV-infected patients, but it is unreasonable to believe that all patients will be ready to take ART successfully. The concept of “test and treat” deserves further investigation before universal adoption. The timing of when to start also is under investigation.

28 Clinical

Pharmacy Practice News • November 2010

Pediatrics

Extravasation Protocols Aim To Improve Neonatal Outcomes Staging system guides treatment decisions at Emory

fter the Association of Women’s Health, Obstetric and Neonatal Nurses published clinical practice guidelines in 2001 for neonatal skin care— including steps to lower the risk for IV infiltration and tissue extravasation—a number of facilities developed their own protocols designed to prevent the problem or manage it when it occurred. Emory University in Atlanta is one such institution. “In the past four to five years, I have not seen the severe burns, sloughing, scabbing and loss of joint movement that was seen prior to use of this protocol,” said Janet L. Thigpen, a board-certified neonatal nurse practitioner in the Department of Pediatrics/ Division of Neonatology at Emory University School of Medicine.

Emory Protocol A detailed description of the Emory protocol written by Ms. Thigpen

and published in Neonatal Network: The Journal of Neonatal Nursing (2007;26:379-384) discusses the prevention, assessment and initial management of IV infiltration and extravasation, along with treatment using antidotes or multiple puncture procedures. “Having nurses trained in meticulous observation of IV sites, as well as rapid response to an infiltrate has greatly reduced morbidity,” Ms. Thigpen said. Observation of IV sites includes hourly evaluations for a lack of blood return, fluid leakage, signs of pain, or swelling, redness and/or coolness of the skin. If IV infiltration has occurred, the first step is to discontinue the IV catheter in the presence of blanching, necrosis, pain at the site or other observations. Restricting bands should be removed, elevation should be considered and a physician or practitioner notified. At this point, clinicians would turn to

Commentary Amber J. Lucas, PharmD, BCPS, FASHP Clinical Pharmacy Specialist, Department of Pharmacy; Saint Luke’s Hospital of Kansas City; Kansas City, Missouri

rom a pharmacy perspective, our involvement in the prevention and treatment of infiltrates/extravasations in our neonatal intensive care unit (NICU) is multidisciplinary. Very similar to the approach taken at Emory University, our nursing staff has protocols in place for the monitoring of both peripheral and central IV sites in neonates. For peripheral IVs, sites are assessed every hour and graded on a 5-point scale, with 0 indicating no signs of pain, swelling or leakage from the site, and the IV site flushes easily; 1 indicating no swelling or leakage from the site, but the patient shows signs of pain with flushing, escalating to a 4, indicating that patients have signs of pain, very marked swelling in entire extremity and/or blanching or other change in skin color, with the skin cool to touch, as well as absent or decreased pulse. Our nurses pull the IV if a baby is graded 2 or higher. For peripherally inserted central catheter lines, a 4-point phlebitis scale is used for grading and is similar to the peripheral IV scale. These protocols have worked well because they are followed absolutely without exception; there have been very few cases of grade 4 extravasations since we implemented the protocol five years ago. In fact, that is the key to any extravasation protocol: The staff must have zero tolerance for this adverse event. Prevention absolutely has to be the focus. Unfortunately, you cannot completely prevent infiltrates/extravasations from ever occurring. For management of existing infiltrates/extravasations, it is imperative that the required medications for treatment are available quickly. We use the same protocol as Emory, with the use of hyaluronidase 1 mL divided into 0.2-mL doses injected subcutaneously around the periphery of the extravasation. Mupirocin cream is then applied to the erythema and purpura at the IV site, with a dressing change daily for 10 days. If significant eschar or scabbing is present at 10 days, the mupirocin cream is changed to a 1:1 mixture of mupirocin ointment and collagenase ointment. If deep fluid, abscess or full-thickness necrosis exists, then plastic surgery is consulted. All NICU protocols (and others in our hospital) are developed with involvement from all disciplines. They are evidence-based and reviewed by the most appropriate committee, in this case a committee that consists of neonatologists, neonatal nurse practitioners, neonatal nurses and neonatal pharmacists. If a medication is unavailable due to shortage or product discontinuation, such as was true of hyaluronidase a few years ago, alternative management plans must be developed.

the staging protocol in place at Emory to determine the degree of required intervention. The staging system breaks down extravasation into four stages based on the degree of damage. In stage 1 extravasation, for example, the patient might have pain at the IV site and cry when the IV cannula is flushed; flushing of the IV cannula may be difficult, but no redness or swelling is observed. In stage 4 extravasation, severe swelling may be observed around the site, in addition to blanching, skin necrosis or blistering, a prolonged capillary refill time greater than four seconds, skin that is cool to the touch and a decreased or absent pulse. Treatment options are different for each stage. For stage 1 extravasation, treatment includes removal of the IV cannula and elevation of the extremity. For stage 2 and higher, an antidote is considered. “The consideration of antidote comes from evaluation by the nurse practitioner or physician regarding severity of extravasation,” said Ms. Thigpen. “This is a judgment call. If there is blistering, discoloration or extreme infiltration, the antidote is used.”

Available Antidotes Although the treatment of IV infiltration/extravasation is controversial, a number of medical therapies are outlined in the Emory protocol. “Hyaluronidase can be used for most neonatal extravasations from IV solutions,” Ms. Thigpen wrote. The protocol calls for 0.2 mL of hyaluronidase to be administered through the IV catheter before removing it, the subcutaneous injection of 0.2 mL at the edge of the infiltration and an additional 0.2 mL injected around the perimeter of the infiltration.

“In the case of peripheral infiltration with extravasation, the use of needle sticks to reduce pressure and the use of hyaluronidase as antidote has been a great success in my practice,” she said.

Kudos for Hyaluronidase Tracy Lawson, MD, a consultant neonatal pediatrician at Ashford and St. Peter’s Hospitals National Health Service Trust in England, has had a similar experience. “I used hyaluronidase to good effect in a previous hospital, and would recommend it. We have not audited this, but in practice when used, extravasation injuries are minimized,” Dr. Lawson said. Internal protocols also have been developed for extravasation injuries at Ashford and St. Peter’s Hospitals. Ph e n to l ami n e, an α- adre n e rg i c blocker, is another medical therapy that can be used to treat extravasation of α-adrenergic drugs. To use phentolamine as an antidote, the medication is diluted to 0.5 mg/mL; then 0.2-mL injections are administered to the extravasated area; blood pressure should be monitored. The protocols of Ashford and St. Peter’s Hospitals and Emory both call for nitroglycerin administration in certain cases. The Ashford and St. Peter’s protocol includes administering nitroglycerin in the form of a transdermal patch; with the Emory protocol, a topical 2% nitroglycerin ointment is applied at a dose of 4 mm/kg body weight. In terms of staff knowledge and dayto-day operations at Emory, Ms. Thigpen said the nursing staff are well informed about the protocols. “The protocols are readily available on computer if review is needed.” —Evan Young

The PROOF is everywhere you look GAmunex is the IGIV therapy supported by robust clinical trials n Proven efficacy in more FDA-approved

indications (CIDP, PI, and ITP)* than any other liquid IGIV1

Important Safety Information for GAmunex Gamunex, Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, is indicated for the treatment of primary humoral immunodeficiency disease (PI), idiopathic thrombocytopenic purpura (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Gamunex does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer. Gamunex is contraindicated in individuals with acute severe hypersensitivity reactions to Immune Globulin (Human). It is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity. There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Lung Injury (TRALI)], hemolytic anemia, and aseptic meningitis in patients administered with IGIV. Thrombotic events have been reported in association with IGIV. Patients at risk for thrombotic events may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy. Gamunex is made from human plasma. Because this product is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. In clinical studies, the most common adverse reactions with Gamunex were headache, fever, chills, hypertension, rash, nausea, and asthenia (in CIDP); headache, cough, injection site reaction, nausea, pharyngitis, and urticaria (in PI); and headache, vomiting, fever, nausea, back pain, and rash (in ITP). The most serious adverse reactions were pulmonary embolism (PE) in one subject with a history of PE (in CIDP), an exacerbation of autoimmune pure red cell aplasia in one subject (in PI), and myocarditis in one subject that occurred 50 days post-study drug infusion and was not considered drug related (in ITP). *CIDP=chronic inflammatory demyelinating polyneuropathy; PI=primary immunodeficiency; ITP=idiopathic thrombocytopenic purpura. Reference: 1. Data on file. Talecris Biotherapeutics, Inc. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see adjacent page for brief summary of GAmunex full Prescribing Information.

Evidence based. Patient proven. To get GAMUNEX call 1-888-MY-GAMUNEX (694-2686) USA Customer Service 1-800-243-4153 Clinical Communications 1-800-520-2807 Reimbursement Help line 1-877-827-3462 ÂŠ2010 Talecris Biotherapeutics, Inc.

www.gamunex.com

July 2010

GX104-0610

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to � Hyperproteinemia, increased serum viscosity and hyponatremia use GAMUNEX®, Immune Globulin Intravenous (Human), 10% occur in patients receiving IGIV therapy. Caprylate/Chromatography Purified, safely and effectively. See � Thrombotic events have occurred in patients receiving IGIV therapy. full prescribing information for GAMUNEX. Monitor patients with known risk factors for thrombotic events; GAMUNEX (Immune Globulin Intravenous [Human], 10% Caprylate/ consider baseline assessment of blood viscosity for those at risk of Chromatography Purified) 10% Liquid Preparation hyperviscosity. Initial U.S. Approval: 2003 � Aseptic Meningitis Syndrome has been reported with GAMUNEX and other IGIV treatments, especially with high doses or rapid infusion. WARNING: ACUTE RENAL DYSFUNCTION and FAILURE � Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. See full prescribing information for complete boxed warning. � IGIV recipients should be monitored for pulmonary adverse reactions � Renal dysfunction, acute renal failure, osmotic (TRALI). nephrosis, and death may be associated with Immune Globulin Intravenous (Human) (IGIV) products � The product is made from human plasma and may contain in predisposed patients. infectious agents, e.g., viruses and, theoretically, the CreutzfeldtJakob disease agent. � Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing ADVERSE REACTIONS sucrose. GAMUNEX does not contain sucrose. � Administer IGIV products at the minimum concentration � PI – Most common drug related adverse reactions during clinical available and the minimum infusion rate practicable. trials were headache and cough. � ITP – Most common drug related adverse reactions during clinical INDICATIONS AND USAGE trials were headache, vomiting, fever, and nausea. GAMUNEX is an immune globulin intravenous (human), 10% liquid � CIDP – Most common drug related adverse reactions during clinical indicated for treatment of: trials were headache and fever. � Primary Humoral Immunodeficiency (PI) To report SUSPECTED ADVERSE REACTIONS, contact Talecris � Idiopathic Thrombocytopenic Purpura (ITP) Biotherapeutics, Inc. at 1-800-520-2807 or FDA at 1-800-FDA-1088 � Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) or www.fda.gov/medwatch. CONTRAINDICATIONS DRUG INTERACTIONS � Anaphylactic or severe systemic reactions to human immunoglobulin � IgA deficient patients with antibodies against IgA and a history of � The passive transfer of antibodies may interfere with the response to live viral vaccines. hypersensitivity � The passive transfer of antibodies may confound the results of WARNINGS AND PRECAUTIONS serological testing. IgA deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions. USE IN SPECIFIC POPULATIONS Epinephrine should be available immediately to treat any acute � In patients over age 65 or in any patient at risk of developing renal severe hypersensitivity reactions. insufficiency, do not exceed the recommended dose, and infuse � Monitor renal function, including blood urea nitrogen, serum GAMUNEX at the minimum infusion rate practicable. creatinine, and urine output in patients at risk of developing acute renal failure. � Pregnancy: no human or animal data. Use only if clearly needed. �

Talecris Biotherapeutics, Inc. Research Triangle Park, NC 27709 USA U.S. License No. 1716

08939392/08939393-BS Revised: October 2008

Clinical 29

Pharmacy Practice News • November 2010

Critical Care Achieving SSC goals reduces costs, saves lives

Large Health System Slashes Sepsis Mortality C

atholic Healthcare West, a 41-hospital health system based in California, Arizona and Nevada, has reduced mortality by 33% and cut costs by $36 million after implementing a severe sepsis prevention initiative three years ago. Launched in July 2007, the CHW “surviving sepsis” initiative followed the recommendations of the National Surviving Sepsis Campaign (SSC), which aimed to raise awareness and improve diagnosis and treatment of sepsis. According to the campaign, more than 750,000 cases of severe sepsis occur annually in North America, with 210,000 fatalities, making it the No. 1 cause of inpatient mortality. The goal of the SSC campaign was for hospitals to reduce sepsis-related mortality by 25%—a target that CHW clearly had in mind when it embarked on its own initiative. In 2007, before the health-system’s sepsis improvement program was in place, the severe sepsis mortality rate was 36.8%; by 2010, that rate had dropped to 25.85%. Direct costs per case had also dropped significantly, from $16,128 per case in 2007 to $14,303 in 2010. Pharmacists were a key part of the implementation of CHW’s strategy, said Kathy Hirokawa, PharmD, director of pharmacy at St. Mary Medical Center, in Long Beach, Calif., part of the CHW network. “We were part of the initial continuous quality improvement team, planning the implementation of the whole process, along with physicians, nurses and the quality department.” The team implemented the severe sepsis bundles, sets of evidence-based care components for a given disease that, when consistently applied, had been determined to achieve at least a 25% reduction in mortality from severe sepsis or septic shock. At the pharmacy end, that meant antibiotic selection for the automated dispensing cabinet in the emergency department, as well as the

‘We are a good quick reference for the nurse, to let her know that the antibiotics the patient is already on look OK, or that she needs to call the doctor for new orders.’ —Kathy Hirokawa, PharmD

distribution process, ensuring that the correct medications were rapidly dispensed to the correct patient. “Before this, we didn’t have a lot of antibiotics in the Pyxis cabinets, because the pharmacists wanted to review what would be ordered,” Dr. Hirokawa said. “So we decided, with the committee, that we would put at least three or four key antibiotics into the cabinets, including vancomycin and levofloxacin.” The hospital also implemented a “sepsis response team” for patients already in the hospital who are suspected of developing sepsis. “The rapid response team is called, assesses the patient and the sepsis response team is activated if sepsis is a possibility based on signs and symptoms,” Dr. Hirokawa said. “The pharmacist is either a physical part of the team, or at a minimum, available by

phone. He or she reviews the current medications, focusing on antibiotics, and makes a recommendation to modify or add antibiotics, if indicated. While this doesn’t happen frequently, it has expedited turn-around time for patients already admitted to the hospital, where there is a shorter time-frame requirement.” “From a pharmacy standpoint, it ties into your clinical workflow and isn’t a huge time commitment,” she noted. “But it can make an enormous difference in response time and clinical results, especially since attendings [frequently] aren’t here when a patient starts to go septic— we’re a good quick reference.”

Impressed by Results Gita Patel, PharmD, of the Medical Center of Plano, Texas, who also saw positive results when her team imple-

mented a similar campaign in 2007, was impressed. “It was like reading about our hospital, only seeing it as a whole systems initiative,” said Dr. Patel, now the division director of clinical pharmacy services for North Texas and Central/ West Texas divisions of HCA Healthcare. “It’s hard enough to do at the facility level, and to do at a systems level with 40 hospitals—that’s great.” A sepsis mortality rate of over 60% spurred the Medical Center of Plano to launch its campaign, which involved a similar multidisciplinary team devising order sets for early screening in the emergency department and on the floors. “We decreased the time to first antibiotic, a lot more fluids were given, lactic acid levels were drawn—it was very consistent care,” said Dr. Patel. “Similarly to CHW, we achieved a 40% reduction in sepsis mortality.” Since the initial campaign, the medical center has continued to review its results and records about 77% overall compliance with the severe sepsis bundles. “Those patients treated with the algorithm bundle have a mortality rate in the very low 20-percentile range, while other sepsis patients have a mortality rate in the upper 50-percentile range,” Dr. Patel said. “Now, if there’s a patient with sepsis who is not being treated with the bundle, the doctor is called in [to a committee] for an explanation. The medical executive team has decided that this should be the standard of care for sepsis patients.” The multidisciplinary approach to the campaign is critical, Dr. Hirokawa said. “We had great buy-in from the emergency room doctors, the ICU medical director and medical residents. They were all essential to implementing our guidelines. You can’t approach a project like this in silos.” —Gina Shaw

Neuromuscular Blockers May Help Avoid Paralytics in ARDS U sing a neuromuscular blocking agent to induce muscle paralysis in patients with early, severe acute respiratory distress syndrome (ARDS) helps improve their odds of survival without causing muscle weakness, according to a recent study. In the double-blind ACURASYS trial in France, study authors randomly assigned 340 patients with severe ARDS—a life-threatening lung condition marked by inflam-

mation, excess fluid in the alveolar air sacs, low blood oxygen and respiratory distress—to receive either cisatracurium besylate (Nimbex, Abbott) or placebo. The study was conducted at 20 hospitals throughout France. Results, published Sept. 16 in The New England Journal of Medicine, showed that 178 patients in the cisatracurium group had a lower risk for death (hazard ratio, 0.68) compared with 162 patients in the placebo group

(P=0.04). The crude 90-day mortality rate was 31.6% in the cisatracurium group and 40.7% in the placebo group (P=0.08), and the 28-day mortality was 9.6 percentage points lower among patients in the cisatracurium group versus the placebo group (23.7% vs. 33.3%; P=0.05). The beneficial effect of cisatracurium was confined to the two-thirds of patients presenting with the severest form of ARDS, based on arterial blood oxygen values. Patients who received cisatracurium

•

see PARALYTICS, page 30

30 Clinical

Pharmacy Practice News • November 2010

Critical Care

PARALYTICS continued from page 29

(150 mg) also had significantly more ventilator-free days than the placebo group during the first 28 and 90 days, had more days free of organ failure (other than the lungs) during the first 28 days, and spent significantly more days outside the intensive care unit (ICU) between day 1 and day 90. The rate of muscle weakness did not differ significantly between the groups. Based on these findings, lead author Laurent Papazian, MD, PhD, of the Université de la Méditerranée in Marseille, France, told Pharmacy Practice News that he recommends neuromuscular blocking agents for ARDS at all hospitals, but only for patients with severe hypoxemia. He added that the drug must be administered early in the course of ARDS (the first day or two) and for a short duration (48 hours or less). Dr. Papazian said further study could help determine whether the use of neuromuscular blocking agents for only 24 hours would be beneficial, and how the drug helps, although he believes it decreases ventilator-associated lung injuries.

‘It remains unclear in the study whether the rapid administration of cisatracurium after intubation truly allowed ICU clinicians adequate time to try the many non-paralytic strategies that have been shown to reduce ventilator-associated dysynchrony in this population ....’ —John W. Devlin, PharmD, FCCM paralysis based on the number of clinically detectable muscle twitches on a 0 to 4 scale. “Pharmacists in the ICU should evaluate this study in the context of current ventilation and sedation/analgesia

strategies for ARDS management at their institution before adopting continuous neuromuscular [blocking] therapy in this population on a widespread basis,” Dr. Devlin said. He further cautioned that the results of this study

may not be reproducible with other paralytic agents, or when paralytics are either not started soon after intubation or continued for prolonged periods. —Karen Blum

Critical Care Pharmacist’s View John W. Devlin, PharmD, FCCM, associate professor and director of the critical care pharmacy fellowship program at Northeastern University and Tufts Medical Center in Boston, said he thought the study was “particularly noteworthy,” given that most ICUs over the past decade have moved away from routine administration of continuous infusions of a neuromuscular blocker in ARDS patients because of their association with prolonged muscle weakness. That trend can also be due, he said, to the availability of newer ventilator and sedation strategies that counteract the ventilator-associated dysynchrony that frequently occurs in ARDS patients managed with a low tidal volume strategy. However, he said, “It remains unclear in the study whether the rapid administration of cisatracurium after intubation truly allowed ICU clinicians adequate time to try the many nonparalytic strategies that have been shown to reduce ventilator-associated dysynchrony in this population, such as aggressive sedation and opioid administration, and various ventilator adjustments.” Dr. Devlin also noted that study patients had their sedation monitored with a sedation scale instead of bispectral monitoring, and did not receive “train-of-four” monitoring, where clinicians estimate the level of a patient’s

Humulin N is now available in a smaller vial.*

Indication, continued

Lilly also offers Humalog and Humulin R U-100 in a smaller vial size.*

Humalog should be used with longer-acting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.

The smaller vials are designed to give hospitals ﬂexibility when evaluating insulin storage and distribution (ﬂoor stock vs individual patient supply), in addition to the 10 mL vial and Humalog® KwikPen™. Same bar-coding technique, same color-differentiating system, smaller size. • Humalog® (insulin lispro injection [rDNA origin]) NDC Number - 0002-7510-17 • Humulin® N (NPH human insulin [rDNA origin] isophane suspension) NDC Number - 0002-8315-17 • Humulin® R U-100 (regular insulin human injection, USP [rDNA origin]) NDC Number - 0002-8215-17 * Smaller vials contain 3 mL of insulin in a 5 mL vial.

Humalog Indication Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control of hyperglycemia.

HI65435

0710 PRINTED IN USA

Humalog Important Safety Information Contraindications Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients. Warnings Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of action. Therefore, when used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an insulin pump). Glucose monitoring is recommended for all patients with diabetes. The safety and effectiveness of Humalog in patients less than 3 years of age have not been established.

Clinical 31

Pharmacy Practice News • November 2010

Practice Pearl

We Want Your Pearls Do you have an interesting practice pearl you’d like to share? If so, send it to smtilyou@mcmahonmed.com. Pearls should: • Focus on a clinical or operational problem at your institution, with tips (“tricks of the trade”) on how to manage the problem via an innovative system or strategy • Offer insights that are not widely known, understood or published • Explain why the pearl should be implemented on a widespread basis • Not exceed 500 words

Readers whose Practice Pearls are accepted for publication will be paid a $100 honorarium.

Introducing our newest small vial for an even larger range of options.

Important Safety Information, continued

Warnings, continued There are no adequate and well-controlled clinical studies of the use of Humalog in pregnant or nursing women.

Other Side Effects, continued Because of the difference in action of Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those who are fasting, have autonomic neuropathy or renal impairment, are using potassium-lowering drugs, or taking drugs sensitive to serum potassium level).

Starting or changing insulin therapy should be done cautiously and only under medical supervision. Hypoglycemia Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia can happen suddenly, and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening. Other Side Effects Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and hypersensitivity. Systemic allergy is less common, but may be life-threatening.

Please see reverse side for Brief Summary of full Prescribing Information. Please see full user manual that accompanies the pen. Humalog® and Humalog® KwikPen™ are registered trademarks of Eli Lilly and Company and are available by prescription only. Humulin® is a registered trademark of Eli Lilly and Company.

32 Clinical

Pharmacy Practice News • November 2010

Patient Care

COLLABORATION continued from page 1

another, a pre-visit planning session with a pharmacist prior to a doctor visit substantially improved medication appropriateness, as well as lab test completion. The third study demonstrated the pharmacist’s role in improving blood pressure control. The findings build upon an expanding body of data on the payoffs of pharmacist collaboration, some of which date back more than 30 years, according to Bill Jones, MS, RPh, clinical

associate professor at the College of Pharmacy at the University of Arizona, in Tucson. If only those findings were more frequently put into practice, Mr. Jones told Pharmacy Practice News. “We’ve had all of this information for years. The question I have is why are we not applying it? It’s mind-boggling to me, to really be honest about it.” Tracey Taveira, PharmD, CDOE, associate professor of pharmacy at the University of Rhode Island in Kingston, agreed. Pharmacists provide a “very cost-efficient way” to improve chronic disease management, she said.

But Dr. Taveira, who has conducted collaborative care research and practices at the Providence VA Medical Center, said that reimbursement continues to be a major obstacle. Traditionally, the Veterans Affairs system has been one of the leaders in collaborative care, which can refer to a variety of arrangements, ranging from multidisciplinary teams to a pharmacist with direct-prescribing privileges. She predicted that other medical facilities may follow suit and start to elevate the pharmacist’s role, as health care moves toward a more comprehensive medical home treatment approach.

Cardiovascular Collaboration In one of the studies (abstract 37) presented at ACCP, Veterans Affairs patients in Gainesville, Fla., benefitted from closer heart failure monitoring, including that done by a pharmacist, starting in the hospital and later through an outpatient clinic. The program, launched in 2008 at Malcom Randall VA Medical Center in Gainesville, identified any patient admitted to the hospital with heart failure either as a primary or secondary diagnosis. From that point onward, these patients not only received additional

HUMALOG® INSULIN LISPRO INJECTION (rDNA ORIGIN) BRIEF SUMMARY: Consult package insert for complete prescribing information. INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used without a longer-acting insulin when used in combination therapy with sulfonylurea agents. Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients with type 2 diabetes. CONTRAINDICATIONS: Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or any of its excipients. WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an external insulin pump). External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin. Patients should carefully read and follow the external insulin pump manufacturer’s instructions and the “PATIENT INFORMATION” leaflet before using Humalog. Physicians should carefully evaluate information on external insulin pump use in the Humalog physician package insert and in the external insulin pump manufacturer’s instructions. If unexplained hyperglycemia or ketosis occurs during external insulin pump use, prompt identification and correction of the cause is necessary. The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION). Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using an external insulin pump. Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the need for a change in dosage. PRECAUTIONS: General—Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins. As with all insulin preparations, the time course of Humalog action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress. Hypoglycemia—As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control. Renal Impairment—The requirements for insulin may be reduced in patients with renal impairment. Hepatic Impairment—Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary. Allergy—Local Allergy—As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Systemic Allergy—Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life-threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving Humulin R® (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053). Antibody Production—In large clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy. Usage of Humalog in External Insulin Pumps—The infusion set (reservoir syringe, tubing, and catheter), Disetronic® D-TRON®2,3 or D-TRONplus®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external insulin pump should not be exposed to temperatures above 37°C (98.6°F). In the D-TRON ®2,3 or D-TRONplus ®2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be selected every 48 hours or less. When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and Storage). Information for Patients—Patients should be informed of the potential risks and advantages of Humalog and alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia, and periodic assessment for diabetes complications. Patients should be advised to inform their physician if they are pregnant or intend to become pregnant. Refer patients to the “PATIENT INFORMATION” leaflet for timing of Humalog dosing (< _15 minutes before or immediately after a meal), storing insulin, and common adverse effects. For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the “PATIENT INFORMATION” leaflet that accompanies the drug product and the User Manual that accompanies the delivery device. They should also reread these materials each time the prescription is renewed. Patients should be instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose of needles. Patients should be advised not to share their Pens with others. For Patients Using External Insulin Pumps: Patients using an external infusion pump should be trained in intensive insulin therapy and in the function of their external insulin pump and pump accessories. Humalog was tested in the MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir), and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 insulin pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. The infusion set (reservoir syringe, tubing, catheter), D-TRON®2,3 or D-TRONplus ®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced, and a new infusion site selected every 48 hours or less. Humalog in the external pump should not be exposed to temperatures above 37°C (98.6°F). A Humalog 3 mL cartridge used in the D-TRON ®2,3 or D-TRONplus ®2,3 pump should be discarded after 7 days, even if it still contains Humalog. Infusion sites that are erythematous, pruritic, or thickened should be reported to medical personnel, and a new site selected. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. Laboratory Tests—As with all insulins, the therapeutic response to Humalog should be monitored by periodic blood glucose tests. Periodic measurement of hemoglobin A1C is recommended for the monitoring of long-term glycemic control. Drug Interactions—Insulin requirements may be increased by medications with hyperglycemic activity, such as corticosteroids, isoniazid, certain lipid-lowering drugs (eg, niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy (see CLINICAL PHARMACOLOGY). Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (eg, octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients. Mixing of Insulins—Care should be taken when mixing all insulins as a change in peak action may occur. The American Diabetes Association warns in its Position Statement on Insulin Administration, “On mixing, physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological response to the insulin mixture may differ from that of the injection of the insulins separately.” Mixing Humalog with Humulin® N or Humulin® U does not decrease the absorption rate or the total bioavailability of Humalog. Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect compared with regular human insulin. Pregnancy—Teratogenic Effects—Pregnancy Category B—Reproduction studies with insulin lispro have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to Humalog. There are, however, no adequate and well-controlled studies with Humalog in pregnant women. Because

animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the ﬁrst trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted. Nursing Mothers—It is unknown whether Humalog is excreted in signiﬁcant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both. Pediatric Use—In a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf life may be reduced (see DOSAGE AND ADMINISTRATION). Geriatric Use—Of the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were 65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed.

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ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a difference in frequency of adverse events between the 2 treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Whole—allergic reactions (see PRECAUTIONS). Skin and Appendages—injection site reaction, lipodystrophy, pruritus, rash. Other—hypoglycemia (see WARNINGS and PRECAUTIONS). OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent premeal hyperglycemia. When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longer-acting insulin being given may need to be adjusted when using Humalog. The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin preparations, the time course of action of Humalog may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques. Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30, and Humulin® R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted Humalog may remain in patient use for 28 days when stored at 5°C (41°F) and for 14 days when stored at 30°C (86°F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump. Parenteral drug products should be inspected visually before use whenever the solution and the container permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be refilled with insulin. External Insulin Pumps—Humalog was tested in MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. HOW SUPPLIED: Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each presentation containing 100 units insulin lispro per mL [U-100]): 10 mL vials NDC 0002-7510-01 (VL-7510) 3 mL vials NDC 0002-7510-17 (VL-7533) NDC 0002-7516-59 (VL-7516) 5 x 3 mL cartridges 3 5 x 3 mL prefilled insulin delivery devices (Pen) NDC 0002-8725-59 (HP-8725) 5 x 3 mL prefilled insulin delivery devices (Humalog® KwikPen™ ) NDC 0002-8799-59 (HP-8799)

Reprints of Pharmacy Practice News articles are available in minimum quantities of 500. Reprints can be ordered in black & white or 4-color versions and printed on 80-lb. glossy stock. Standard turnaround time is 4 weeks. For specific price quotes, call Dave Kaplan at

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MiniMed® and Polyﬁn® are registered trademarks of MiniMed, Inc. Disetronic®, H-TRONplus®, D-TRON®, and Rapid® are registered trademarks of Roche Diagnostics GMBH. 3 3 mL cartridge is for use in Eli Lilly and Company’s HumaPen® MEMOIR™ and HumaPen® LUXURA™ HD insulin delivery devices, Owen Mumford, Ltd.’s Autopen® 3 mL insulin delivery device, and Disetronic D-TRON ® and D-TRONplus ® pumps. Autopen® is a registered trademark of Owen Mumford, Ltd. HumaPen®, HumaPen® MEMOIR™ and HumaPen® LUXURA™ HD are trademarks of Eli Lilly and Company. Other product and company names may be the trademarks of their respective owners. 2

Storage —Unopened Humalog should be stored in a refrigerator (2° to 8°C [36° to 46°F]), but not in the freezer. Do not use Humalog if it has been frozen. Unrefrigerated (below 30°C [86°F]) 12 vials, cartridges, Pens, and KwikPens must be used within 28 days or be discarded, even if they still contain Humalog. Protect from direct heat and light. Use in an External Insulin Pump—A Humalog 3mL cartridge used in the D-TRON®2,3 or D-TRONplus®2,3 should be discarded after 7 days, even if it still contains Humalog. Infusion sets, D-TRON ®2,3 and D-TRONplus ®2,3 cartridge adapters, and Humalog in the external insulin pump reservoir should be discarded every 48 hours or less. Literature revised December 7, 2009 KwikPens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA. Pens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France. Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Hospira, Inc., Lake Forest, IL 60045, USA or Lilly France, F-67640 Fegersheim, France. Cartridges manufactured by Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA. www.humalog.com Copyright © 1996, 2008, Eli Lilly and Company. All rights reserved.

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Clinical 33

Pharmacy Practice News • November 2010

Patient Care clinical attention in the hospital but also were given the option of follow-up at an outpatient clinic after discharge. “In general, most of our patients have had heart failure for quite a few years,” said Shawn Anderson, PharmD, one of the study’s researchers and a clinical pharmacy specialist who worked with patients to adjust their medications. “The medications—from a pharmacy perspective—are not optimized the way they should be.” The analysis, which tracked results for fiscal year 2009, found 236 patients enrolled in the heart failure program; the mean age was 71 years. For several medications, including β-blockers and loop diuretics, compliance remained similar to baseline—91% and 88%, respectively. But the researchers did report a 60% increase from baseline for use of spironolactone and digoxin. Several additional outcomes improved. During the first two quarters of 2010, a total of 29 heart failure patients were readmitted within 30 days, a 53% decline from the first two quarters of 2009, when 62 patients were readmitted. The average hospital length of stay (LOS) also decreased from 6.1 days in the previous fiscal year to 5.2 days during the year of the study. Although there are potential cost savings related to reducing LOS, it was difficult to develop cost savings figures without a proper control group, Dr. Anderson said. It helped that the clinical team, including the pharmacist, got to know the patients on the inpatient side first before meeting with them at the outpatient clinic, Dr. Anderson said. “We definitely think it’s important to have both components of a heart failure program.” To date, there are relatively few data on heart failure and collaborative care,

so the findings are interesting in that context, said C. Michael White, PharmD, FCP, FCCP, professor of pharmacy at the University of Connecticut, in Storrs. Dr. White, who specializes in cardiac

‘We are making the decisions, changing the medications, running the labs.’

—Sherry Laguardia, PharmD

care, also pointed to the high cost of treating heart failure patients, including readmissions. “Even if the service costs money to run, the health system might save a lot of money because of the reduction in readmissions.”

Hypertension Responds To Team Approach Pharmacists also played an influential therapeutic role in another cardiovascular study (abstract 16), involving a pharmacy–cardiologist collaborative hypertension clinic at Texas Tech University Health Sciences Center, in Lubbock. Although the pharmacists consulted with the cardiologists on unusual cases, typically they took a lead role in medication therapy, said Sherry Laguardia, PharmD, one of the study’s researchers, who now is an assistant professor in the pharmacy practice management division at Texas Tech University Health Sciences Center School of Pharmacy, in Abilene. “We are making the decisions, changing the medications, running the labs,” she said. The study, which was a retrospective chart review, looked at the results of the hypertension clinic compared with care provided through the outpatient cardiology clinics. Before enrollment, none of the patients had their blood pressure under control. By the

Teaming Up for Better Parenteral Nutrition and Mental Health

last clinic visit, 49% of patients in the pharmacist–cardiologist collaborative clinic had reached their blood pressure goal compared with 31% of the control group (P=0.0456).

harmacists can collaborate in areas far removed from traditional chronic diseases like diabetes and heart failure, as two ongoing projects presented at the ACCP meeting illustrate. At Le Bonheur Children’s Hospital in Memphis, a pharmacy-directed service is helping to manage an average of 40 patients on parenteral nutrition daily. The multi-clinician group is particularly focused on reducing complications related to long-term parenteral nutrition use in patients with short bowel syndrome. Subgroups have been established, each chaired by a pharmacist. Some goals include developing a protocol to decrease catheter-related infections and standardizing parenteral nutrition delivery in liver disease. Preliminary data regarding specific interventions and outcomes are in the works (abstract 271). Two psychiatric pharmacists are providing direct mental health treatment at an outpatient clinic through the University of California, San Diego. Since the program was launched in mid-2009, they have managed the care of more than 50 mental health patients, under a collaborative practice protocol with psychiatrists. Along with medication management and adverse effects monitoring, the pharmacists are providing other services, including psychiatric evaluation and therapy referral. The pharmacists’ caseload continues to grow (abstract 276). —C.H.

Getting blood pressure levels under control did not necessarily require more medications. The median number of medications was three in the intervention group and two in the control group, both before and during the study period. The researchers did not break down the types of drugs taken by class or examine related costs, Dr. Laguardia said. But the pharmacist-led clinic was far more aggressive in monitoring the patients than is typical cardiologist care, with 10 visits annually compared with 3.4 visits in the control group (P<0.0001). “A lot of the times the patients we got were patients [whose blood pressures] weren’t easily controlled by the cardiologist, so they would send them to us,” Dr. Laguardia said. “Some of these patients needed more follow-up to bring them to their blood pressure goal.”

Boosting Medication Appropriateness High-risk patients also were the primary target at another pharmacy-led program, recently launched at the Veterans Affairs Salt Lake City Health Care System. Pharmacists met with patients who had multiple medical conditions two to three weeks before their doctor’s visit, to address any medication issues and ideally improve the effectiveness of the drugs they were taking. The study (abstract 20), a retrospective chart review involving 203 patients with a mean age of 68 years, looked at a four-month period ending in February 2010. The patients involved were either taking more than 10 medications or were diagnosed with at least three medical conditions and taking more than seven medications. In the 53 patients who saw a pharmacist, medication appropriateness scores improved by 77% versus 14% in the control group, who saw the same physicians but without the pre-visit pharmacy appointment (P<0.05). The mean number of medications per patient decreased by 1.8, starting from

a baseline of 16.7, for patients who received the pharmacist’s input. In contrast, in the control group, it increased slightly from 13.1 to 13.4 medications (P<0.05 for both outcomes). “The doctors liked it [the previsit appointment] because it helped to reduce their time with the patient,” said Michael Katzourakis, PharmD, one of the researchers, who is currently a second-year pharmacy resident at University of Utah Hospitals & Clinics, in Salt Lake City. “They were able to spend less time going over medications and spend more time looking at their medical issues.” In addition, the study identified a net medication cost savings totaling $1,681, or roughly $30 per patient. Those figures included the medication only and not the potential cost savings of fewer medical complications, Dr. Katzourakis said. It would be interesting to follow those patients in terms of long-term medical outcomes, said Providence VA’s Dr. Taveira, “because I’m sure that there would be savings related to improvements in health outcomes.” Dr. Katzourakis first became interested in the pre-visit concept when, as a fourth-year pharmacy student, he assisted with an outpatient pharmacyled clinic at the University of Utah. At Salt Lake City’s VA system, he would identify patients with complex medical issues who might benefit, and then would meet with them several weeks before their physician appointment. The patients would bring in their medications and the appointments could last an hour. With the closer oversight, related laboratory work was far more likely to be completed prior to the appointment—96% of tests in the pharmacist-led group compared with 43% in the control group. In some cases, patients’ medication doses were adjusted. Sometimes medications were discontinued entirely because they were no longer needed, Dr. Katzourakis said. He described one patient who was taking some three dozen drugs, a regimen that ultimately was reduced by 10 to 12 drugs after meeting with a pharmacist. —Charlotte Huff

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36 Clinical

Pharmacy Practice News • November 2010

Research News

New Hormone Therapy Will Shake Up Treatment for mCRPC Milan—The landscape for treating metastatic castration-resistant prostate cancer (mCRPC) is about to change again, according to experts in the field who have reviewed data from a recent Phase III trial. The study showed that adding abiraterone acetate (Ortho Biotech) to prednisone improved overall survival (OS) by four months in patients with mCRPC who had progressed after treatment with docetaxel. Abiraterone is the first hormone therapy that has been proven to increase survival in patients with prostate cancer after chemotherapy. “This represents a new treatment option for patients with metastatic castration-resistant prostate cancer,” said Johann de Bono of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust in London. He presented the results of the trial at the European Society for Medical Oncology (ESMO) Congress (abstract LBA5), held in October. Most prostate cancer experts expect the FDA to approve the drug in the near future, thus adding to the expanding options for mCRPC. In 2010, the FDA approved cabazitaxel (Jevtana, Sanofi-aventis) in patients with mCRPC after progression with docetaxel therapy and sipuleucel-T (Provenge, Dendreon) for the treatment of asymptomatic or minimally symptomatic patients with mCRPC. According to Michael Carducci, MD, AEGON Professor in Prostate Cancer Research at the Johns Hopkins Kimmel Cancer Center, Baltimore, abiraterone may have a broader use than patients with mCRPC who have failed docetaxel. “If you are a betting person, the big discussion is whether the label is going to be broad or narrow,” said Dr. Carducci, who was on the scientific advisory board of Cougar Biotechnology, the company that developed the drug. “Because prostate cancer physicians and other providers think of this as a hormonal drug—and most hormonal drugs are used prior to chemotherapy—when this drug comes out, I think people are going to want to use this up front.” Abiraterone acetate is a first-in-class intracrine androgen biosynthesis inhibitor that works by blocking CYP17 and inhibiting persistent androgen synthesis from adrenal and intratumoral sources. The drug was first designed and synthesized at The Institute of Cancer Research, Sutton, United Kingdom, and the first clinical trials were conducted at the Royal Marsden Hospital. The trial presented at ESMO, called COU-AA-301, involved 147 centers in 13 countries and included 1,195 patients with mCRPC who previously had

received docetaxel. Patients were randomized in a 2:1 fashion to receive prednisone (5 mg twice daily) and abiraterone (1,000 mg once daily) or prednisone and placebo. During an interim analysis in August, the median OS was 14.8 months in the abiraterone arm and 10.9 months in the control arm (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.54-0.77; P<0.0001). The median number of months on therapy was eight months in the abiraterone arm and four months in the placebo arm. Treatment was ongoing in 28.1% of patients receiving abiraterone and 13.7% of patients receiving placebo.

A Well-Tolerated Drug The drug was very well tolerated. Some adverse events were slightly more common in the abiraterone arm, including fluid retention (30.5% vs. 22.3%), hypokalemia (17.1% vs. 8.4%), liver function test abnormalities (10.4% vs. 8.1%), hypertension (9.7% vs. 7.9%) and cardiac disorders (13.3% vs. 10.4%). Grade 3/4 events, however, were infrequent. “We now have unequivocal evidence that inhibition of persistent androgen synthesis and androgen receptor signaling remains key in targeting survival,” said Cora Sternberg, MD, head of the Department of Medical Oncology, San Camillo, and Forlanini Hospital, Rome, Italy, who was not involved with the study. “Abiraterone sets a new standard of therapy in the treatment of metastatic castration-resistant prostate cancer post-docetaxel.” A Phase III trial testing abiraterone in patients pre-docetaxel is expected to report results in 2011, but many clinicians believe the drug will be used before docetaxel, regardless of what label is approved. “I would be hardpressed to figure out why it wouldn’t work pre-chemo,” Dr. Carducci said. He projects that many clinicians will use abiraterone first and then move to sipuleucel-T, docetaxel and cabazitaxel, in that order. When asked why he thought clinicians would use abiraterone over sipuleucel-T, he said that sipuleucel-T doesn’t improve some clinical benefit measures, like prostate-specific antigen (PSA) levels, that physicians are used to monitoring, whereas abiraterone does and is orally administered. In the abiraterone arm of the COUAA-301 study, there were statistically significant improvements in all secondary end points, including median time

to PSA progression (10.2 vs. 6.6 months; HR, 0.58; 95% CI, 0.46-0.73; P<0.0001), median radiographic progression-free survival (5.6 vs. 3.6 months; HR, 0.67; 95% CI, 0.580.78; P<0.0001) and PSA response (39% vs. 10.1%; P<0.0001). Oliver Sartor, MD, LaBorde Professor for Cancer Research at Tulane Cancer Center, New Orleans, who with Dr. deBono and others conducted the Phase III trial that led to cabazitaxel’s approval, predicted that cabazitaxel and abiraterone “will have an important role. It would not surprise me to see abiraterone being used earlier in the mCRPC treatment paradigm, but issues of cost and insurance coverage will [have to be] addressed. Cabazitaxel is most likely to be used after docetaxel progression,” he said. Dr. Sartor said that a large trial comparing cabazitaxel with docetaxel ther-

Bethesda. “However, the real excitement comes with the combination of abiraterone plus cabazitaxel or docetaxel.” Such an approach, which combines androgen deprivation therapy (i.e., abiraterone) with taxane-based chemotherapy, has already been shown to be effective in patients with mCRPC, Dr. Figg noted. He cited, as an example, a recent Phase I study he co-authored of high-dose ketoconazole plus weekly docetaxel. (In high doses, ketoconazole is a testosterone and androgen blocker.) The study (J Urol 2010;183:22192226) included 42 patients with mCRPC treated with weekly docetaxel, increasing from 5 to 43 mg/m2, in combination with ketoconazole, 600 to 1,200 mg daily. Decreases in PSA of 50% or greater were seen in 62% of the patients, he noted. Median OS was 22.8 months in all patients, but was significantly greater in docetaxelnaïve patients than in those pretreated with docetaxel (36.8 vs. 10.3 months, P=0.0001).

‘The real excitement comes with the combination of abiraterone plus cabazitaxel or docetaxel.”

—William D. Figg, PharmD

apy is starting soon and will address cabazitaxel’s potential in first-line chemotherapy. Dr. Sternberg said that if clinicians are going to use abiraterone longerterm, then they need to work out the proper dose of steroids or whether abiraterone can be tolerated without steroids. Dr. Sternberg said that in three of four recent mCRPC Phase II trials, the majority of patients did not receive corticosteroids but had their toxicity managed with a mineralocorticoid antagonist or low-dose steroids, if needed. “I think this really needs to be worked out—the exact dose of cortisone that is needed—especially if we are thinking about giving these drugs long-term,” Dr. Sternberg said. “The long-term effects of androgen deprivation therapy are loss of muscle mass, sarcopenia and obesity, and can include bone loss that can lead to osteoporosis and fractures.”

NIH Pharmacist’s View “I would agree with Dr. Carducci that it’s very likely that abiraterone will ultimately be used earlier in the treatment of the disease,” said William D. Figg, PharmD, MBA, section head, molecular pharmacology section and clinical pharmacology program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, in

Asked to explain why docetaxelnaïve patients had the best response in his study, versus the Marsden trial, in which docetaxel-resistant patients fared the best, but with lesser gains in OS, he said, “It could be that resistant or pretreated patients are farther in the course of their disease.” He concluded that “the bottom line is that if you look at the ketoconazole/docetaxel overall survival results—especially in the docetaxel-naïve group—this is the highest OS ever reported in this disease.” Thus, he added, “regimens that combine docetaxel with an androgen blocker such as abiraterone or ketoconazole need to be studied further, because there’s a strong potential for huge gains in overall survival.” As for the prospects of abiraterone’s approval by the FDA, Dr. Figg replied, “I’d say it’s a sure thing.” But he stressed that although both abiraterone and cabazitaxel will likely be approved for similar indications, due to the exigencies of the drug development process, “these really are very different medications—one’s a chemotherapy, the other is an androgen inhibitor. So their use in clinical practice will be quite different.” —Kate O’Rourke, with additional reporting by David Bronstein

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Pediatric Cancer Center Excels in Oncology Informatics Tampa, Fla.—St. Jude Children’s Research Hospital in Memphis, Tenn., has been honing its informatics system over the past several years, adding components and refining processes. In a presentation at the American Society of Health-System Pharmacists summer meeting, Don Baker, PharmD, MBA, St. Jude’s clinical decision support officer, described the hospital’s experiences in developing its oncology informatics system, sharing the hospital’s growing pains in getting its system to where it is today. St. Jude uses a closed-loop chemotherapy process, said Dr. Baker. The hospital’s suite of electronic medical record (EMR) applications is centered on a “database and repository from which other applications pull information to present to users.” The system includes an EMR, which allows clinicians to view results; place orders; look at research trial protocols; view patient profiles; document medications; and view rules,

alerts, and so on. Other components of the system are pharmacy (inpatient and outpatient), scheduling, clinical trials, pathology, medical transcription, surgery, medical records, radiology and patient management. Reviewing the steps St. Jude used to implement and maintain this comprehensive system, Dr. Baker said, the process started with an evaluation of the current system and a reengineering and process-mapping phase. This

This is Part 2 of a two-part series on oncology informatics applications. Part 1, which appeared in the September issue, discussed some system challenges that clinicians face when applying informatics in the oncology setting and offered some techniques to address these challenges. This article describes the overall electronic chemotherapy process in place at St. Jude Children’s Research Hospital in Memphis, Tenn., and discusses specific technologies that play an integral role in that process.

was followed by designing, building, training, implementation, support and follow-up. “All of the steps from design on down really are dependent on the

first step,” the evaluation of the current system and the hospitals’ needs. He further explained that during the initial

•

see PEDIATRIC CANCER, page H2

ERBITUX Increased Overall Survival in Both: Squamous Cell Carcinoma of the Head and Neck (SCCHN)

EGFR-Expressing Metastatic Colorectal Cancer (mCRC)

in Combination With RT in Locoregionally Advanced Disease

after Irinotecan and Oxaliplatin Failure as a Single Agent

Basic Steps in St. Jude’s Closed-Loop Chemotherapy Process Days or weeks prior to the day of chemotherapy MD, nurse practitioner (NP) or physician assistant (PA) initiates plan for clinic visits, laboratory and radiology orders, infusion center appointment. Clinic nurse reviews those orders. Day of chemotherapy MD/NP/PA evaluates patient, performs dose calculations and generates the actual chemotherapy orders. Clinic nurse double-checks entries. Clinic nurse documents double checks directly within the order set. Oncologist modifies orders as needed and notes that orders are “OK to Give.” Oncologist designates the orders as real “instead of being in a planned status.” Pharmacist receives printed requisition for the orders in the pharmacy and the orders also go into an electronic work queue. Pharmacist verifies the orders in the pharmacy system and performs double-checks. Another pharmacist performs double-checks and documents within the order set in the electronic medical record.

ERBITUX Indications Head and Neck Cancer ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck

Metastatic Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX EGFR=epidermal growth factor receptor; RT=radiation therapy.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

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PEDIATRIC CANCER continued from page H1

process, it is crucial to put together a team that includes administrative decision makers and subject experts (clinical staff, pharmacy, nursing) who “are really involved with the processes,” as well as application analysts “who are familiar with the system and its capabilities.” The electronic chemotherapy process was implemented on a framework of chemotherapy ordering that has been well established at St. Jude over the past 40 years. The process incorporates

‘We do standardization, but we have to do individualization as well. The system needs to be flexible enough to handle that.” —Amy H. Seung, PharmD, BCOP many safety mechanisms to prevent errors, noted Dr. Baker. This includes limiting who can order chemotherapy to attending oncologists and approved nurse practitioners, physician assistants and pediatric hematology-oncology fellows, for example. The process also includes formal, required training

programs, careful review of protocols and treatment plans, and standardized and validated preprinted order forms. It prohibits the use of abbreviations, acronyms and brand names. There also are various redundant checks in the process: Before a dose is administered, orders and doses are reviewed by at

least two pharmacists, by an oncologist with chemotherapy prescribing privileges, and by at least three nurses. The electronic system needed to be able to incorporate all the safety components that were part of the paper system. In making the switch, the team looked “at steps in the chemotherapy process and where they could fail and how we could prevent that [failure],” said Dr. Baker. In reevaluating the hospital’s process map as it shifted “from paper-based processes to electronic processes,” the team went step by step to identify issues or gaps that could

ERBITUX Signiﬁcantly Increased SCCHN in Combination With RT in Locoregionally Advanced Disease Survival in Combination With RT (N=424)*1,2 ERBITUX (cetuximab) + RT (n=211)

Median overall survival 49.0 months

RT alone (n=213)

29.3 months

45%

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year overall survival rate 55%

19.7 month improvement

P=0.05

RT=radiation therapy; HR=hazard ratio; CI=conﬁdence interval. A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information for SCCHN ■ The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

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In Focus (http://www.ncbi.nlm.nih.gov/ bookshelf/br.fcgi?book=aps2v2&part=advanc es-baker_107). Alluding to the infamous failed O-ring that led to the Challenger space shuttle disaster, Dr. Baker said, “We do know that in complex high-risk systems, small things can matter a lot.” Based on their FMEA, the team decided that the hospital’s electronic system would not have provided any improvement over the paper system and was not ready to be to put in place. So, Dr. Baker said, “we waited and communicated with our vendor about our concerns.”

pose a problem, he noted, adding that team members continue to analyze the issue until it is resolved. St. Jude did run into some setbacks when initially considering the switch to computerized prescriber order entry for chemotherapy orders in 2005, according to Dr. Baker. Concerns about whether the vendor could handle these complicated electronic orders prompted the team to conduct a failure mode and effects analysis (FMEA), looking at every step of the process, down to the smallest aspect, and systematically quantifying the risk for harm for each step

•

Overall Survival in Both: EGFR-Expressing mCRC after Irinotecan and Oxaliplatin Failure as a Single Agent Median Overall Survival, All Patients (N=572)†1 6.14 months ERBITUX + BSC (n=287)

4.57 months BSC alone (n=285)

34% improvement

HR: 0.77; 95% CI: 0.64-0.92; P=0.0046

BSC=best supportive care. CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome measure of the trial was overall survival.1

† NCIC

■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1

ERBITUX Safety Information for EGFR-Expressing mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/ desquamation (12%), and other-gastrointestinal (10%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

see PEDIATRIC CANCER, page H4

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Subsequently, the vendor made several improvements to the software, and the hospital was able to make the switch. The improvements included the capability to build order sets with preestablished time relationships between orders and automated checks of pertinent clinical results (e.g., if a protocol required patients’ absolute neutrophil count to be greater than 1,000, then that could be built into the order set). Clinicians now are able to place a single

start date and time on the set of orders and not have to manage each order within the order set individually. Order sets that are specific to protocols and chemotherapy regimens have proved to be an essential component of St. Jude’s successful implementation of CPOE for chemotherapy, according to Dr. Baker. He said that the hospital has over 3,000 order sets in place. Recognizing that the electronic process fundamentally changes “the way prescribers and pharmacists communicate regarding the details of an order,” the team looked carefully at the steps in

the chemotherapy process that had the highest risk, and they developed risk mitigation strategies to address them. One problem that could occur with the electronic system is that special information provided by the prescriber (e.g., infusion time) could be overwritten with default information by the pharmacy system. Another potential problem is that the options listed for the prescriber might not include all the options available in the pharmacy system. The mitigation strategies the St. Jude’s team implemented to reduce these risks were review and removal

of some default infusion values in the pharmacy system, the addition of some user-defined fields in order-entry formats for clarity and discussions with software vendors to improve the functionality for oncology orders. The basic steps in the current St. Jude process are listed in the sidebar on page 37. Improvements of this electronic system over paper systems include the provision of relevant clinical information for prescribers on ordering screens; automated decision support for prescribers, such as allergy and drug interaction checks and custom rules; electronic

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 ( 0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

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In Focus documentation of plan review by nurses and pharmacists; the elimination of poor handwriting; reduction of transcription errors; and inclusion of recent, standardized patient information on the pharmacy printouts—such as weight, body surface area, clinical trial protocol information and the name of the attending physician—which is rarely included on handwritten orders. Dr. Baker noted that St. Jude continues to work with its software vendor to improve the system. Future improvements include an oncology-specific flow sheet to merge laboratory values with

oncology-specific parameters and a cancer staging documentation tool. But in the meantime, he said the electronic system works very well, improving efficiency and enhancing clarity of drug orders. Noting that the vendor has been flexible in getting the software to be a good fit for St. Jude’s process, he said, “we’ve massaged it in a way that we believe meets our needs.” Amy H. Seung, PharmD, BCOP, clinical specialist in hematologic malignancies at The Johns Hopkins Hospital, in Baltimore, said that she and her colleagues are going through a similar process. Dr.

Seung echoed Dr. Baker’s comments that this strategy requires “looking at each individual step” in the chemotherapy process. “You are truly dissecting the entire chemotherapy process from decisions on therapy all the way down to monitoring the patient after therapy is given and decision support for thinking about what’s going to be the next step” for the patient. “Having all the stakeholders involved in the process is critical,” Dr. Seung added. For the system to work optimally, she explained, all the differing perspectives of nurses, pharmacists, physicians

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2010, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ, 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US10AB08604

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and so on need to be considered. But Johns Hopkins is a little different from St. Jude’s in that Hopkins treats both pediatric and adult populations. So the hospital has to approach and build the pharmacy system a little differently for these different populations, Dr. Seung noted. This is “usually because of volume issues and some adverse reactions/supportive care issues,” she said. “We do standardization, but we have to do individualization as well. The system needs to be flexible enough to handle that.” —Sarah Tilyou

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In Focus

Osteoporosis Risk Still Under-recognized in Prostate Cancer Austin, Texas—Less than one-fourth of veterans on androgen deprivation therapy for prostate cancer had their bone density checked during the treatment, according to a study presented at the annual meeting of the American College of Clinical Pharmacy. Although the low rate was better than that in several previous studies, it shows that there is a persistent lack of awareness that this hormone treatment places men at risk for potentially debilitat-

sity test at the Tennessee facility. This rate compared favorably with three previous studies involving veterans; the composite testing rate for the three studies combined was 11.5% (P<0.05). “We wanted to use that as a benchmark to see how our population compared,” said Brent Salvig, PharmD, BCPS, clinical pharmacy specialist at the health care system. “We were doing better. Still,

ing osteoporosis, according to the investigators, from the VA Tennessee Valley Healthcare System, in Nashville. The study—a retrospective medical records search—focused on 219 men who had taken at least one dose of goserelin or leuprolide during a four-year period ending September 2009 (abstract 173). Of those men, 22.8% had undergone a bone mineral denERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 Chills1 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 3 43 2 21 1 Alanine Transaminase, high 3 38 1 24 1 Aspartate Transaminase, high 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 Skin/Appendages Acneform Rash4 87 17 10 1 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction. Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

Hem/Onc Pharmacy H7

Pharmacy Practice News • November 2010

In Focus less than one in four patients is having a bone mineral density test done.”

Low Screening Rate Not a Surprise That screening rate, albeit quite low, is not surprising, said Hau Liu, MD, MBA, MPH, clinical assistant professor at Stanford University Medical Center, in Stanford, Calif., who has studied osteoporosis in men. In fact, many of these older men likely should have been evaluated anyway, given their age, even if they weren’t on androgen deprivation therapy, he said.

The findings provide “another piece in raising the awareness of osteoporosis risk in men,” Dr. Liu said. “We tend to think of this less as a disease in men. But I think that thinking is changing.” Dr. Liu was a co-author of a review of osteoporosis screening research in men that was published in Annals of Internal Medicine (2008;148:685-701). Based on their review of evidence, the authors reported that there is a moderate level of evidence that prolonged use of androgen deprivation therapy is a moderate to strong predictor for increased risks for low bone mass and

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2:

Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 Body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 3 Infusion Reactions 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 Mouth Dryness 11 0 4 0 Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. Adverse events were graded using the NCI CTC, V 2.0. 3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care 2

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. • Aseptic meningitis DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

related fractures in men. More recently, a group of researchers in Australia used three-dimensional techniques to study androgen deprivation therapy and bone fragility. By examining the bones of 26 men taking the drugs for prostate cancer, over the course of a year, they detected weakening in the bones’ underlying structure, according to the study, slated to be published this December in the Journal of Clinical Endocrinology & Metabolism. In the analysis from Tennessee, 87% of the male subjects were aged 60 years or older. As part of a secondary

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

objective, researchers also assessed if the men would have been otherwise eligible for a bone mineral density test prior to androgen deprivation therapy. Slightly more than half—53%— were classified as intermediate to high osteoporosis risk based on a screening tool that used height and weight to calculate a risk score. To boost bone density screening, one strategy might be to set a clinical reminder in the VA’s electronic medical records system, alerting the prescribing physician that a patient might be a candidate for this test, based on the medication history, Dr. Salvig said. If this path is followed, at a VA facility or elsewhere, the pharmacist could play an important role in related counseling on medication options if the test did identify osteoporosis, he said. “Going down that path, you are obligated to treat, and it’s not always easy.” —Charlotte Huff

More ACCP Coverage On the Web • Prescribing errors account for majority of HIV drug mishaps.

• A new program doubles the likelihood that pregnant women will be counseled about the risks of teratogenic medications.

• Researchers among the first to document the extent of medication errors in emergency medicine settings.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

ER-B0001A-09-10

Rev September 2010

Each of these articles can be accessed by scanning the adjacent 2D barcodes. For instructions, see page 3.

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Clinical 37

Pharmacy Practice News • November 2010

Educational Review

Managing Intravenous Iron in the Oncology Setting SARA S. KIM, BS, PHARMD, BCOP Pharmacy Clinical Coordinator Hematology/Oncology/Stem Cell Transplantation The Mount Sinai Medical Center New York, New York

he prevalence of anemia in patients with cancer is up to 90%,1 and it is most often associated with the underlying malignancy

and/or cancer treatment.

Despite the high prevalence of anemia in this patient population, IV iron supplementation has not been applied rigorously as an adjunct to erythropoietin-stimulating agents (ESA) in oncology practice. In fact, less than 10% of patients with chemotherapy-induced anemia (CIA) are supplemented with IV iron as an adjunct to ESA, which may, in part, contribute to the high rates of ESA

nonresponsiveness in cancer patients (35%-50%).2-6

Types of Anemia Two main types of anemia are seen in patients with cancer. The first is functional iron deficiency, which occurs when ESA therapy accelerates the rate of erythropoiesis, increasing the iron demand by the bone marrow. Essentially, the body is unable

to release stored iron fast enough to allow the incorporation of iron into red blood cells during erythropoiesis. The second is absolute iron deficiency. Absolute iron deficiency occurs in the setting of acute blood loss or impaired iron absorption, in which the release of inflammatory cytokines leads to an upregulation of hepcidin, a 25-amino acid polypeptide produced by hepatocytes

Table. Commercially Available IV Iron Preparations High-MolecularWeight Iron Dextran (Dexferrum, American Regent)

Low-MolecularWeight Iron Dextran (Infed, Watson)

Ferric Gluconate (Ferrlecit, Sanofi-aventis)

Iron Sucrose Ferumoxytol (Venofer, (Feraheme, American Regent) Amag)

Molecular weight (Da)

265,000

165,000

289,000-440,000

34,000-60,000

75,000

Test dose required

Yes; 25 mg slow IV push and observe for 1 h

Dosage

100 mg IV over 5 min once weekly for 10 doses or total dose infusion over several hours

125 mg IV over 1 h once weekly for 8 doses or 200 mg IV over 3-4 h every 3 wk for 5 doses

200 mg IV over 510 mg IV; 1 h every 2-3 wk push once, or 200 mg IV over followed by a 2-5 min every 1-4 second dose wk 3-8 d later

Black box warning

Yes

To calculate total dose of elemental iron for iron dextran: total dose of elemental iron (mL) = 0.0442 (desired Hba–observed Hb) × LBW (kg) + 0.26 × LBW (kg) a

Desired Hb=12 g/dL

Hb, hemoglobin; LBW, lean body weight Based on references 9-13, 15, 20.

that is both an acute phase protein and a major hormone regulator of iron homeostasis; it interferes with both the enteral iron absorption and iron release from macrophages, and it promotes iron degradation. Unlike functional iron deficiency, where iron stores are adequate, absolute iron deficiency is associated with measurable reduction in serum and stored iron. Erythropoiesis requires close interaction between iron and erythropoietin. Parenteral iron has been shown to improve the efficacy and shorten the duration of ESA therapy, which suggests a synergistic effect between parenteral iron and ESAs.

Main Causes of the Underuse of IV Iron in Cancer Patients Despite these benefits, IV iron remains underused in this setting for several reasons. One reason is that a serum ferritin level less than 100 ng/mL often is the only diagnostic tool used to assess the need for iron repletion. Although the benefits of iron supplementation in conjunction with ESA therapy in patients with CIA are well established—even in patients with transferrin saturation (TSAT) up to 35% and a serum ferritin level up to 800 ng/mL—many patients falling within appropriate levels do not receive therapy. Another barrier to IV iron therapy is the fear Text continues on page 38

38 Clinical

Pharmacy Practice News • November 2010

Educational Review Text continued from page 37

of anaphylactic-type reactions. The concern with anaphylactic-type reactions with IV iron products stems from the untoward events associated with the high-molecular-weight iron dextran product (Dexferrum, American Regent), which resulted in the addition of a black box warning to the product label about the risk for a potentially fatal anaphylactic-type reaction and about the requirement for a test dose prior to the first dose.7 In contrast, with low-molecularweight iron dextran products, the incidences of infusion-related reactions and fatal adverse events (AEs) have been shown to be very rare (0.5% and 0.0005%, respectively).8 Additionally, infusion-related reactions associated with low-molecular-weight iron products are mild, self-limited, and do not recur with rechallenge; therefore, routine medical interventions (such as histamine-1 blockers and epinephrine) are not recommended in this setting. This is because diphenhydramine and epinephrine can potentially cause a significant vasoactive reaction, mimicking an anaphylactic-type reaction. There are 5 parenteral iron formulations commercially available in the United States (Table)9-13; iron dextran (Dexferrum; Infed [Watson]), sodium ferric gluconate (Ferrlecit, Sanofiaventis), iron sucrose (Venofer, American Regent), and ferumoxytol (Feraheme, Amag). Iron dextran complexes are indicated for patients with documented iron deficiency when oral iron therapy is not feasible, whereas the indication for other available preparations (sodium ferric gluconate, iron sucrose, and ferumoxytol) is limited to patients with chronic kidney disease and iron deficiency.

Treatment Recommendations/ Guidelines Until recently, no clear recommendation existed on iron repletion in cancer patients. The updated recommendation by American Society of Hematology/American Society of Clinical Oncology was to “institute iron supplementation when indicated”; recommendations on optimal timing or frequency of the iron therapy were inadequate due to lack of available data.14 The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (v2.2011) recommend that IV iron be considered for the management of functional iron deficiency (defined as serum ferritin ≤800 ng/mL and TSAT <20%) in patients receiving ESAs.15 The NCCN also notes that most of the reported iron

d ex t ra n – r e l a t e d AEs are associated with high-molecular-weight iron dextran; therefore, the guideline recommends the use of lowmolecular-weight iron dextran over highmolecular-weight iron dextran.15

IV versus Oral Iron Supplementation IV iron often is a better choice than oral iron in the oncology setting because of factors that can impair enteral absorption of iron in patients with cancer. For example, malignancy and/or chemotherapy can impair gastrointestinal (GI) tract integrity. Also, upregulation of hepcidin can occur as a result of inflammatory cytokine release in these patients and in patients with CIA. In addition to these factors, the poor bioavailability of oral iron products and their undesirable GI adverse effects (ie, emesis, diarrhea, constipation, and dark stool) often contribute to poor patient compliance. Data also support the use of IV therapy over oral therapy in conjunction with ESAs. In CIA, at least 3 randomized trials have demonstrated superiority of IV iron (low-molecularweight iron dextran; ferric gluconate; iron sucrose) to oral iron supplementation as an adjunct to ESA therapy. Auerbach and colleagues randomized 157 patients to receive IV iron, oral iron, or no iron as an adjunct to epoetin alpha 40,000 units per week. They observed a significant improvement in hematologic response in the IV iron group compared with the oral or no iron groups (68% vs 35% and 25%, respectively).16 The mean increases in hemoglobin (Hb) in the IV, oral, and no iron arms were 2.5, 1.5, and 0.9 g/dL, respectively. In a subsequent study by Henry and colleagues, 187 patients were randomized to receive IV iron, oral iron, or no iron as an adjunct to epoetin alpha 40,000 units per week. There was a significant improvement in hematologic response in the IV iron group compared with the oral or no iron groups (73% vs 46% and 41%, respectively); the mean increases in Hb in the IV, oral, and no iron arms were 2.4, 1.6, and 1.5 g/dL, respectively.17 Bastit and colleagues also investigated the role of IV iron as an adjunct to ESA (darbepoetin alpha 500 mcg every 3 weeks). The investigators randomized 396 patients to

either IV iron or no iron arms; there was a significantly improved hematologic response in the IV iron arm (86% vs 73%) and the IV arm also required fewer red blood cell transfusions (9% vs 20%).18

Pharmacoeconomic Factors A recent pharmacoeconomic analysis performed in a community practice setting demonstrated a significant improvement in cost-effectiveness of ESA therapy with the addition of IV iron in patients with CIA.19 The pharmacoeconomic analysis included office visits, administration expenses, and pharmacy and drug costs. The yielded cost savings per patient was $1,300 per 12-week treatment cycle, translating to a weekly cost savings of $100 per patient. This strategy represents a significant cost-saving potential in oncology practice, as well as for the global health care system.

Conclusion Determining the need for iron repletion solely based on the serum ferritin level and/or TSAT at the time of initiating ESA therapy can result in suboptimal response to ESA therapy. Mounting evidence indicates that IV iron supplementation should become a routine component of ESA therapy in all patients with CIA whose TSAT is less than 35% and whose serum ferritin is 800 ng/mL or lower. This approach for anemia management has been shown to improve treatment outcomes by reducing the requirement for red blood cell transfusions and to improve the costeffectiveness of ESA therapy in the oncology setting. Therefore, the use of parenteral iron in the management of anemia in patients with CIA should be expanded to optimize ESA therapy and patient outcomes.

References 1.

Knight K, Wade S, Balducci L. Prevalence and outcomes of anemia in cancer: a systematic review of the literature. Am J Med. 2004;116S(suppl 7A):11S-26S.

2. Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized double-blind, placebo-controlled trial. J Clin Oncol. 2001;19(11):2865-2874. 3. Cascinu S, Fedeli A, Del Ferro E, Luzi Fedeli S, Catalano G. Recombinant human erythropoietin treatment in cisplatinassociated anemia: a randomized, double-

blind trial with placebo. J Clin Oncol. 1994;12(5):1058-1062. 4. Case DC Jr, Bukowski RM, Carey RW, et al. Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. J Natl Cancer Inst. 1993;85(10):801-806. 5. Henry DH, Brooks BJ Jr, Case DC Jr, et al. Recombinant human erythropoietin therapy for anemic cancer patients receiving cisplatin chemotherapy. Cancer J Sci Am. 1995;1(4):252-260. 6. Markman M, Reichman B, Hakes T, et al. The use of recombinant human erythropoietin to prevent carboplatin-induced anemia. Gynecol Oncol. 1993;49(2):172-176. 7. FDA Labels for Dexferrum (Iron Dextran Injection) http://www.fda.gov/ Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ ucm186899.htm. Accessed October 6, 2010. 8. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21(2):378-382. 9. Dexferrum (iron dextran) prescribing information. Shirley, NY: American Regent, Inc.; 2008. 10. Infed (iron dextran) prescribing information. Morristown, NJ: Watson Pharma, Inc.; 2009. 11. Ferrlecit (sodium ferric gluconate) prescribing information. Bridgewater, NJ: Sanofi-aventis US LLC; 2010. 12. Venofer (iron sucrose) prescribing information. Shirley, NY: American Regent, Inc.; 2006. 13. Feraheme (ferumoxytol) prescribing information. Lexington, NY: AMAG Pharmaceuticals; 2009. 14. Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26(1):132-149. 15. National Comprehensive Cancer Network. Cancer- and Chemotherapy-Induced Anemia. Version 2.2011. http://www.nccn. org/professionals/physician_gls/PDF/ anemia.pdf. Accessed October 6, 2010. 16. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapyrelated anemia: a multicenter, open label, randomized trial. J Clin Oncol. 2004;22(7):1301-1307. 17. Henry DH, Dahl NV, Auerback M, Tchekmedyian S, Laufman LR. Intravenous ferric gluconate improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12(2): 231-242. 18. Bastit L et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alfa administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008;26(10):1611-1618. 19. Auerbach M, Pappadakis J, Doherty E. Therapeutic and financial optimization of anemia management in cancer patients with chemotherapy-related anemia through low molecular weight iron dextran administration. Presented at: Annual Meeting of the American College of Clinical Pharmacy; October 14-17, 2007; Denver, CO. Abstract 188. 20. Shord SS, Hamilton JM, Cuellar S. Parenteral iron with erythropoiesisstimulating agents for chemotherapyinduced anemia. J Oncol Pharm Pract. 2008;14(1):5-22.

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Chemically stable for 24 hours at room temperature post reconstitution1 Latex-free, preservative-free and sulfur-free1 formulation Robust supply

SAFETY INFORMATION

Brevital® should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than the practitioner performing the procedure should be present to continuously monitor the patient. Brevital® Sodium is contraindicated in patients in whom general anesthesia is contraindicated, in those with latent or manifest porphyria, or in patients with a known hypersensitivity to barbiturates. Intra-arterial injection of barbiturate solutions can result in necrosis, which may lead to gangrene and possible amputation and thereby should be avoided. Caution should be exercised in debilitated patients or patients with impaired function of respiratory, circulatory, renal, hepatic or endocrine systems and in those with severe anemia or those who are extremely obese. Side effects include but are not limited to circulatory depression, hypotension, respiratory depression (including apnea), skeletal muscle hyperactivity (twitching), seizures, emergence delirium, restlessness, anxiety, nausea, hiccups, emesis, coughing and pain at the injection site. Following massive exposure to any barbiturate, pulmonary edema, circulatory collapse with loss of peripheral vascular tone, and cardiac arrest may occur.

How supplied NDC

Name

42023-105-01 Brevital® Sodium C-IV (methohexital sodium injection, USP) ®

42023-106-01 Brevital Sodium C-IV (methohexital sodium injection, USP)

Strength

Vial Size

Pack Size

500 mg

50 mL MDV

2.5 gm

References: 1. JHP Pharmaceuticals, Brevital Sodium Prescribing Information. Rochester, MI. January 2009.

50 mL MDV

See Full Prescribing Information

For more information about Brevital, please visit www.brevital.com, or call JHP Customer Service at 877-JHP-4JHP (877-547-4547). MK230B

40 Clinical

Pharmacy Practice News • November 2010

Anticoagulation

DOLLARS continued from page 1

(UPMC) outpatient anticoagulation service over the course of one year, compared with a similar group receiving standard physician-managed care. “A lot of us have thought the case was rested over the advantages of pharmacist-managed anticoagulation services,” said Deanne L. Hall, PharmD, assistant professor of pharmacy and therapeutics pharmacist at UPMC, and lead author of the study (abstract 11). “Pharmacists are already well-versed in warfarin phar-

macology and all its potential drug–drug and disease-state interactions. And they can take the pressure of this time-intensive management off physicians so they can focus on others.” Despite those benefits, only about 40% of patients on warfarin in the United States are followed by an anticoagulation service. The rest undergo the traditional management, in which their physician performs the monitoring—obtaining frequent blood draws, reviewing lab results, assessing the patient and making treatment adjustments. The likely holdup, according to Dr.

Hall, is a lack of evidence that the services are financially sound. In an attempt to fill that void with a true dollar amount, Dr. Hall and her colleagues studied individuals treated between October 2007 and September 2008. One group of 175 outpatients received warfarin management via usual medical care and another 175 through a pharmacist-managed anticoagulation service. Based on medical claims data, the team found the costs to be significantly lower for those managed by the pharmacists’ service compared with the costs for those

receiving standard care. Direct anticoagulation care costs were $35,456 and $111,586, whereas overall medical care costs were $754,191 and $1,480,600, for the pharmacist-managed versus usual medical care groups. After accounting for operational costs, the researchers calculated a total cost savings of $694,416 for the pharmacist-managed service over the course of the study. Those savings were directly attributable to the superior clinical outcomes seen in the pharmacist-treated patients, according to the investigators. Specifically, patients in the anticoagulation services group had significantly fewer anticoagulation-related adverse events (14 vs. 41), hospital admissions (30 vs. 85) and emergency room visits (60 vs. 143), compared with the standard care group (P<0.0001 for all). They also spent a larger portion of their time in the therapeutic range based on international normalized ratio readings (73.7% vs. 61.3%; P<0.0001). No differences were found in the number of warfarin refills.

Results a “Win, Win, Win” The services are a “win, win, win” for the health care system, physicians and patients, said Steven Meisel, PharmD, director of patient safety at Fairview Health Services in Minneapolis. “The services improve patient satisfaction, as well as knowledge and understanding of the risks and benefits of anticoagulation therapy.” In the process, Dr. Meisel added, “you’re using people who are less expensive than physicians and who are getting better outcomes.” Dr. Hall suggested that the ultimate goal would be to secure reimbursement for these pharmacist-managed services. Currently, pharmacists are not approved health care providers under the federal government for the purposes of reimbursable clinical services; the existing avenues of pay for anticoagulation management only are available for physicians and nurse practitioners. The team is looking into feasible business models, she added, to “help practitioners and health plans work together to provide patients these services in a financially sound way.” Asked to comment on the study, Ann Wittkowsky, PharmD, director of anticoagulation services at the University of Washington Medical Center in Seattle, stressed that “warfarin therapy is fraught with complications and requires a systematic approach to assure effectiveness and safety. The infrastructure that this requires, including both personnel and systems support, can be costly. Health care systems may be more willing to devote the resources to this infrastructure if they can be assured that it is cost-effective.” —Lynne Peeples

Clinical 41

Pharmacy Practice News • November 2010

Women’s Health

Pharmacists Boost Awareness of Emergency Contraception Austin, Texas—Just 10 minutes of counseling can substantially boost a woman’s knowledge about emergency contraception, both its availability and how to correctly take the medication, according to researchers from the University of Arkansas for Medical Sciences. They conducted a study at an affiliated outpatient women’s clinic in early 2010 to assess the benefits of a relatively brief pharmacist counseling session. In a follow-up survey, conducted immediately afterward, the 117 women involved— nearly all of them pregnant—raised their average knowledge score from 5.4 to 10.7 out of a possible 13 (P<0.0001), according to data presented at the annual meeting of the American College of Clinical Pharmacy (abstract 218). “Even if we prevented one or two or three pregnancies, any decrease in the number of unintended pregnancies in this population would be huge,” said Denise Ragland, PharmD, CDE, associate professor in the College of Pharmacy at the University of Arkansas for Medical Sciences, in Little Rock, and one of the researchers. “It was nice to empower the patient with the knowledge they need to make their own medical care decisions.” Pharmacists can play a key role in educating women not just about emer-

en received a $10 gift card for participation, because they were giving half an hour of their time, Dr. Ragland said.) The pharmacists provided an overview of emergency contraception, including when to take the medication and related symptoms, among other facts. “The comment I remember most was, ‘Gee, I wish I had

known about this four months ago,’ ” Dr. Ragland said. The post-counseling survey was conducted immediately, but the knowledge appeared to stick: In a survey conducted one to five months later, the average score was 10.3. The brief counseling session also included details about contraceptive options besides emergen-

cy contraception, Dr. Ragland stressed. The educational approach could easily be used in busy waiting room settings, she added. “It was not only feasible but very effective to do with women waiting in a crowded waiting room with time on their hands,” she said. “It also was an excellent opportunity for student pharmacists to practice their counseling skills.” —Charlotte Huff

Ready to Use Wherever. Whenever.

gency contraception, but also other contraceptive options, said Karen Farris, PhD, a professor at the University of Iowa College of Pharmacy, in Iowa City. Dr. Farris recently authored a review article published in the Journal of the American Pharmacists Association, examining pharmacist partnerships and pregnancy prevention (2010:50;604-612). The Arkansas findings illustrate the large gaps in women’s knowledge, said Dr. Farris, pointing out that they initially could not answer half of the questions. “If a patient gets counseling in a physician’s office, then that is fantastic,” she said. “But I think a pharmacist may need to follow up and confirm that they understand the information and that they remember it.” In the Little Rock study, 78% of the pregnancies were not planned. Nearly half of the women had completed at least some college education. Before the counseling session, 30% didn’t know anything about emergency contraception—a statistic that Dr. Ragland described as an improvement over a survey she was involved with several years ago. At that time, at least half of the women were unaware of emergency contraception. To provide counseling, pharmacists would ask the women in the waiting room to step into a side room, where they would get the surveys and related education, if they consented. (The wom-

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42 Operations & Management

Pharmacy Practice News â&#x20AC;˘ November 2010

Leadership in Action

Emotional Intelligence in Leadershipâ&#x20AC;&#x201D; Communication and Empathy â&#x20AC;&#x153;The single biggest problem in communication is the illusion that it has taken place.â&#x20AC;? â&#x20AC;&#x201D;George Bernard Shaw

he world today requires us to be even better communicators than in times past. Of course, communicat-

ing with other human beings has never been easy. But with the advent of even more sophisticated ways to confuse and confound each other, we must nudge our skills to ever-higher levels. Although the Internet has expanded our ability to communicate efficiently (i.e., communicate with more people in less time), it can also lead to new catego-

ries of misunderstandings and depersonalize our interactions. For example, I recently conducted several webinars, wherein I spoke to an online audience of several hundred people whom I could not see or hear. I sat in front of my computer, advancing my slides one by one, wondering if my audience was laughing at my jokes, staring off into space,

in Your Inbox %%% kf i\Z\`m\ k_\ dfek_cp \$e\njc\kk\i ]ifd

â&#x20AC;&#x153;Leadership in Actionâ&#x20AC;? is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Caritas Christi, Boston. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ caritaschristi.org.

Ernest R. Anderson Jr., MS, RPh

or nodding enthusiastically along with each salient point I made. The same thing can happen with e-mail and even phone communication. Without the exchange of nonverbal visual signals, we may overlook nuance, such as a â&#x20AC;&#x153;yesâ&#x20AC;? thatâ&#x20AC;&#x2122;s really a â&#x20AC;&#x153;maybe, although Iâ&#x20AC;&#x2122;m not really sure what you just meant by that.â&#x20AC;? We may miss opportunities to ask clarifying questions or give further explanation. New obstacles require correspondingly sharper skills. So, how can you keep your own communication skills up to snuff? Personally, I believe that itâ&#x20AC;&#x2122;s important to start with what Steven R. Covey, in his book â&#x20AC;&#x153;The 7 Habits of Highly Effective Peopleâ&#x20AC;? (New York, NY: Simon and Schuster; 1989), has named Habit 5: â&#x20AC;&#x153;Seek first to understand, then to be understood.â&#x20AC;?

Communication Competency Na ddd ]UN_ZNPf]_NPaVPR[Rd` P\Z

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded Web site links that give you instant access to additional information as well as unique searching features and printing capabilities. Each installment contains brief summaries of the most important articles from the current monthâ&#x20AC;&#x2122;s issue, and breaking news ahead of print.

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Understanding is the ultimate goal of communication. Aside from its practical byproductâ&#x20AC;&#x201D;accurately conveying informationâ&#x20AC;&#x201D;understanding is, in and of itself, a powerful way to bridge gaps and defuse contention. It requires listening with an open mind, demonstrating an empathetic attitude and asking for suggestions. Ultimately, the message must be received with its senderâ&#x20AC;&#x2122;s intent intact. This usually requires free-flowing communication devoid of defensiveness, aggression or hostility. Reldan Nadlerâ&#x20AC;&#x2122;s book â&#x20AC;&#x153;Leadersâ&#x20AC;&#x2122; Playbook: How to Apply Emotional Intelligenceâ&#x20AC;&#x201D;Keys to Great Leadershipâ&#x20AC;? (Santa Barbara, CA: Psyccess Press; 2006) outlines a set of strategies for improving our communication skills: Empathy. Empathy is not only an element of your Emotional Intelligence quotient (EQ), it is also a building block for other EQ â&#x20AC;&#x153;competencies,â&#x20AC;? such as communication skills, trustworthiness, self-awareness, the ability to build bonds and resolve conflict, a service attitude, leadership abilities, and the ability to be a catalyst for change and influence others. Empathy is the ability to understand others through both verbal and nonverbal cues. It displays active interest. A good example is sensing anotherâ&#x20AC;&#x2122;s frustration with a particular situation through body language and asking about it. Build effective rapport. Many people listen with the goal of responding, as opposed to with the goal of understanding. Barriers to effective listening can

Operations & Management 43

Pharmacy Practice News • November 2010

Leadership in Action include thinking of your response while you should be listening, focusing on other things outside of the conversation while pretending to listen, or interrupting the speaker. Good communication requires a high level of trust between two parties. Trust is usually built slowly over time, but where it exists, communication will always flow more easily. Reiterate important messages. As leaders, we often need to repeat the same message to several people, both privately and in groups. Even though we may get tired of repeating ourselves, we must recognize that people require

processing time for our messages and their consequences. We may have been thinking about an issue for several weeks before we share it with others. We need to give them some time to let it sink in, too. Confirm understanding. Remember to measure how well your intended message was received. Ask for feedback to confirm understanding. Repeat yourself from a different angle to get the message across. Remember,

everyone absorbs information in different ways. Use anecdotes. Telling stories can be a very powerful way to help drive a message home. Similarly, pictures, graphs, slides and demonstrations can all clarify the points we are making. Provide clarity. Sometimes we need to connect the dots for people to understand us. Don’t assume that your listener will reach the same conclusion that you did.

Seek feedback. To truly know if your message was understood, ask for feedback. We often make assumptions that our communication was clear. If you are presenting to a group, seek private feedback from several individuals. Giving someone permission ahead of time to provide you feedback is often helpful and encourages listening and evaluation. Good communication is fundamental to all that we do as leaders. Working to sharpen your emotional intelligence in this area yields great rewards—both personally and professionally.

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Accountability in Leadership

he next book that I’m going to use as a taking-off point for future columns is called “Accountability Leadership,” by Gerald Kraines, MD (Pompton Plains, NJ: Career Press; 2001). Those organizations that apply the principles of Accountability Leadership will significantly boost their potential for success.

Vials are back! No thawing required!

This concept of leadership involves aligning the organization in its strategies and structures, motivating capable employees to meet their commitments, and encouraging teamwork to optimize results and yield a highly responsive, highly performing accountable culture. Sound too good to be true? We will apply the Accountability Leadership principles to how we should be leading our pharmacy departments. The principles have broad applicability as we launch projects, develop people and steer our departments in new directions. The economic pressures are changing the way we take care of patients. We are implementing technologies to allow pharmacists to broaden their patient care roles. We must align our pharmacy expertise to address the unmet needs that will be created in this new era of health care. I look forward to having you join me in exploring these issues and opportunities. —Ernie Anderson

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44 Policy

Pharmacy Practice News • November 2010

FDA Watch

PRADAXA continued from page 1

“As we move away from clinical trials and into the real world, we might lose the potential for seeing traditional, warfarin-managed patients in an anticoagulation clinic setting. Such anticoagulation clinics acted as safety nets for some patients,” said James B. Groce III, PharmD, clinical pharmacy specialist in anticoagulation at Moses Cone Health System Department of Pharmacy, in Greensboro, N.C. Dr. Groce said he worries that without access to such clinics, these patients will become “out of sight, out of mind.” That may happen, he warned, “if the messaging that dabigatran does not require monitoring” is pushed too hard. “We should still encourage patient monitoring to enforce the importance of compliance and hypervigilance about the symptoms that might portend therapeutic misadventures at the other extreme, like bleeding,” said Dr. Groce. As a graphic illustration of the importance of keeping a close watch on patients, Dr. Groce told the story of a patient he recently saw in his clinic who had just been discharged from the hospital after being treated for an arterial embolic event that necessitated amputation of his right lower extremity. “When querying the patient regarding any problems, he commented: ‘I have a little bleeding on my left foot.’ Closer examination revealed that this diabetic patient had an ulcerated area upon his second toe of the remaining extremity.

The consequences of this going missed could have been catastrophic for this patient who was not scheduled to be seen for three more weeks.” In the anticoagulation clinic, when patients were being seen for international normalized ratio (INR) determinations and anticoagulation management and oversight, “there was an opportunity to make other interventions that were and are important for patient care,” Dr. Groce added. “I worry that this opportunity may go lost now if patients are not being seen as regularly as they were on warfarin.” Ann K. Wittkowsky, PharmD, clinical professor, University of Washington School of Pharmacy, Seattle, echoed Dr. Groce’s concerns. “The approval of dabigatran [Pradaxa, Boehringer Ingelheim] is a major victory for patients with AF because the drug does not require routine coagulation monitoring or frequent dose adjustments and is not impacted by dietary vitamin K intake,” Dr. Wittkowsky noted. But to be safe and effective, and for patient outcomes to mimic those seen in clinical trials, “more is required than simply writing a prescription.” Dr. Wittkowsky also noted that dabigatran has not been investigated in mechanical valve replacement and other cardiovascular disorders and predicted that “warfarin will not disappear. Anticoagulation clinics will not shut their doors. But the landscape is certainly about to change and the potential for overall benefit to patients is considerable.”

‘Warfarin will not disappear; anticoagulation clinics will not shut their doors. But the landscaping is certainly about to change and the potential for overall benefit to patients is considerable.’ —Ann K. Wittkowsky, PharmD

‘The physicians can talk about how great this new drug is, but it is the pharmacist who is left with the practical concerns like how much does it cost, who is it best for, what are the drug interactions, and the fact that it can’t be administered down a feeding tube.’ —Sarah A. Spinler, PharmD The Approval Data Dabigatran has been generating a buzz ever since the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial were announced at the 2009 European Society of Cardiology Congress and published in The New England Journal of Medicine (N Engl J Med 2009;361:11391151). The noninferiority RE-LY study included 18,113 patients who were randomized to unblinded adjusteddose warfarin administration or to blinded administration of two doses of dabigatran (110 or 150 mg) twice daily. Patients were followed for a median of two years, and the primary outcome was stroke or systemic embolism. Rates of the primary outcome were 1.69% per year in the warfarin group vs. 1.53% per year in the group that received 110 mg of dabigatran (relative risk [RR], 0.91; 95% confidence interval [CI], 0.74-1.11; P<0.001 for noninferiority), and 1.11% in the group that received 150 mg of dabigatran (RR, 0.66; 95% CI, 0.53-0.82; P<0.001 for superiority). In its briefing document to the committee, the FDA stated that dabigatran should be approved in the 150-mg dose, but not the 110-mg dose, and that a superiority claim over warfarin should not be granted. Boehringer Ingelheim had wanted dabigatran’s label to recommend the 150-mg dose, with consideration of the 110-mg dose in patients at a high risk for bleeding. The FDA’s viewpoint won out: it approved the 150-mg bid dose, along with a 75-mg bid dose intended for patients with poor renal function (creatinine clearance of 15 to 30 mL/min), but chose not to approve the 110-mg formulation. (The 75-mg bid dose was not evaluated in the RE-LY study). Panel member Steven Nissen, MD, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation, in Ohio, disagreed with the FDA and said he thought keeping the 110-mg dose as an option was a good idea. “My feeling was that we needed the lower dose because there are people who are more fragile and more vulnerable in whom the alternative to getting a lower dose

would be to get nothing at all,” he told Pharmacy Practice News. Sanjay Kaul, MD, a cardiologist on the panel from Cedars Sinai Heart Institute, Los Angeles, disagreed. “I think the FDA should approve just the 150-mg dose,” he told Pharmacy Practice News prior to the approval being announced. “If they approve both doses, and they tell physicians in the label that 110 mg is the safer dose and is associated with less bleeding, then more likely than not, most physicians are going to opt for the safer dose,” he explained. “This would be compromising the efficacy of dabigatran.” The issue of cost is another factor that may affect usage of the drug, Dr. Kaul noted. Right now, in countries where it is approved for the prophylaxis of deep vein thrombosis after knee and hip replacement, the price of dabigatran ranges from about $8 to $12 per day for a 35-day treatment. When it goes on the market for use in patients with AF, it will have to be given lifelong. “It’s an expensive drug and I think that’s the elephant in the room. The company has got to get the price right,” he said.

Many Questions Remain There is no doubt that dabigatran’s entry onto the market will mean new challenges for pharmacists, Sarah A. Spinler, PharmD, professor of clinical pharmacy at Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, told Pharmacy Practice News. One challenge is the many unanswered questions that remain about the drug’s impact. “Will it be cost-effective, especially for individual centers where the time in therapeutic range is high? Presentations on the new generation of anticoagulants always emphasize that the medications have fewer drug interactions than warfarin. “That’s certainly true, but it’s not zero,” Dr. Spinler said. (Drugs that dabigatran does interact with include verapamil, ketoconazole, amiodarone, clopidogrel, erythromycin, digoxin and other P-glycoprotein [Pgp] substrates.) “There are fewer drug interactions, and the product labeling indicates that the interaction with only one agent, rifampin, is significant enough

Policy 45

Pharmacy Practice News • November 2010

FDA Watch to warrant adjustment in dosage. But dabigatran hasn’t been tested with that many medications at this time,” she noted. “For instance, the labeling states that the [rifampin interaction] results should not be extrapolated to other agents. This wording is problematic for pharmacists, who will need to keep abreast of which medications have been tested in combination with dabigatran.” Another issue is the composition of the dabigatran capsule. “The bioavailability increases by 40% when you take the formulation out of the pellets and ingest the drug that way. So you cannot crush the pellet for patients who have difficulty swallowing; it has to remain intact,” she said. Use of the drug during surgery is another concern, Dr. Spinler noted, because such patients are at risk for bleeding complications. “While the Pradaxa product label recommends withholding dabigatran from one to four days prior to surgery, depending on the patients’ creatinine clearance (this came out of the study design of the RE-LY trial), there is no published experience with this strategy.”

‘We should still encourage patient monitoring to enforce the importance of compliance and hypervigilance about the symptoms that might portend therapeutic misadventures at the other extreme, like bleeding.’ —James B. Groce III, PharmD Another potential problem is the lack of a reversal agent with direct thrombin inhibitors. “So when patients bleed, we just stop dabigatran and hope it goes away quickly,” she noted. Finally, “a reduced dose of 75 mg twice daily is recommended for patients with creatinine clearance between 15 mL/min and 30 mL/min based upon pharmacokinetic data. But there is no published safety data with this dosage regimen in this population,” Dr. Spinler said. “The product labeling states that for patients with creatinine clearance less than 15 mL/min, no dose can be recommended. But it does not list Stage 5 chronic kidney disease as a contraindication, leaving practitioners in the dark about what to do.” Dr. Spinler added that dabigatran is removed by hemodialysis; thus, “the precise dosing of dabigatran in that patient group for therapeutic effect is not known.

Other Warfarin Alternatives In the Pipeline

ith FDA approval of dabigatran all but certain, there are new warfarin alternatives in various stages of development waiting in the wings. Data on three of the new oral anticoagulants—apixaban (Bristol-Myers Squibb/Pfizer), rivaroxaban (Zarelto, Bayer/Johnson & Johnson) and betrixaban (Portola Pharmaceuticals/Merck) were presented at the recent European Society of Cardiology (ESC) Congress in Stockholm.

Betrixaban in Phase II EXPLORE-Xa Trial Betrixaban is a direct-acting oral factor Xa inhibitor with a 20- to 24-hour half-life and minimal renal excretion. The drug had been shown to be safe and well tolerated in patients with AF in the Phase II EXPLORE-Xa trial,

So I would recommend avoiding dabigatran in this patient group until more information is available. Warfarin is a better option for now.” “These are the [issues] that pharmacists are left to deal with,” Dr. Spinler said. “The physicians can talk about how great this new drug is, but it is the pharmacist who is left with the practical concerns like how much does it cost, who is it best for, what are the drug interactions, and the fact that it can’t be administered down a feeding tube,” she said. “Still, all things considered, dabigatran sounds very promising.” —Fran Lowry —Fra

‘A new era of anticoagulation therapies is approaching for a number of clinical indications that will benefit patients suffering from thromboembolic disease.’ —Harald Darius, MD during which three doses of betrixaban—40, 60 and 80 mg given once daily—were compared with adjusted-dose warfarin (INR 2-3). The results showed that, compared with warfarin, betrixaban decreased the rate of bleeding in AF patients who had at least one risk factor for stroke. At the ESC meeting, a subanalysis of EXPLORE-Xa was presented, highlighting betrixaban’s effects on pharmacodynamic markers (abstract 107). The analysis showed that the observed median INR level in the warfarin group after one week was 2.44, and the time in treatment range was 64%. The mean antifactor Xa activities at steady state were 0.0804, 0.118, 0.127 and 0.0545 IU/mL for the three betrixaban dosages and warfarin arms, respectively. All doses of betrixaban were associated with anti-factor Xa activity, which increased as the dose increased.

Rivaroxaban in the EINSTEIN DVT trial In the EINSTEIN DVT study, rivaroxaban was found to be noninferior to standard therapy for acute, symptomatic deep vein thrombosis. The direct oral factor Xa inhibitor was compared with low-molecular-weight heparin, followed by warfarin in more than 3,400 patients with DVT but without concomitant symptomatic pulmonary embolism. Patients received oral rivaroxaban 15 mg twice daily for the first three weeks, followed by 20 mg once daily or body weight-adjusted enoxaparin 1 mg/kg twice daily, followed by warfarin or acenocoumarol for three, six or 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent venous thromboembolism (VTE), and the principal safety outcome was the composite of major and clinically relevant nonmajor bleeding. There was no significant difference between the two treatments, although rivaroxaban demonstrated a trend toward superiority in warding off recurrent VTE and major bleeding complications. Harald Darius, MD, from Vivantes Neukoelln Medical Center, Berlin, Germany, who discussed the results at the ESC congress, said there are a number of questions that remain, but nevertheless, he announced that he “firmly believes that a new era of anticoagulation therapies is approaching for a number of clinical indications that will benefit patients suffering from thromboembolic disease.” Rivaroxaban already is approved for the prophylaxis of DVT and VTE in patients undergoing knee and hip surgery in Europe but remains unapproved in the United States, despite the recommendation to approve the drug by the FDA’s Cardiovascular and Renal Drugs Advisory Committee in March 2009.

AVERROES and Apixaban In the AVERROES (Apixaban versus Acetylsalicylic Acid to Prevent Strokes) trial (abstract 3769), patients with AF who were unable to take warfarin had a significantly lower risk for stroke or systemic embolic events with apixaban than with aspirin. The annual rate of stroke or systemic embolism, which was the primary outcome, was 4% per year with aspirin and 1.7% per year with apixaban (hazard ratio [HR], 0.43; 95% CI, 0.30-0.62; P=0.000004). The rate of major hemorrhage was 1.2% per year with aspirin and 1.5% per year with apixaban (HR, 1.26; 95% CI, 0.79-2.00; P=0.33). The rate of hemorrhagic stroke was similar in both treatment groups, 0.2% (HR, 1.15; 95% CI, 0.42-3.17; P=0.79). —F.L.

46 Clinical

Pharmacy Practice News • November 2010

Educational Review

New Strategies in Antimicrobial Stewardship: Managing Patient Care

WILLIAM FORD, MD Cogent Medical Director/Section Chief Temple University Health System Philadelphia, Pennsylvania

ver the past 25 years, the use of antimicrobial

COMMENTARY STEVEN J. MARTIN, PHARMD, BCPS, FCCM

agents has been steadily increasing. This growth can be attributed to the explosion

of pharmacologic agents produced by industry in response to a society demanding a rapid cure.

Scan for PDF of this review; see p. 3 for instructions

KYLIE MUELLER, PHARMD, BCPS

Along with this rise in use comes the burden

Antibiotic Stewardship Pharmacist

of multidrug-resistant organisms (MDROs).

Overview of Antibiotic Stewardship These organisms increase morbidity, mortality, and the overall cost of health care.1 Organisms such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and multidrug-resistant klebsiella are just a few of the evergrowing list of drug-resistant hospitalacquired and community-associated (CA) infections. In 2007, recognizing this growing problem, the Infectious Disease Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA), released updated guidelines calling for comprehensive infection control and antimicrobial stewardship programs (ASPs) to improve clinical outcomes and stay the flood of rising costs and resistance (Table 1).2 The past decade witnessed the emergence of a plethora of MDROs. It is now “evening news”-

worthy to mention MRSA or VRE. CA-MRSA is approaching 50% to 75% of all staphylococcal infections in certain parts of the country.3 These numbers have prompted many medical centers to revitalize their ASPs. Hospital–acquired infections, especially MDROs, have become common and antimicrobial stewardship is needed to fundamentally lessen the trend (Table 2).4 ASPs should not be myopic in their view. An all-inclusive analysis is needed to appreciate fully the scope and effect programs have on patient treatment regimens and the financial well-being of the hospital. The core strategies of a well-organized and executed ASP fall into 2 general categories: antibiotic restriction or prospective audit and feedback.5

Antibiotic Restriction Using antibiotic restriction as a means of stewardship is a singular “gatekeeper” approach. Although

Professor and Chairman Department of Pharmacy Practice

University of Toledo Medical Center Toledo, Ohio

they do reduce the pharmacy’s upfront acquisition costs, antibiotic restriction programs generally restrict only high-cost drugs but not lower cost drugs that often are used inappropriately; thus they fall short in the crucial area of health-system fiscal responsibility. Many would argue that substituting a more expensive antibiotic with a cheaper alternative saves money for the pharmacy—and therefore the health system; however, this only is correct from an acquisition cost perspective. Unfortunately, many health systems can end up bankrupt even if the pharmacy stays in “the black.” Pharmacy directors and hospital chief financial offers (CFOs) need to take a global healthsystem stance. Inappropriate substitution of an antibiotic in some cases can increase a patient’s duration of therapy, hospital length of stay (LOS), and overall resource utilization. It is well documented that

antimicrobial resistance is related to the selective pressure associated with use of antimicrobial agents. It also has been theorized that reducing the use of these agents may result in a reversal of drug resistance.6 In instances such as these, formulary restrictions often are put in place to curb the use of specific antimicrobial agents. At this point, therapies are still prescribed by attending physicians, although a consult with an infectious disease (ID) specialist is required prior to authorization of therapy. Approval traditionally is obtained via phone or formal consult—where alternative therapies are discussed. A study of this method from 1995 to 1996 found that class restriction alone was unlikely to eliminate antimicrobial resistance. The study noted that although resistance to the restricted agents was reduced, resistance developed to other agents not on restriction.7 It was concluded Table begins on page 56; Text continues on page 50

48 Clinical

Pharmacy Practice News • November 2010

Educational Review Review continued from page 46

Elements of the ASP

Stewardship Team and Administrative Support

Table 1. Guidelines for Developing an ASP Recommendations

Rating

Core members of a multidisciplinary antimicrobial stewardship team include an ID physician and a clinical pharmacist with ID training who should be compensated for their time, with the inclusion of a clinical microbiologist, an information system specialist, an infection control professional, and a hospital epidemiologist being optimal.

AIII

Collaboration between the antimicrobial stewardship team and the hospital infection control and P&T committees, or their equivalents, is essential.

AIII

The support and collaboration of hospital administration, medical staff leadership, and local providers in the development and maintenance of ASPs is essential.

AIII

It is desirable that ASPs function under the auspices of quality assurance and patient safety.

AIII

The ID physician and the head of pharmacy, as appropriate, should negotiate with hospital administration to obtain adequate authority, compensation, and expected outcomes for the ASP.

AIII

Hospital administrative support for the necessary infrastructure to measure antimicrobial use and to track use on an ongoing basis is essential.

AIII

Prospective audit of antimicrobial use with direct interaction and feedback to the prescriber, performed by either an ID physician or a clinical pharmacist with ID training, can reduce inappropriate use of antimicrobials.

Formulary restriction and preauthorization requirements can lead to immediate and significant reductions in antimicrobial use and cost.

AII

Formulary restriction and preauthorization requirements may be beneficial as part of a multifaceted response to a nosocomial outbreak of infection.

BII

The use of preauthorization requirements as a means of controlling antimicrobial resistance is less clear, because a long-term beneficial impact on resistance has not been established, and in some circumstances, use simply may shift to an alternative agent, with resulting increased resistance.

BII

In institutions that use preauthorization to limit the use of selected antimicrobials, monitoring overall trends in antimicrobial use is necessary to assess and respond to such shifts in use.

BIII

Education is considered an essential element of any program designed to influence prescribing behavior and can provide a foundation of knowledge that will enhance and increase the acceptance of stewardship strategies.

AIII

Education alone, without incorporation of active intervention, is only marginally effective in changing antimicrobial prescribing practices and has not demonstrated a sustained impact.

BII

Multidisciplinary development of evidence-based practice guidelines incorporating local microbiology and resistance patterns can improve antimicrobial use.

Guideline implementation can be facilitated through provider education and feedback on antimicrobial use and patient outcomes.

AIII

There are insufficient data to recommend the routine use of antimicrobial cycling as a means of preventing or reducing antimicrobial resistance over a prolonged period of time. Substituting one antimicrobial for another may transiently decrease selection pressure and reduce resistance to the restricted agent. Unless the resistance determinant has been eliminated from he bacterial population, however, reintroduction of the original antimicrobial again is likely to select for the expression of the resistance determinant in the exposed bacterial population.

CII

Antimicrobial order forms can be an effective component of antimicrobial stewardship and can facilitate implementation of practice guidelines.

BII

There are insufficient data to recommend the routine use of combination therapy to prevent the emergence of resistance.

CII

Combination therapy does have a role in certain clinical contexts, including use for empirical therapy for critically ill patients at risk for infection with MDR pathogens, to increase the breadth of coverage and the likelihood of adequate initial therapy.

AII

Streamlining or de-escalation of empirical antimicrobial therapy on the basis of culture results and elimination of redundant combination therapy can target more effectively the causative pathogen, resulting in decreased antimicrobial exposure and substantial cost savings.

AII

Optimization of antimicrobial dosing based on individual patient characteristics, causative organism, site of infection, and pharmacokinetic and pharmacodynamic characteristics of the drug is an important part of antimicrobial stewardship.

AII

A systematic plan for parenteral to oral conversion of antimicrobials with excellent bioavailability, when the patient’s condition allows, can decrease hospital length of stay and health care costs.

Development of clinical criteria and guidelines allowing conversion to use of oral agents can facilitate implementation at the institutional level.

AIII

Health care information technology can improve antimicrobial decisions through the incorporation of data on patient-specific microbiology cultures and susceptibilities, hepatic and renal function, drug–drug interactions, allergies, and cost. Preferred formats are: • Electronic medical records,

AIII

• CPOE, and

BII

• Clinical decision support.

BII

However, implementation of these features has been slow, and conformation of the technology to the clinical environment remains a challenge.

Table continues on page 50

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50 Clinical

Pharmacy Practice News • November 2010

Educational Review

Elements of the ASP

Table 1. Guidelines for Developing an ASP (continued) Recommendations

Rating

Computer-based surveillance can facilitate good stewardship by more efficient targeting of antimicrobial interventions, tracking of antimicrobial resistance patterns, and identification of nosocomial infections and adverse drug events.

BII

The clinical microbiology laboratory plays a critical role in antimicrobial stewardship by providing patient-specific culture and susceptibility data to optimize individual antimicrobial management and by assisting infection control efforts in the surveillance of resistant organisms and in the molecular epidemiologic investigation of outbreaks.

AIII

Both process measures (did the intervention result in the desired change in antimicrobial use?) and outcome measures (did the process implemented reduce or prevent resistance or other unintended consequences of antimicrobial use?) are useful in determining the impact of antimicrobial stewardship on antimicrobial use and resistance patterns.

BIII

ASP, antimicrobial stewardship program; CPOE, computerized prescriber order entry; ID, infectious disease; MDR, multidrug resistant; P&T, Pharmacy and Therapeutics Adapted from reference 2.

Text continued from page 46

that both restriction and infection control were needed to control the spread of resistance.

Prospective Audit And Feedback Prospective antibiotic auditing and feedback is a second approach to antibiotic stewardship. This strategy

does not completely restrict antibiotic usage and allows practitioners and pharmacy staff to communicate and discuss treatment options. It serves the purpose of keeping antibiotics from being inappropriately prescribed while still aiming to decrease resistance trends. The benefit of this system is that emphasis is placed on using antibiotics appropriately, and

does not simply implement complete restriction that will likely transfer the burden of resistance to another agent.8 Although this method requires increased upfront costs and overhead (ie, dedicated pharmacy staff for auditing and communication), the downstream positive returns have the potential to quickly pay for the additional expense.9

Programmatic Infrastructure And Cost Savings Whether the prospective audit and communication method or the formulary restriction method is used, dedicated staff and resources need to be mobilized and budgeted. A successful ASP needs complete buy-in from appropriate hospital administration. Text continues on page 52

Table 2. Distribution and Rank Order of Selected Pathogens Associated With Cases of HAIs Reported to the NHSN, January 2006–October 2007, by Type of HAI Overalla

Pathogen

No. (%) of pathogenic isolates

CoNS Staphylococcus aureus

CLASBI

Rank

No. (%) of pathogenic isolates

5,178 (15.3)

4,913 (14.5)

Enterococcus species

CAUTI

Rank

No. (%) of pathogenic isolates

3,900 (34.1)

1,127 (9.9)

VAP

Rank

No. (%) of pathogenic isolates

234 (2.5)

208 (2.2)

Rank

No. (%) of pathogenic isolates

Rank

79 (1.3)

965 (13.7)

1,456 (24.4)

2,108 (30.0)

E. faecalis

1,177 (3.5)

627 (5.5)

335 (3.6)

21 (0.4)

194 (2.8)

E. faecium

1,888 (5.6)

942 (8.2)

562 (6.0)

38 (0.6)

345 (4.9)

NOS

1,028 (3.0)

265 (2.3)

496 (5.3)

18 (0.3)

249 (3.5)

Candida species

C. albicans

2,295 (6.8)

673 (5.9)

1,361 (14.5)

140 (2.4)

115 (1.6)

Other Candida species or NOS

1,333 (3.9)

669 (5.9)

613 (6.5)

20 (0.3)

30 (0.4)

Escherichia coli

3,264 (9.6)

310 (2.7)

2,009 (21.4)

271 (4.6)

671 (9.6)

Pseudomonas aeruginosa

2,664 (7.9)

357 (3.1)

938 (10.0)

972 (16.3)

390 (5.6)

Klebsiella pneumoniae

1,956 (5.8)

563 (4.9)

722 (7.7)

446 (7.5)

213 (3.0)

Enterobacter species

1,624 (4.8)

443 (3.9)

384 (4.1)

498 (8.4)

293 (4.2)

Acinetobacter baumannii

902 (2.7)

252 (2.2)

109 (1.2)

498 (8.4)

42 (0.6)

Klebsiella oxytoca

359 (1.1)

99 (0.9)

85 (0.9)

128 (2.2)

47 (0.7)

Other

5,267 (15.6)

1,201 (10.5)

1,321 (14.1)

1,375 (23.1)

1,363 (19.4)

Total

33,848 (100)

11,428 (100)

9,377 (100)

5,960 (100)

7,025 (100)

CAUTI, catheter-associated urinary tract infection; CLABSI, central line–associated bloodstream infection; CoNS, coagulase-negative staphylococci; HAI, health care–associated infection; NHSN, National Healthcare Safety Network; NOS, not otherwise specified; SSI, surgical site infection; VAP, ventilator-associated pneumonia a

SSI

The overall total includes data for 58 pathogens associated with postprocedure.

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52 Clinical

Pharmacy Practice News • November 2010

Educational Review Commentary

Text continued from page 50

Staffing should reflect the overall hospital size and the goals set forth by the program.10 If the audit and feedback strategy is used, dedicated staff will need to be in place, often necessitating new hires. A larger academic medical center likely will need a fulltime clinical pharmacist for case and susceptibility review, and to communicate data to the team. Conversely, a smaller community hospital may require only a part-time pharmacist or a well-trained nurse to perform this task. This strategy obviously requires more resources but continues to allow for more physician autonomy in antibiotic selection. The paradigm also prevents delay of treatment because it allows the prescribing physician to initiate therapy, likely with a broad-spectrum agent, and then scale back this therapy if needed on further review from an ID specialist or pharmacist. If the prior authorization/formulary restriction technique is used, fewer dedicated resources are needed upfront. This strategy typically creates an immediate cost savings because many newer antimicrobial agents are restricted. Although the upfront savings of this technique are attractive, other factors must be considered. This type of ASP requires prior authorization for initiation of therapy, which can result in treatment delays. Agents to be placed on restriction are determined by surveillance data of drug-resistance patterns from an institution. Resources will need to be allocated to the ongoing monitoring of resistance trends by a Pharmacy and Therapeutics (P&T) committee to establish whether the formulary restriction is affecting resistance in a positive or negative manner. Frequent input also will be needed from an ID specialist with regard to antibiogram data, continuous monitoring and updating of the formulary, and dissemination of this information to the medical staff. All of these processes must be integrated to create a successful ASP. The additional infrastructure, regardless of the technique used, will need to be justified. A fully functional ASP, regardless of the type, can have a positive impact both clinically and financially. The best way to ensure this is to comprehensively explain the ASP’s goals before inception. Traditionally, this is done with a reduction in acquisition cost for the pharmacy budget. Most CFOs easily can grasp and appreciate this metric. However, given the change in hospital operations surrounding efficiency, pay-for-performance, and quality metrics, a fully functioning ASP will need to

Antimicrobial Stewardship: The Pharmacist’s Perspective Steven J. Martin, PharmD, BCPS, FCCM Professor and Chair Department of Pharmacy Practice

Kylie Mueller, PharmD, BCPS Antibiotic Stewardship Pharmacist University of Toledo Medical Center, Toledo, Ohio

n his review, “New Strategies in Antimicrobial Stewardship: Managing Patient Care,” William Ford, MD, from Temple University Health System, in Philadelphia, provides a brief overview of antimicrobial stewardship and strategies for enhancing antimicrobial stewardship programs (ASPs). Recognizing the rising use of antimicrobials and the emergence of multidrug-resistant organisms (MDROs), Dr. Ford points to good antimicrobial stewardship as essential to reverse these trends and improve the appropriate use of antimicrobials. Dr. Ford also points out that the resources required for a successful stewardship program depend on the hospital size and the overall structure of the ASP. In the case of a pharmacy-run ASP, the pharmacy department should learn to optimize use of available resources and establish a team approach. Dr. Ford focuses on 2 main antimicrobial stewardship strategies: antimicrobial restriction and prospective audit and feedback. Both strategies have advantages and disadvantages. Most institutions likely will require an approach that incorporates a combination of both strategies, depending on the goals and resources of an organization. Dr. Ford also mentions generic substitution as a stewardship strategy. Substituting generic medications for their brand-name equivalents is always good practice as a cost-savings method. Another important stewardship strategy is the development of clinical guidelines or pathways that incorporate the institution’s specific resistance data and formulary considerations. With the rise of computerized prescriber order entry, clinical guidelines can be easily incorporated to improve empiric antimicrobial use. Clinical guidelines also can integrate patient-specific data with information from the institution’s antibiogram to select the best antimicrobial regimen for each patient. Although clinical guidelines help in the selection of empiric antimicrobial regimens, streamlining or de-escalation is always necessary once culture and sensitivity information is available and patients are showing signs of clinical improvement and resolution of the infection. Dr. Ford supports the establishment of goals for the ASP that are focused on a reduction in costs as well as an improvement in resistance patterns. However, cost savings can be difficult to measure and are not the most important metric by which to gauge success of an ASP. Most hospital administrators will require a cost justification for the resources required to run an ASP. One point not mentioned by Dr. Ford is that improving resistance patterns in the hospital will likely require addressing the broader problem of antimicrobial use in the community. Antimicrobial use in the community likely is a driving factor in the development of MDROs, and drives the development of antimicrobial resistance. For a hospital-based ASP, a reduction in resistance is a metric that can be difficult to prove and may also require several years to show substantial changes. Targeted reductions in outbreaks, such as Clostridium difficile–related diarrhea, or extended-spectrum β-lactam–producing Klebsiella pneumoniae, are an excellent opportunity for ASPs to reduce focused resistance concerns. Another important goal not mentioned in the article that may be incorporated into ASPs is to decrease overall antimicrobial use. This can be measured by use of defined daily doses or days of therapy. By reducing antimicrobial use, ASPs can minimize toxicities and reduce selection of pathogenic organisms (C. difficile, vancomycin-resistant enterococci, fungal infections). An additional goal for ASPs might be to improve empiric antimicrobial use. The literature has shown that inadequate empiric antimicrobial therapy results in worse patient outcomes. Therefore, improving antimicrobial use at the start can improve clinical outcomes. Finally, Dr. Ford comments that hospitalists are in a good position to partner with the ASP team because they have incentive to reduce resource use and decrease length of stay. However, as he points out, hospitalists only care for approximately 20% to 30% of all inpatients nationally, leaving the vast majority of patients without access to hospitalist care. Therefore, the responsibility for antimicrobial stewardship will most likely fall on others. In conclusion, antimicrobial stewardship has become a critical component of hospital care. Goals should be established for each ASP account for clinical and economic aspects. The strategies used for each ASP should be specific to institutions but likely will require a combination of techniques to achieve the desired outcomes.

incorporate these measures into its initial metrics.11 LOS, for example, is a metric that has become standard at most hospitals. ASPs typically do not acknowledge this metric, mainly because it is difficult to measure and track. The argument against using LOS as an indicator of an ASP’s success often has been that it is too difficult for the pharmacy department

to equate for confounding variables from patient to patient. However, the classic scenario whereby a newer “more expensive” (when based solely on acquisition cost) drug is swapped out for a generic antibiotic illustrates how LOS should be recognized as a practical metric. When a “less expensive” drug is used, there is a “real” cost savings from

the perspective of the pharmacy because the acquisition costs for the pharmacy have decreased. Generic substitution has been the traditional model of savings and is the easiest method for hospital finance to use a marker of success. However, when a system-of-care cost is considered in lieu of purely acquisition Text continues on page 54

54 Clinical

Educational Review Text continued from page 52 TYGACIL® (tigecycline) Brief Summary See package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. INDICATIONS AND USAGE TYGACIL is indicated for the treatment of adults with complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillinsusceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis. TYGACIL is indicated for the treatment of adults with complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros. TYGACIL is indicated for the treatment of adults with community-acquired pneumonia infections caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila. CONTRAINDICATIONS TYGACIL is contraindicated for use in patients who have known hypersensitivity to tigecycline. WARNINGS AND PRECAUTIONS Anaphylaxis/Anaphylactoid Reactions Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including TYGACIL, and may be life-threatening. TYGACIL is structurally similar to tetracycline-class antibiotics and should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics. Hepatic Effects Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse events may occur after the drug has been discontinued. Mortality Imbalance and Lower Cure Rates in Ventilator-Associated Pneumonia A study of patients with hospital acquired pneumonia failed to demonstrate the efficacy of TYGACIL. In this study, patients were randomized to receive TYGACIL (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received TYGACIL had lower cure rates (47.9% versus 70.1% for the clinically evaluable population) and greater mortality (25/131 [19.1%] versus 14/122 [11.5%]) than the comparator. Use During Pregnancy TYGACIL may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline [see USE IN SPECIFIC POPULATIONS]. Tooth Development The use of TYGACIL during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with TYGACIL have shown bone discoloration. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated. Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Patients With Intestinal Perforation Caution should be exercised when considering TYGACIL monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with TYGACIL and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/ septic shock. The 6 patients treated with TYGACIL had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established. Tetracycline-Class Effects TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL. Superinfection As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken. Development of Drug-Resistant Bacteria Prescribing TYGACIL in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, 2514 patients were treated with TYGACIL. TYGACIL was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of treatment-emergent adverse reactions through test of cure reported in 2% of patients in these trials. Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in 2% of Patients Treated in Clinical Studies Body System Adverse Reactions Body as a Whole Abdominal pain Abscess Asthenia Headache Infection Cardiovascular System Phlebitis Digestive System Diarrhea Dyspepsia Nausea Vomiting Hemic and Lymphatic System Anemia Metabolic and Nutritional Alkaline Phosphatase Increased Amylase Increased Bilirubinemia BUN Increased Healing Abnormal Hypoproteinemia SGOT Increasedb SGPT Increasedb Nervous System Dizziness Skin and Appendages Rash

TYGACIL (N=2514)

Comparatorsa (N=2307)

6 3 3 6 8

4 3 2 7 5

12 2 26 18

11 2 13 9

4 3 2 3 4 5 4 5

3 2 1 1 3 3 5 5

Vancomycin/Aztreonam, Imipenem/Cilastatin, Levoﬂoxacin, Linezolid. b LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy. In all Phase 3 and 4 studies that included a comparator, death occurred in 3.9% (147/3788) of patients receiving TYGACIL and 2.9% (105/3646) of patients receiving comparator drugs. An increase in all-cause mortality has been observed across phase 3 and 4 clinical studies in TYGACIL treated patients versus comparator. The cause of this increase has not been established. This increase should be considered when selecting among treatment options. (See Table 2.) Table 2. Patients with Adverse Events with Outcome of Death by Infection Type TYGACIL Infection Type

n/N

Approved Indications cSSSI 12/834 cIAI 40/1382 CAP 12/424 Combined 64/2640 Unapproved Indications HAP 65/467 Non-VAPa 40/336 25/131 VAPa RP 11/128 DFI 7/553 Combined 84/1148

n/N

Comparator %

Risk Difference* % (95% CI)

1.4 2.9 2.8 2.4

6/813 27/1393 11/422 44/2628

0.7 1.9 2.6 1.7

0.7 (-0.5, 1.9) 1.0 (-0.3, 2.2) 0.2 (-2.3, 2.7) 0.7 (-0.0, 1.6)

13.9 11.9 19.1 8.6 1.3 7.2

56/467 42/345 14/122 2/43 3/508 61/1018

12.0 12.2 11.5 4.7 0.6 6.0

1.9 (-2.6, 6.4) -0.3 (-5.4, 4.9) 7.6 (-2.0, 16.9) 3.9 (-9.1, 11.6) 0.7 (-0.8, 2.2) 1.2 (-1.0, 3.4)

CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections. * The difference between the percentage of patients who died in TYGACIL and comparator treatment groups. a These are subgroups of the HAP population. Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis). In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see WARNINGS AND PRECAUTIONS]. The most common treatment-emergent adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with TYGACIL and comparators were either mild or moderate in severity. In patients treated with TYGACIL, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe). In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL and 6% for levofloxacin. Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%). The following adverse reactions were reported infrequently (<2%) in patients receiving TYGACIL in clinical studies: Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis Cardiovascular System: thrombophlebitis Digestive System: anorexia, jaundice, abnormal stools Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia, hyponatremia Special Senses: taste perversion Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia Skin and Appendages: pruritus Urogenital System: vaginal moniliasis, vaginitis, leukorrhea Post-Marketing Experience The following adverse reactions have been identified during postapproval use of TYGACIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Anaphylaxis/anaphylactoid reactions, acute pancreatitis, hepatic cholestasis, and jaundice. DRUG INTERACTIONS Warfarin Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin [see CLINICAL PHARMACOLOGY (12.3) in full Prescribing Information]. Oral Contraceptives Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects—Pregnancy Category D [see WARNINGS AND PRECAUTIONS] Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg·hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose. There are no adequate and well-controlled studies of tigecycline in pregnant women. TYGACIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TYGACIL is administered to a nursing woman [see WARNINGS AND PRECAUTIONS]. Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of effects on tooth development, use in patients under 8 years of age is not recommended [see WARNINGS AND PRECAUTIONS]. Geriatric Use Of the total number of subjects who received TYGACIL in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out. No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline [see CLINICAL PHARMACOLOGY (12.3) in full Prescribing Information]. Hepatic Impairment No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response [see CLINICAL PHARMACOLOGY (12.3) and DOSAGE AND ADMINISTRATION (2.2) in full Prescribing Information]. OVERDOSAGE No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of TYGACIL at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose intravenous toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD50 was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis. This Brief Summary is based on TYGACIL direction circular W10521C013 ET01, revised 09/09.

cost, additional metrics need to be considered. Obviously, calculations of cost savings are never as straightforward as one would like; factors such as patient–payer (insurance) mix and hospital capacity all must be factored into any financial model before a program’s inception. However, if the substitution of a generic antibiotic lengthened a patient’s LOS, even by 0.5 of a day, then any initial pharmacy-level cost savings would be lost.

Tailoring Treatment Substituting a less expensive drug for a more expensive one based on acquisition costs limits the ability of pharmacists and physicians to use real minimum inhibitory concentration (MIC) data from antibiograms to tailor treatment. Communication is imperative if an ASP is to effectively monitor and disseminate information between the pharmacy, the clinical microbiology lab, and the infection control department. An ideal ASP team would be comprised of an ID physician, a clinical pharmacist with ID training, an infection control professional, a hospital epidemiologist, and an information systems specialist. Smaller institutions may be unable to staff such a team, whereas larger institutions may struggle with communication and management of patient load. For an ASP to function properly, a point person able to communicate patient data to the team must be in place. Whether an audit and feedback or formulary system is in place, the impact is going to be seen first and foremost at the bedside. It is the treating physician who will require working knowledge of the institution’s protocols and the steps needed to either obtain antimicrobial authorization or to consult a specialist to discuss appropriate therapy. One particular medical specialist perfectly poised to partner with pharmacy and the ASP team is the hospitalist. Responsible for “managing” the care of a patient, the hospitalist is aware of all specialist consults and antimicrobial therapies that have been administered to the patient. Hospitalists practice almost exclusively in the hospital setting and have as their mission not to view patient care in a vacuum, as well as decreasing the hospital’s cost of overall care. Hospitalists traditionally are charged with LOS and resource utilization reduction, making them a source of data for cost-savings information that may

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Pharmacy Practice News • November 2010

Educational Review be associated with the implementation of an ASP. Hospitalists, who now care for approximately 20% to 30% of all inpatients, are perfectly suited for a partnership with pharmacy and the P&T committee.12 In consult with pharmacy and specialists, hospitalists are able to ensure delivery of the most appropriate course of therapy on an individual patient-level basis. Complete formulary restriction does not allow this new medical specialty the ability to view antibiotic selection as a system cost reduction because an improvement in patient LOS is not merely a financial benefit. If patients are treated with a targeted regimen and a shorter drug course, a resulting reduction in antimicrobial pressure might reduce not only LOS but also overall resistance.13

Conclusion The position that certain drugs need to be saved can lead to inappropriate drug therapy for the patient and may increase or shift resistance trends in the institution and lead to extended patient LOS. It will be the attending hospitalist who will oversee the implementation of de-escalation therapy, receive realtime feedback regarding MIC and culture data and traffic case data to the information specialist so that resistance trends may be monitored. Each hospital and pharmacy is best poised to judge their individual needs; however, a team approach, rather than purely a pharmacy- or specialist-driven solution should be the goal. Collaboration with hospital finance, pharmacy, ID, and hospital medicine will allow for a new team of practitioners who’s aim is to improve clinical outcomes, while simultaneously curbing antimicrobial resistance and promoting hospital fiscal responsibility.

healthcare-associated infections: annual summary of data reported to the national healthcare safety network at the Centers for Disease Control and Prevention, 2006–2007. Infect Control Hosp Epidemiol. 2008;29(11):996-1011. 5. Owens RC, Shorr A, Deschambeault A. Antimicrobial stewardship: shepherding precious resources. Am J Health Sys Pharm. 2009;66(12 suppl 4):S15-S22. 6. Rahal JJ, Urban C, Horn D, et al. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. JAMA. 1998;280(14):1233-1237. 7. Burke JP. Antibiotic resistance—squeezing

the balloon? JAMA. 1998;280(14):1270-1271. 8. Owens RC Jr. Antimicrobial stewardship: concepts and strategies in the 21st century. Diagn Microbiol Infect Dis. 2008;61(1):110-128. 9. Drew R, White R, MacDougall Cet al. Insights from the Society of Infectious Disease Pharmacists on antimicrobial stewardship guidelines from the Infectious Disease Society of America and the Society for Healthcare Epidemiology of America. Pharmacother. 2009;29(5):593-607. 10. Carling P, Fung T, Killion A, Terrin N, Barza M. Favorable Impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Contr Hosp Epidemiol. 2003;24(9):699-706.

11. Fraser GL, Stogsdill P, Dickens JD Jr, Wennberg DE, Smith RP Jr, Prato BS. Antibiotic optimization: an evaluation of patient safety and economic outcomes. Arch Int Med. 1997;157(15);1689-1694. 12. Society of Hospital Medicine. 2010 State of Hospital Medicine Report. http://www. hospitalmedicine.org/AM/Template. cfm?Section=Surveys2&Template=/CM/ HTMLDisplay.cfm&ContentID=18601. Accessed October 14, 2010. 13. Harbath S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Inappropriate initial antibiotic therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003;115(7);529-535.

All Hands On Deck … L January 15 – 19, 2011 L San Diego, California, USA L San Diego Convention Center … for the Society of Critical Care Medicine’s (SCCM) 40th Critical Care Congress, the largest multiprofessional critical care event of the year. In January, nearly 6,000 critical care professionals from around the world will come together in San Diego, California, USA, for the Critical Care Congress and its highly-regarded educational program: L cutting-edge educational sessions L hands-on workshops L compelling plenary sessions L captivating symposia

San Diego is known for its perfect temperatures, dramatic coastlines, historical architecture, vibrant downtown, world-renowned zoo, and stunning scenery. SCCM puts it all at your doorstep with hotel accommodations that are within walking distance to the Convention Center and the city’s top attractions. The USS Midway Museum, a San Diego landmark, will serve as the site of the Society of Critical Care Medicine’s 40th anniversary celebration.

References 1.

Cosgrove SE. The impact of antimicrobial resistance on health and economic outcomes. Clin Infect Dis. 2003;36(11):1433-1437.

2. Dellit TH, Owens RC, McGowan R et al. Infectious Disease Society of America and the Society of Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(1);159-177. 3. Fadheel Z. Comparison of methicillin resistance Staphylococcus-aureus carriage rate in the general population with the health-worker population. NZ J Medical Lab Science. 2008;62:4-6. 4. Hidron AI, Edwards JR, Patel J, et al for the National Healthcare Safety Network Team and Participating National Healthcare Safety Network Facilities. Antimicrobialresistant pathogens associated with

SETTING THE COURSE FOR CRITICAL CARE

56 Technology

Pharmacy Practice News • November 2010

Infectious Disease

Automation, Education Help Boost Vaccination Rates said. “Previously, it was Austin, Texas—Pneumococan automatic unscheduled cal vaccine administration order. The record would rates at Emory University indicate that the patient Hospital in Atlanta jumped needed to receive this vacdramatically after the implecine, but did not specify a mentation of a new vaccine time or date. The protocol screening protocol, investigators reported at the American Scan for ASHP flu was that, before discharge, College of Clinical Pharmacy resource page; see the nurse was supposed to p. 3 for instructions notice that and give the vacannual meeting. The new protocol included an electron- cine before the patient left the hospital. ic screening tool, nurse education and the A lot of vaccines were probably missed generation of automatic vaccine orders, just because of timing.” With the new system, pneumococcal when indicated. To assess its effectiveness, researchers randomly sampled vaccines for appropriate patients are 300 electronic medical records during a automatically scheduled for 9 a.m. on the four-month interval before and after the first day following screening. They can new protocol was instituted. Although be rescheduled at physician request, but vaccine screening rates were similar in cannot be left as “unscheduled orders”— both groups (96% pre-implementation and 99.3% post-implementation; P=0.06), vaccine administration (the primary end point) was significantly higher postimplementation: 74.2% of patients were vaccinated, versus 19.1% before the program was launched (P<0.001). “These results were surprising even to us; we had thought that vaccine administration rates would improve, but we did not expect the size of the improvement,” said lead author Jennifer Smith, PharmD, now assistant professor in the College of Pharmacy at the University of Louisiana-Monroe. “We do theorize that at least part of the increase was due to improved documentation; prior to the new protocols, it was possible that some of the vaccines were being administered but not placed in the record.” The gap in record keeping was due to the fact that, before the protocol change, pneumococcal vaccines were generally given at discharge, which might have led to some being missed in the record, Dr. Smith noted.

‘We particularly need to contrast the risks associated with vaccines with the risks associated with not getting them and the benefits that the vaccine can provide.’ —Evelyn Hermes-DeSantis, PharmD Two Screens Better Than One The revised protocols improved the hospital’s existing electronic vaccine form by splitting it into two screens; if the indications for pneumococcal vaccine were checked, a second screen specifically for that vaccine would open. “If the nurse selected no contraindications, and the patient had not been recorded as previously receiving the vaccine, the system generated an automatic scheduled order,” Dr. Smith

a specific time must be associated with the order. At the same time, the hospital implemented an electronic “dashboard” system on its intranet, which offers a real-time view of which patients have had their vaccinations, which ones have been screened and which haven’t, colorcoded by unit and by patient room, to assist nurse managers and pharmacists in tracking vaccine administration. “I was very impressed with the improvement in the vaccine administra-

tion rate,” said Evelyn Hermes-DeSantis, PharmD, clinical professor at the Ernest Mario School of Pharmacy at Rutgers University in Piscataway, N.J. “Everyone is trying to figure out how to best maximize pneumococcal vaccine compliance. We have set our vaccines up as a scheduled vaccine on the day of discharge. As soon as the discharge order gets implemented and placed, this automatically comes up as a discharge order and it is

administration. (For resources on how to get a vaccination program started in health systems, visit www.ashp.org/flu).

Patient Education Can Help In addition to vaccine screening and administration, patient education to minimize vaccination refusal also is a key component of any successful vaccination program, be it hospital-based pneumococcal vaccines or childhood immunizations in a

‘If population immunity continues to break down, the door will open wider to diseases that we thought had been vanquished by vaccines.’

—Paul Offit, MD, MPH

given at that point in time.” Vaccinations are increasingly becoming part of the pharmacist’s bailiwick. All 50 states and the District of Columbia now give pharmacists the authority to administer influenza vaccines, and some states allow other types of vaccination as well. The American Pharmacists Association (APhA) estimates that, in 2009, pharmacists administered more than 16 million doses of vaccines. About 14 million of the vaccinations were for influenza, and were primarily administered by community pharmacists, according to Mitch Rothholz, chief of staff at the APhA. That concentration in community pharmacy is not surprising, given the proliferation of walk-up locations in chain and independent drugstores. Nevertheless, hospital-based pharmacists also can be directly involved in vaccine

pediatrician’s office. Dr. Smith noted that in the Emory protocol, although vaccine administration increased, so did refusal, from 9% to 18% (P=0.02). A recent pertussis epidemic in California underscores the hazards of vaccination refusal. More than 4,200 cases of whooping cough have been recorded in the state so far this year, the highest in 55 years. Of the nine patients who died in the epidemic, most had not been vaccinated. In 2008, 11 children in the San Diego area were infected with measles after an unvaccinated child returned home from Switzerland with the infection. In 2009, five children in Minnesota contracted Haemophilus influenzae type B meningitis—a vaccine-preventable infection—and one died. “We are at a crossroads,” said vaccine expert Paul Offit, MD, MPH, professor of pediatrics at the University of Pennsylvania, Philadelphia. “If population immunity continues to break down, the door will open wider to diseases that we thought had been vanquished by vaccines.” “Addressing patients’ health literacy is another key component of any vaccination campaign,” Dr. Hermes-DeSantis said. “We particularly need to contrast the risks associated with vaccines with the risks associated with not getting them and the benefits that the vaccine can provide. Today’s generation often forgets our history of how horrible these communicable diseases were in the past.” Dr. Hermes-DeSantis advises pharmacists to identify the specific concerns each patient or family member may have about vaccines. “Is it their child getting a fever? Is it putting chemicals in their body? Is it ‘I get the flu shot every year, I don’t need another vaccine?’ You need to identify their baseline level of knowledge and use education to take them from that point to where you want them to be.” —Gina Shaw

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Baxter’s Enhanced ENLIGHTENED High-Resolution Bar Code delivers patient safety with greater ease of use

edication error prevention continues to be an area of increased focus in relation to patient safety. The use of bar code scanning technology in the hospital offers healthcare administrators an opportunity to manage this issue at the point of care; studies suggest that a successful bar code scanning program implemented in a hospital can reduce the incidence of medication dispensing errors.1 In one recent study conducted in an academic medical center, the use of a bar code electronic medication administration system provided a ≈ (p<0.001) 51% relative reduction in the rate of potential adverse drug events due to nontiming errors, compared to pre–bar code system installation.2

Nevertheless, a 2009 survey by the American Society of Health-System Pharmacists found that bar code assisted medication administration systems were implemented in 28% of surveyed hospitals.3 While this number represents an upward trend over the past few years, the relatively slow uptake of bar code technology in hospitals may be due in part to a few significant obstacles to successful usage. These obstacles include the lack of appropriate training; work flow redesign; resistance by hospital staff; and issues related to technology, such as problems with software and hardware.1 Keenly aware of the impact that technological issues can make upon hospital processes, Baxter recently introduced an enhanced version of its ENLIGHTENED High-Resolution Bar Code (ENLIGHTENEDHRBC) for its small- and large-volume parenteral solutions portfolio. ENLIGHTENEDHRBC technology, originally introduced in February 2003, was designed to meet data management and patient safety demands with leading-edge technology. At its inception, the ENLIGHTENEDHRBC design featured two bar codes: one indicating the product lot number and expiration, the other representing the GS1 Global Trade Identification Number, or GTIN (GS1 is a type of global standardization used in bar coding). Medication Delivery Baxter and ENLIGHTENEDHRBC are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111314A 10/10

In late 2008, Baxter began working with a few customers and leading scanner manufactures, Honeywell and Motorola on updating its ENLIGHTENEDHRBC bar codes to better meet their needs. In May 2009, Baxter began its rollout of its enhanced bar code, which included a single, larger GS1 GTIN and the removal of the lot and expiration bar code to help improve success rate of first-attempt scans, decrease medication overrides, and minimize variability in scanning techniques. The result? Baxter’s work to exceed its customers’ needs has “improved an already good impression,” says David Breeze, technology systems coordinator at Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina. “The new [bar code] is definitely easy to scan; we usually pick it up on the first flash. It just flows through the system a little more efficiently with that one bar code. We are very happy with Baxter’s efforts to address this situation.” Staff at Children’s Memorial in Chicago, Illinois have experienced higher scan rates and first-attempt scans, as well as fewer medication overrides, says Dan Healy, pharmacy informatics coordinator. “I definitely see [fewer false-positive scans] on the bar code reports,” he adds. At Baystate Health in Massachusetts, Gary Kerr, director of pharmacy services, worked with Pharmacy and Nursing Informatics leaders to observe the nursing staff regarding largevolume parenteral infusions which rarely scanned. Through direct observation it was noticed that two bar codes were adjacent to each other resulting in confusion for the nurse on scanning the correct bar code. The pharmacy department collaborated with Baxter and agreed having a single bar code that featured the enhanced ENLIGHTENEDHRBC bar coding would improve scan rates. Though these new bags are in the early stages of utilization, nurses have noted that scanning is much easier with the single bar-coded bags, says Mark Heelon, medication safety specialist. Also, scanning rates associated with Baxter large volume parenterals have risen substantially, he adds. Although customers may still be cycling through Baxter products with the older ENLIGHTENEDHRBC technology, those that have begun using products with the new bar coding have noticed a positive difference. Customers are pleased with the benefits of the new ENLIGHTENEDHRBC technology; all agree that the general process of integrating bar code medication administration can be complex. “Be prepared to commit more resources than you might think,” advises Breeze. “It’s an extremely labor-intensive program to start. And contact as many institutions as you can [that] use similar software and have similar systems, and get the benefit of their experience. Every system is technically different and has its own challenges.” Yet although the integration of bar coding technology into hospital use does require work, all agree the effort is well worthwhile. Craig Jones, IV pharmacist at Boston Medical Center, a 639-bed medical academic center says “Bar coding in general has been advantageous to us because it helps…put a safeguard in place to ensure patient safety, and that we get the right drug at the right place, at the right time.” References: 1. Nanji KC, Cina J, Patel N, et al. Overcoming barriers to the implementation of a pharmacy bar code scanning system for medication dispensing: a case study. J Am Med Inform Assoc. 2009;16:645-650. 2. Poon EG, Keohane CA, Yoon CS, et al. Effect of bar-code technology on the safety of medication administration. New Engl J Med. 2010;362:1698-1707. 3. Pederson CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: monitoring and patient education—2009. Am J Health-Syst Pharm. 2010;67:542-558.

60 Technology

Pharmacy Practice News • November 2010

Medication Safety

Computers Find New Ways To Muddle Prescriptions San Diego—Punching a prescription into a computer may keep a doctor’s sloppy penmanship from misleading the dispensing pharmacist, but a new study suggests that it also can lead to its own dangerous mishaps. “There’s a big conversion to electronic prescribing going on today,” said David W. Bates, MD, professor of medicine at Harvard Medical School, in Boston. “But there is a downside to the technology, as we found: Nearly any electronic

4 3 x 2

prescribing application can create new errors as well as prevent them.” Dr. Bates and his colleagues decided it would be useful to catalogue these new errors in an effort to minimize them in future computerized prescriber order entry (CPOE) applications. The team reviewed and classified 3,898 electronic prescriptions received by commercial outpatient pharmacy chains across Florida, Arizona and Massachusetts during fall 2008. Of those, 452 (11.6%) con-

tained errors, with rates ranging from 5% to 17.4%, depending on the prescribing system used, the investigators reported at the 2010 annual meeting of the American Society of Anesthesiologists (abstract 183). The most common error was missing information (60.8%), typically an omitted duration, dose or frequency. A lack of clarity (15.9%), conflicting information (15.7%) or an incorrect prescription (7.6%) comprised the remaining errors.

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More than one out of every three errors, a total of 163, were deemed dangerous enough to classify as a potential adverse drug event. Of those, 95 (58.3%) were deemed significant, and 68 (41.7%) were considered serious, the investigators reported. “We were a bit surprised to see [error] rates this high,” Dr. Bates said, “although rates are still considerably higher in nonelectronic systems.” (See sidebar.)

Older Is Not Better Depending on the type of drug being prescribed, handwritten drug orders “can really be a problem,” said Matthew Grissinger, RPh, director of error reporting programs at the Institute for Safe Medication Practices in Horsham, Pa. For example, “some drug names out there look the same only when hand-written. An electronic system can prevent those kinds of [potential errors],” Mr. Grissinger said. “On the flip side, new errors are often introduced.” As for why CPOE systems are prone to their own errors, Mr. Grissinger cited several potential causes. For one, doctors usually are unaccustomed to entering orders into a computer system and it may be easy for them to pick the wrong drug or dose. “How would a pharmacist know if a patient is supposed to get a drug at 10 mg, but the doctor picked 20 mg? The pharmacist wouldn’t even know if the right drug was picked off the list [on the CPOE screen] or not,” he said. The new CPOE systems also contain comment fields where doctors have been known to enter contradictory notes or “correct” a previous error they made in the data entry form. “Pharmacists are not used to having to look at this comment field and recognize that it could be contradictory,” he pointed out. “There’s a lot going on here,” Mr. Grissinger added. “There’s the design of the system, but also the training of physicians and pharmacists.” Dr. Bates, too, pointed to the importance of internal consistency checks, including the setting of default doses. “If a patient is going to be given one tablet daily for seven days, then the amount dispensed should be seven,” he said. “Unfortunately, many applications don’t do that.” Although dosing can be particularly dangerous, such as with antibiotics, perhaps the most important consistency checks relate to kidney issues, added Dr. Bates, noting a number of medications that should have doses modified for patients with renal insufficiency. Stop alerts for physicians are one potentially powerful safeguard offered by electronic systems. A soft stop alert will

Technology 61

Pharmacy Practice News • November 2010

Medication Safety More Data on CPOE Versus Prescription Pad

lthough CPOE systems are not foolproof, there is still a large body of evidence showing that the technology is far superior to handwritten prescriptions. Much of that evidence has been documented in the inpatient setting. But outpatient data are slowly trickling in. A study conducted earlier this year, for example, underscored CPOE’s effectiveness in communitybased, outpatient health care clinics. In the study (J Am Med Inform Assoc 2010;17:78-84), investigators examined the accuracy of more than 10,000 drug orders that were processed before and after CPOE system implementation. They found that the frequency of errors declined from 18.2% to 8.2%— a reduction in adjusted odds of 70% (odds ratio [OR], 0.30; 95% confidence interval, 0.23-0.40). The largest reductions in errors were those attributed to illegible handwriting (97%), use of inappropriate abbreviations (94%) and missing information (85%), the researchers noted. On the inpatient side, even more data favor CPOE—but with some of the studies echoing the pluses and minuses of the findings seen in the Bates et al study. British researchers, for example, compared CPOE with handwritten drug orders in an ICU. The rate of medication errors with CPOE was significantly lower (117 errors from 2,429 prescriptions, 4.8%) than with handwritten drug orders (69 errors from 1,036 prescriptions, 6.7%; P<0.04). However, two of the errors with CPOE led to patient harm, requiring an increase in hospital length of stay. Additionally, three computerized prescription errors that were caught before they reached patients could have led to permanent harm or death, the investigators reported (Crit Care 2005;9:R516-R521). —L.P.

pop up on the computer screen to warn a doctor about possible drug–drug interactions, whereas a hard stop alert is intended to restrict them from moving forward with a contraindicated prescription. A recent study published in the Archives of Internal Medicine (2010; 170:1578-1583) comparing both types of CPOE alerts noted that gains in patient safety had been modest, largely due to frequently overridden soft alerts. In the study, only 13.5% of pharmacistbased (i.e., soft) alerting succeeded in prompting prescribers not to reorder concomitant warfarin and trimethoprim-sulfamethoxazole, versus 57.2% of the harder alerts issued. But the stricter alerts also postponed care for some patients who urgently needed the potentially risky combination. In fact, the study was stopped early

‘It’s not just about getting rid of handwritten prescriptions. Electronic prescribing should be about guiding you to make [the] right decisions, so people aren’t having to call you to make changes and the patient isn’t harmed.’ —Matthew Grissinger, RPh due to these dangerous delays. “It’s not just about getting rid of handwritten prescriptions. Electronic prescribing should

be about guiding you to make [the] right decisions, so people aren’t having to call you to make changes and the patient isn’t harmed,” said Mr. Grissinger. “We’ve got a fragmented health care system out there. All of these systems, including those from labs and

pharmacies, need to work together to provide information. We need to have higher expectations.” About 20% of drug prescribers in the United States are currently using computer-generated prescribing applications, with complete conversion anticipated within the next five years. There are approximately 200 CPOE applications on the market, Dr. Bates said. “Each has its own strengths and weaknesses—an important factor to keep in mind when planning a CPOE rollout.” —Lynne Peeples

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62 Technology

Pharmacy Practice News • November 2010

Bar Coding

Opting To Outsource Bar-Code Packaging Requires Care Atlanta—To outsource or not to outsource medication packaging—that is the question facing more and more hospital pharmacy services, and it is one that needs careful consideration, Noel C. Hodges, RPh, MBA, said at the unSUMMIT for Bedside Barcoding 5th annual meeting. Outsourcing—a formal arrangement between a health care organization and an outside company to obtain selected pharmaceutical services or comprehensive management of the organization’s pharmacy—can be very useful under certain circumstances, said Mr. Hodges, who is director of pharmacy services for HCA Central Atlantic Supply Chain in Richmond, Va.

I don’t have control over the process. I think you walk a very fine line when you start to outsource.” The pharmacy service also runs a risk for becoming highly dependent on the vendor. This can make it difficult to end the relationship if that becomes necessary. “You can become so reliant on that vendor that it becomes operationally and cost-prohibitive to exit that agreement,” Mr. Hodges said.

Cost Is a Major Driver The deciding factor for his health system was reducing pharmacy operating costs. “We wanted to take advantage of the technical expertise that the vendors have. As pharmacists, we should be focusing on our core competency, which is managing medication therapy and managing patients, and not on packaging or repackaging drugs or putting on bar codes. So we really wanted to move

(RFP) is critical, Mr. Hodges noted. “The RFP is formalized and low-risk because you are putting your thoughts on paper, identifying your objectives, and listing specific details and criteria. Then you ask the vendors to tell you exactly what they can do, based on that information. It is a very good process to use.” There are 15 steps in the RFP. It starts with the establishment of an evaluation committee that reviews what is currently done, identifies areas of opportunity, establishes the scope of services and products that are needed, and then identifies possible vendors. When this information is in place, bid documents are developed and sent to the vendors. The resulting bids are analyzed and evaluated by the committee until a vendor is selected. At this point, a letter of understanding is sent to accept the bid. This is followed by a complete contract containing terms and conditions.

‘As pharmacists, we should be focusing on our core competency, which is managing medication therapy and managing patients, and not on packaging or repackaging drugs or putting on bar codes.’

—Noel Hodges, RPh, MBA

“In cases where you have a lack of staff and you can’t hire extra people, it makes sense to outsource the labor component. Or, you might want to lower your cost. In our case, it really was about lowering our packaging cost. You may want to improve quality, you may want to use it because of regulatory reasons, or because it can provide a competitive advantage. These are some of the criteria that the American Society of Health-System Pharmacists uses,” said Mr. Hodges, who developed a centralized bar code–packaging operation for his health system. But there can be problems with outsourcing, he said, speaking from experience. “Going through the process of outsourcing, only to learn that you’re not actually saving money, is one. You’ve got the proposal, you think it looks great on paper, and then you don’t actually realize those savings.” Losing control over critical activities can be another problem. “When we outsourced packaging, I thought we lost control over a very critical process. If a mistake is made, I’m accountable; yet

back to what our core competencies were and invest our pharmacy labor dollars in direct patient care activities,” he said. Once the decision is made to outsource, factors to consider in choosing a vendor include the scope of its services, the ordering and receiving process, the order turnaround time, multiple shipping exchanges, compromised integrity of the product, loss and diversion, and quality of the finished product. “Our first vendor could only do a limited amount, typically just some oral solid stuff. They weren’t really able to help us with the liquids and controlled substances, and some of the respiratory drugs, that need packaging,” Mr. Hodges said. “We also started scanning patients in our radiology department and we needed bar-coded contrast [agents]— that presented another challenge.” The order turnaround time is another important concern. “Turnaround time is the biggest complaint that we have from all of our hospitals. Traditionally, the pharmacy would order today and receive tomorrow. In this model, you order today and you’re probably going to get [the drug] in five to seven days, and that’s a big difference in managing inventory.” When it is time to bid on a product or service, using a Request for Proposal

Once the contract is in place and starts to be executed, it is critically important to monitor the service that the vendor is providing, and also to keep track of savings and compliance. “You can’t just stop after you get the contract in place. The last two steps are vital, not only to the existing contract but to any future contracts that you will do,” Mr. Hodges said. He added that the RFP process has limitations. “It’s not perfect. It is resource-intensive. It is all in writing and requires documentation, so it takes some time to put that together. You can have templates, but you still need to go through the process.”

Leave Negotiating To the Experts When the time comes to negotiate the specific terms of the contract, it’s best to leave that to the experts, Mr. Hodges advised. “The pharmacy can serve as the subject matter expert, but let your contracting department handle the negotiations and contract development—that is what they do best.” He admitted that he used to get involved in negotiating contracts, but eventually realized that he didn’t do a very good job. “Those folks do it for a living, so let them handle it. And besides, there’s

going to be a winner and a loser in that process and ultimately you are going to work with the winner. If you are going through the rigors of contracting and negotiating, and then you’ve got to turn around and work with that vendor, you just want to make sure that there’s not a lot of hard feelings during that negotiation process. So let them do their job. They can hate your contracting department but they’ll love your pharmacy department.” Managing inventory levels becomes crucial when packaging is outsourced. Keeping close track of ordering, delivery and billing is also vital. “Make sure that you are managing your inventory levels. Now that you are going from packaging in-house to the outsource vendor, you may have a long lag time before you get products, and you want to make sure your inventory levels are appropriate,” Mr. Hodges said. Staff needs may change and should be anticipated, he added. “We had about 4 FTEs [full-time equivalents] that we had to re-allocate when we went from in-house packaging to outsource packaging, and we had to make sure we understood what their new roles were going to be.” Finally, keep track of any savings from outsourcing on a monthly basis, Mr. Hodges said.

RFPs Definitely the Way To Go Seth Kuiper, PharmD, lead pharmacy automation specialist at the Cleveland Clinic, in Ohio, said he “strongly agreed” with Mr. Hodges’ statement on formulating a complete RFP for all contracts. “An organization is best served by having a plan and knowing what it needs to achieve that plan. Putting this in writing and having vendors’ written responses helps decision making and also helps to avoid ambiguity in the future,” Dr. Kuiper told Pharmacy Practice News. “We use outsourced packaging sparingly at the Cleveland Clinic. Most outsourced items are items that we either cannot get in unit-dose packaging or cannot be packaged using our highspeed packager or desktop packager because of safety concerns, such as teratogenicity, or packager limitations,” Dr. Kuiper said. He added that outsourcing repackaging is costly, “both in terms of contractual obligations and in cost wrapped up in extra inventory. As [Mr. Hodges] mentioned, there is a significant turnaround time associated with outsourced packaging, forcing us to maintain additional days’ stock.” —Fran Lowry

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64 Spotlight on Blood Factors

Pharmacy Practice News • November 2010

IVIG FAQ

The Beneﬁts of SC Immune Globulins Q: Why should I consider subcutaneous immune globulins now? A: Using the subcutaneous route to

administer immune globulin (Ig) therapy is not new,1 but new subcutaneous Ig products, particularly the newest product, Hizentra immune globulin subcutaneous 20% liquid (CSL Behring),2 offer clinicians and patients an improved subcutaneous option.

ring),3 is a 16% concentration, but it does not have the same bioavailability as IV products. In contrast, Hizentra has a 20% concentration, making it easier to attain the desired IgG levels, with lower volumes and time. Although peak IgG levels are lower with subcutaneous injections than with IV injections, the overall trough levels are about 1.3 times higher with subcutaneous

mary immunodeficiency disorders, it is not unusual for IV access to become increasingly difficult. Use of small or fragile peripheral veins may lead to extravasations, multiple IV punctures, and, potentially, phlebitis at the injection site. It may be desirable to consider subcutaneous administration as an alternative for these patients. Additionally, in general, slowing the rate of infusion

Table. Comparison of IV and Subcutaneous Ig Administration Characteristics

Product Type

Concentration

Dose

Weight, kg

Total Grams and Volume

Max Volume Per Injection Site, mL/h

Number of Injection Sites

Total Infusion Time, h

Intravenous

10%

500 mg/kg every 4 wk

35 g = 350 mL

1 (IV)

3-4

Subcutaneous

16%

35 g × 1.37a/4=12 g

75 mL

1.9

Subcutaneous

20%

35 g × 1.53a/4=13.4 g

67 mL

1.34

bioavailability adjustment factors

Ig, immune globulin; IV, intravenous

Subcutaneous Ig administration has been used with intravenous Ig (IVIG) products, but there have been problems with this approach. Although the IV products were safe for use, the maximum concentration of these products was, and still is, 10%. Attempts to super-concentrate lyophilized products resulted in very viscous solutions that were difficult to reconstitute and inject. For the 10% products, the volume required for use was too high for most patients to tolerate. The first FDA-approved subcutaneous product, Vivaglobin (CSL Beh-

administration. Using the bioavailability adjustment factors as demonstrated in the Table, the areas under the curve are similar for both methods of administration. With 1.0 considered 100% bioavailable, other methods of administration require an adjustment in dose to achieve the equivalent blood level. Three additional reasons to consider subcutaneous administration are: 1) the patient has poor venous access, 2) the patient has intractable adverse reactions, and 3) to improve the patient’s quality of life (QoL). For patients receiving IVIG chronically for indications such as pri-

IVIG Medication Safety: A Stepwise Guide to Product Selection and Use

can minimize adverse events associated with IVIG. Although this may extend the time of administration considerably, it often allows the patient to tolerate the infusion. However, in some situations, such as rigors or aseptic meningitis, the slower rate of infusion may not lessen the adverse reaction. In these cases, subcutaneous administration is associated with a reduced rate of adverse reactions, possibly because of the lower peak levels of IgG and lower rate of absorption.4 Another reason to consider subcutaneous administration is related to the overall time and expense of the related

IVIG FAQ is authored by Jerry Siegel, PharmD, FASHP, Clinical Associate Professor, College of Pharmacy, The Ohio State University Medical Center, Columbus. Dr. Siegel welcomes readers’ questions on IVIG therapy: Jerry.Siegel.rx@gmail.com

Jerry Siegel, PharmD

health care. Although IVIG products are administered once every 3 to 4 weeks, the time of infusion is longer with IV administration than with subcutaneous administration. In addition, travel time to an infusion center, potential caregiver time for transportation, and overall time lost from work or school may impact patient and caregiver QoL. At-home administration of subcutaneous Ig can be done at a time selected by, and convenient for, the patient. Children and adults can be taught to self-administer subcutaneous Ig and experience minimal adverse reactions. Less disruption to normal routines is highly desirable to improve the QoL of patients with chronic disorders. Physicians, pharmacists and nurses should become aware of the subcutaneous Ig options that are available so they can have a positive impact on patient care by identifying opportunities for subcutaneous product consideration.

References 1. Moore ML, Quinn JM. Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century. Ann Allergy Asthma Immunol. 2008;101(2):114-121. 2. Hizentra (prescribing information). Kankakee, IL: CSL Behring; 2010. 3. Vivaglobin (prescribing information). Kankakee, IL: CSL Behring; 2010. 4. Gardulf A, Hammerstrom L, Smith CI. Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet. 1991;338(8760):162-166.

This new review by Jerry Siegel, PharmD, is designed to help clinicians maximize the safe use of IVIG and to reduce the adverse events associated with the infusion of these products. Several algorithms guide the decision-making process and address all major IVIG products currently in use.

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66 Spotlight on Blood Factors

Pharmacy Practice News • November 2010

Q&A

The Pharmacist’s Role in Managing Hemophilia Scott W. Savage, PharmD, MS, clinical manager, Department of Pharmacy, and clinical assistant professor, UNC Eshelman School of Pharmacy at University of North Carolina (UNC) Health Care, North Carolina Cancer Hospital, Chapel Hill, talks with Pharmacy Practice News about the role pharmacists can play in the management of patients with hemophilia.

PPN: What is the role of the pharmacist in managing patients with hemophilia? Dr. Savage: I think it is twofold. In a hospital environment, the pharmacist is in a position to assist the physician and the nursing staff as medication managers for patient care. Once the physician prescribes the product, the challenge for the pharmacist is to make sure that the product is prepared correctly and is monitored correctly for safety and efficacy. If you are in an academic medical center that is associated with a hemophilia center, obviously there is a lot of expertise. But if you are in a community hospital, pharmacists have the potential to be on the front lines to assist general medicine practitioners, to help them gain knowledge of the disease and the alternatives for treatment. The issue of hemophilia treatment and its relationship with a specialty pharmacy depends, of course, on where the patient lives. Without a doubt, if you are a patient who lives in an area where there is a recognized hemophilia center, I think that’s the type of care that all hemophiliacs should receive. But if you are not in such an area, then you have to establish the knowledge base of your primary physician. Can that physician and hemophilia patient establish the care that is needed from a pharmacy perspective with some of the specialty pharmacy chains? Most specialty pharmacies have the products that patients need. They also have access to a pharmacist who will answer questions 24/7. That is always a good thing to have. There is definitely a place for the specialty pharmacy on the patient care team on the outpatient side that your corner drugstore may not offer. There’s no reason not to get that level of pharmacy services. Patients can work with their physicians to make sure they have the appropriate pharmacist contact and/or nursing contact that they need. Some specialty pharmacies will involve nursing time as well. If the patient has a factor product that requires admin-

istration, does the specialty pharmacy offer nursing services, such as in-home nursing services? These all are things to think about. PPN: What are some of the problems that a patient would encounter, where the pharmacist could help?

Part 2 of a Two-Part Series. Part 1 (September Issue): New Treatment Options for Coagulopathies. To access, visit www.pharmacypracticenews.com.

Pharmacists in community hospitals can be on the front lines to help general medicine practitioners gain knowledge of hemophilia and the alternatives for treatment. Patients in rural areas who do not have access to such specialized centers need to be able to ask: “Is the physician comfortable, do I have nursing care, do I have pharmacist care, do I have counseling care?” The patient has to make sure that those things are there. Hemophilia centers have the ability to make sure that the patient has those options available to them. I would not say, however, that one practice site is better than the others. It’s more about understanding the need of care and what questions to ask. It’s making sure that they have the contacts to empower their care.

Dr. Savage: Pharmacists can help with any questions related to the medications, such as preparation and even the challenges of assuring the dosing that the patient is getting—by that I mean what is written on the prescription—is accurate. Many of the products used to treat hemophilia can vary in units or activity of the factor. PPN: What do you feel is the best site of care for hemophilia patients? Dr. Savage: I’m not sure if I could categorize one as the “best,” but there are benefits to accessing care via a freestanding hemophilia center. These centers typically have multidisciplinary teams to provide essential services to the patient. The prescriber is comfortable with the disease and the treatment of the patient. He or she is at a level of competency where there is a level of comfort in doing what is needed to treat

these patients, not only understanding their day-to-day needs but also what complications can arise over time. From a nursing care perspective, it is important to have outpatient services so that patients can get the nursing care they may need. Finally, does the hemophilia center have the capability of dispensing the medications? If it does not, can it recommend nationally known specialty pharmacy vendors who offer such services? Something that is definitely needed in this patient population is psychosocial or family counseling. This helps assure an understanding of what the risks for injury are throughout the life span, what are the risks for having a family or having children—in short, life planning. Counseling on the psychosocial issues that hemophiliacs experience is crucial. It is a benefit to have that total support blanket of all the health care practitioners.

PPN: You are in North Carolina, in Chapel Hill. You must see a variety of patients. Dr. Savage: Yes, we are a freestanding hemophilia center—UNC Harold R. Roberts Comprehensive Hemophilia Diagnostic and Treatment Center. We have a large group of patients who we care for from the time of birth until death. It definitely is a family environment. We have a lifelong relationship with our patients. We see kids go from newly diagnosed to productive members of society to having a family, all the time being appropriately cared for. We offer a unique service to patients. In fact, many patients will relocate to this area just for this care. The National Hemophilia Foundation articulates what the total care team should consist of. We have hematologists, pediatricians, nurses, social workers, physical therapists, orthopedists, dentists and pharmacists. All of these specialties are available at comprehensive hemophilia centers. —Compiled by Fran Lowry

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Richard J. Hamilton, MD, FAAEM, FACMT This guide continues its tradition as the leading portable drug reference packed with vital drug information to help clinicians make better decisions at the point of care. Each edition is meticulously peer-reviewed by experts. It details typical drug dosing (both FDA-approved and offlabel uses), available trade and generic formulations, metabolism, safety in pregnancy and lactation, relative drug pricing information, Canadian trade names and an herbal and alternative therapies section. PPN1110

70 Up Front

Pharmacy Practice News • November 2010

Awards ‘Doing this research based on genotype, we can now say that we know why albuterol is not working so well for a given patient.’

ASHP HONORS continued from page 11

when physicians manage hypertension,” said Gail Ardery, PhD, RN, a senior research assistant at the College of Pharmacy. “The pharmacists were simply more successful by focusing on this single disease state. I think it’s a matter of attention, knowledge and driving toward a goal.”

Student Researcher Finds Genetic Role for CF Patients’ Albuterol Response Ever wonder if polymorphisms in the gene for β2-adrenergic receptors might affect the response of cystic fibrosis patients to albuterol? Neither had Brittany Traylor, PharmD. But the first-year resident at the University of Arizona’s School of Pharmacy Practice and Science in Tucson did have an interest in genetics, so when

—Brittany Traylor, PharmD assistant professor Eric M. Snyder, PhD, decided to investigate the gene’s role in cystic fibrosis (CF), he tapped Dr. Traylor to collect and analyze the data and prepare the manuscript. The results were deemed worthy of this year’s ASHP Foundation’s Student Research Award. “Brittany was nominated for this research award because she played a remarkable role” in conducting the study, Dr. Snyder said. “Because of her commitment to research, clinical practice and education, Brittany has a bright future as a pharmacist.” Albuterol has long been known to stimulate the β2-adrenergic receptors, resulting in mucociliary clearance in

the lungs, but some CF patients respond better than others to the drug. Their study examined whether two common variants in the encoding gene might explain differences in response. They recruited 20 healthy subjects and 18 subjects with CF and conducted tests of the influence of albuterol on the subjects’ diffusing capacity of the lungs for carbon monoxide, alveolar-capillary membrane conductance, pulmonary capillary blood volume and peripheral oxygen saturation. Among healthy subjects, they found no difference on those measures at baseline or in response to albuterol according to genetic variations of the gene, ADRB2, at amino acid 27. Within

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the CF group, however, they found differences in lung diffusion and peripheral oxygen saturation according to the two genetic variants significant enough to play a potential role in treatment options. “Doing this research based on genotype, we can now say that we know why albuterol is not working so well for a given patient,” Dr. Traylor said. “Further research might show that different types of beta agonists might be better able to help these patients who don’t respond to shortacting medication.” The paper is being submitted to a journal under both of their names, but the ASHP Foundation award is all Dr. Traylor’s. “I was really surprised when I got the call from ASHP to say I had been selected for the award,” she said. “I am really proud to be honored.” —Dan Hurley

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Dosage

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Oral administration of tablets without regard to meals 15 mg

30 mg

• Titrate at intervals of ≥24 hours, up to a maximum of 60 mg/day • Fluid restriction during the first 24 hours of therapy with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium and should be avoided – Fluid restriction with SAMSCA may increase risk of dehydration and hypovolemia • Patients can and should drink in response to thirst

SAMSCA® (tolvaptan), the first and only oral vasopressin V2-receptor antagonist that increases free water clearance and serum sodium concentrations 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%). 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 previous page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. US Patent Nos: 5,258,510 and 5,753,677. Samsca is a trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

June 2010

0710A-0776A