July 2011 digital edition of Pharmacy Practice News by McMahon Group

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Ye La rv t oy eda Bre Se t e a pa a s pa ke ge r 38 k r in te re st .

The Pharmacist’s News Source

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Volume 38 • Number 7 • July 2011

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ISMP pushes for more flexibility

CMS 30-Minute Rule On Drug Administration Seen as Risk to Patients

he Centers for Medicare & Medicaid Services’ (CMS) rule requiring that medications be given within 30 minutes before or after their scheduled time has prompted many health-system nurses to adopt rushed and risky workaround practices that increase the potential for serious errors, according to the Institute for Safe Medication Practices (ISMP). ISMP and other groups, including the American Society of Health-System Pharmacists (ASHP) and the American Pharmacists Association (APhA), have asked CMS to implement a more flexible approach to administration timeliness, one that retains the 30-minute rule for time-critical medications but allows others a wider dosing latitude. At least one hospital already has taken the more flexible approach to drug administration, despite the risk for being

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in this issue Up Front

Capsules Video-based learning may be best tool for teaching pharmacy technicians.

Clinical ASHP Summer Meeting: Initiatives reduce ‘alert fatigue’ during drug order verification.

Pain Medicine New clues emerge for understanding opioid abuse.

Operations & Mgmt

Leadership Building the next generation of pharmacy leaders.

see 30-MINUTE RULE, page 6

Technology

Each Member of BCMA Team Should Be a Key Player in Patient Safety Louisville, Ky.—The most important factor in implementing a successful bar code medication administration (BCMA) program is ensuring that all players in the process feel that they are accountable to one another. Moreover, that sense of shared responsibility can’t only be present in the rank-and-file staff tasked with implementing BCMA. “It has to be present all the way up to the top at the executive level,” said Karla M. Miller, PharmD, BCPP, director of pharmacy at the Hospital Corporation of America (HCA), in Nashville, Tenn. For BCMA to work, a multidisciplinary team that works well together is essential, Dr. Miller said at the 2011 unSummit for Bedside Barcoding meeting. All members must feel a sense of responsibility not only for

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see ACCOUNTABILITY, page 50

Bar Coding VA initiative slashes BCMA scanning errors.

FDA, Joint Commission poised to issue new guidances following ISMP Alert

Medication Safety

More mentoring nuggets from Ernie Anderson Jr.

A Call to Action on Sterile Compounding Gains Traction

hree months ago, the Institute for Safe Medication Practices (ISMP) called on regulatory agencies to increase oversight of compounding pharmacies in the wake of nine deaths in Alabama linked to contaminated admixtures. It now appears that at least two of those agencies—the FDA and the United States Ph ar mac opeia (US P)— are beginning to respond, according to interviews with several top officials. The deaths have been attributed to an outbreak of Serratia marcescens in outsourced total parenteral nutrition solutions shipped by a single compounding pharmacy. In the ISMP’s Medication Safety Alert! on the outbreak, the group recognized the importance and practicality of contracting with compounding pharmacies.

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Educational Review

Pharmaceutical Issues in Patients Receiving Enteral Nutrition insert after page

REPORT Flebogamma® DIF: A Highly Purified Intravenous Immunoglobulin See insert after page 28.

see TPN POLICY, page 8

After Heart Transplant, Hospital Admissions Often Are Drug-Related San Diego—Drug-related problems were determined to be the primary cause of hospital admissions in 40% of heart transplant patients treated at a Missouri center, according to a study presented at th e annual meeting of the International Society for Heart and Lung Transplantation. More than half of the drug problems were deemed to be preventable,

reported co-investigator Kristin Repp, PharmD, clinical pharmacy coordinator at Saint Luke’s Northland Hospital, in Kansas City. Drug-related problems in the 300 patients studied were classified by type, pharmacologic class and impact on hospital length of stay (LOS). The researchers used the Adverse Drug Reaction Scale (Naranjo algorithm) to rank the reactions according

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see TRANSPLANT, page 44

New Product CareFusion announces the launch of their Pyxis EcoStation™ system. See page 53.

Products for pharmacy automation, medication management, and more. See insert after page 20.

DANGEROUS

PHARMACEUTICAL WASTE. Is your facility at risk?

Hospital pharmacies throughout the United States purchase well over 4 billion hazardous materials each year, generating more than 84,000 tons of hazardous pharmaceutical waste.1 The EPA has stepped up enforcements to ensure that pharmaceutical waste is managed safely from the moment it is generated and finally disposed.2 Pharmacists are responsible for the “cradle to grave” management of pharmaceuticals. CareFusion now offers Pyxis EcoStation™ system, a proprietary, automated waste management system that helps hospitals identify, classify, sort and segregate pharmaceutical waste, while providing pharmaceutical waste records to facilitate tracking and regulatory controls of more than 180,000 National Drug Codes.

Learn how CareFusion can help your hospital measurably improve pharmaceutical waste management by visiting carefusion.com/rxwastemanagement.

Pyxis

1 Fein, Adam J. Pembroke Consulting, Inc. 2010-11 Economic Report on Retail and Specialty Pharmacies, December 2010. 2 Accessed from http://www.epa.gov/oecaerth/civil/rcra/rcraenfstatreq.html. © 2011 CareFusion Corporation or one of its subsidiaries. All rights reserved. EcoStation and Pyxis are trademarks or registered trademarks of CareFusion Corporation or one of its subsidiaries. DI2904 (0611)

Pharmacy Practice News • July 2011

Up Front 3

Capsules

surf

For Pharmacy Technician Learning, Let’s Go to the Video!

JULY 2011

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Leadership in Pharmacy: A Cheat Sheet of Best Practices 2. Management of Warfarin Therapy (educational review) 3. Pain Contracts: Are They Really Worth the Hassle? 4. Tainted TPN Cases Put Focus on <797> Rules 5. New Reporting Tool May Provide Better Measure of Hospital Safety Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here

‘We need to do a better job

first

of developing dynamic leaders in our profession who can stand in front of administrators and clinicians and represent pharmacy.’’ —Michael O’Neal, RPh

See article, page 36

he pen may be mightier than the sword in some battles, but in the arena of pharmacy technician learning, video is the ultimate weapon, a new study suggests. In the study, pharmacy technicians who were taught the basics of unit-dose medication dispensing via a video nearly doubled their ability to discuss what they were taught compared with conventional, textbased learning. The text—an article chosen from a major pharmacy reference—described the procedural view of unit-dose medication dispensing. The video, created in Apple iMovie, depicted how staff members complete the unit-dose process from start to finish. Following a review of each teaching tool, 20 technicians were asked to discuss the unit-dose process with a pharmacy manager. After reading the article, 45% of the technicians were able to successfully discuss the process and how it benefited patients, versus 85% of the technicians in the video-watching arm of the study. The latter group also reported a better understanding of their role in support of the pharmacist, according to the investigators, led by Daniel I. Shifrin, of the Everest Institute in South Plainfield, N.J. A second video, featuring pharmacy technician students, was also part of the study and included instructions on a variety of pharmacy tasks. The students displayed enthusiasm as they focused on the various functions, according to Mr. Shifrin. Major benefits included: 1) pharmacy technician students teaching others in their own words and 2) the availability to traiΩn 24 hours a day, he noted. “I’ve been involved with training and teaching for many years and have found this approach to be one of the most innovative methods,” Mr. Shifrin told Pharmacy Practice News. “Using staff members to make training videos is quite effective,” he noted, adding that this technique “could be easily adapted to needs of a hospital pharmacy.” —Kevin Enright

To Scan 2-D Bar Codes in PPN: 1.

Download the FREE Microsoft Tag Reader application through your smartphone browser.

Open the Tag Reader and let it focus on the bar-code image to instantly access related materials and/or Web sites.

The Book Page

McMahonmedicalbooks.com Pharmacology Flash Cards, Edition 2 George M. Brenner, PhD See page

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Michele McMahon Velle, MAX Graphics/Creative Director

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Volume 38 • Number 7 • July 2011 • pharmacypracticenews.com

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

Internal Medicine

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What Sets Us Apart , Brings You Together

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SIGMA, SIGMA Spectrum and the SIGMA logo are trademarks of SIGMA International General Medical Apparatus, LLC. Baxter is a trademark of Baxter International Inc. KLAS is a trademark of Klas Enterprises, LLC. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 450434 06/11

Best in KLAS for Smart Pumps-LVP

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“The wireless capability, the drug library, and the user friendliness of the SIGMA pump set it apart for us. It was much more user friendly than the other pumps — Director of Pharmacy we looked at.” 2

“Best in KLAS” for Smart Pumps – LVP in the “2011 Top 20 Best in KLAS Awards: Medical Equipment & Infrastructure” Report, www.KLASresearch.com.© 2 Smart Pumps 2011: The FDA Steps In – Providers Reactions to Market Turmoil, www.KLASresesarch.com.© 2011 KLAS Enterprises, LLC. All rights reserved.

6 Policy

Pharmacy Practice News • July 2011

Medication Safety

30-Minute Rule continued from page 1

cited by CMS for noncompliance with the 30-minute rule. “Clinically, it’s not important that we give a digoxin exactly at 10 o’clock or at plus or minus 30 minutes,” said ISMP president Michael R. Cohen, RPh, MS, ScD. “It will have no material effect on the patient whatsoever if we give it at 11 o’clock or 9 a.m. In fact, nurses tell us that is how patients give it at home– anytime they remember to take it.”

and immunosuppressants to prevent organ rejection. Medications dosed more frequently than every four hours would also fall into this category. A one-hour dosing window would apply to drugs scheduled more often than once daily and up to every four hours, and those given daily, weekly or monthly would have a two-hour dosing window. Exceptions to the tiered approach

Changes recommended by ISMP appear in its final Acute Care

Guidelines for Timely Administration of Scheduled Medica tions, published in May. It proposes a tiered dosing strategy, retaining the 30-minute requirement for medications that need to be given at specific times for optimal effect and safety, including opioids for chronic pain and palliative care, rapid-acting insulins

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Volume 38 • Number 5 • May 2011

Hematology/Oncology Pharmacy Edition

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Psychiatric Medication in this issue Error Rates Slashed Via Clinical Hem/Onc Pharmacy e-Prescribing Initiative Japan nuclear crisis shakes U.S. drug supply.

omputerized prescribing and error reporting systems combined to reduce the rate of medication mistakes in the psychiatric unit at an inner-city Baltimore hospital by more than 80%, report Johns Hopkins researchers. The findings, published in the March issue of the Journal of Psychiatric Practice Practice, represent the largest study to date evaluating such an intervention in the field and extend evidence of the benefit of electronic prescribing in reducing drug errors across all areas of medicine ((J Psychiatr Pract 2011;17:81-88). “Whenever there is a human interface with medication, there is a possibility of error,” said Geetha Jayaram, MD, MBA, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, in Baltimore. Everything from indecipherable handwriting and inaccurate transcriptions, to miscalculations and administration mistakes, even

Opti

mize d for wide scr disp een lays

•

see DRUG ERRORS, page 71

Critical Care Statins in the ICU: ready for prime time?

Pain Medicine Pain contracts: are they really worth the hassle?

n advanced e-learning program offers pharmacists the opportunity to build the skills needed to be tomorrow’s clinical and management leaders, while also earning advanced credit toward master’s degree programs. The program is the result of an alliance between the ASHP Foundation’s Center for Health-System Pharmacy Leadership and GlobalHealth Education, an online educational services firm based in West Palm Beach, Fla. The initiative is an extension of efforts that began in 2008, when the center enrolled its first Pharmacy Leadership Academy (PLA) class. That first class came about in response to research that suggested a dramatic crisis in leadership within health-system pharmacy. “The world has only gotten more complicated

•

see ACADEMY, page 64

Helping Cancer Patients Quit Smoking Pays Off

28 52

Operations & Mgmt

Leadership in Action It shouldn’t be lonely at the top.

Technology

Telepharmacy Rural health-system reaps benefits of round-the-clock drug order review.

Policy

FDA Watch

Online Academy Prepares Future Pharmacy Leaders

A call to action for the profession

Finally, a new drug for melanoma approved.

Educational Reviews

Drug Interactions in Post-Kidney Transplant Patients See page

Optimizing Warfarin Therapy Insert after page

Quality-of-Life Implications for Patients With Hereditary Angioedema Who SelfAdminister C1 Inhibitor

Salt Lake City—Smokers who develop cancer may think it is too late to improve their health by kicking the habit. That is a dangerous misconception that caregivers need to correct, according to Jane Pruemer, PharmD, BCOP, professor of clinical pharmacy practice at the James L. Winkle College of Pharmacy, University of Cincinnati Barrett Cancer Center, in Ohio. “You really need to stress that if they continue to smoke, they are at a greater risk for developing a second

maligancy, worse outcomes in general and poorer quality of life [QoL] than patients who manage to quit.” But merely highlighting those risks is not enough. Pharmacists who encounter such patients “should consider it their duty to also help them quit,” Dr. Pruemer said at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). In fact, quitting smoking can be one of the single most effective strategies to improve outcomes in

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see QUIT SMOKING, page 9

In ER-positive breast cancer …

Presurgical Endocrine Therapy May Be Clue to Tumor Resistance Salt Lake City—The way a tumor responds to a short course of endocrine therapy given before scheduled surgery in women with estrogen receptor (ER)–positive breast cancer may predict how the malignancy will respond to long-term adjuvant

antiestrogen treatment, according to new research presented at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). Just two weeks of treatment with letrozole in presurgical ER-positive

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see BIOMARKERS, page 23

See page 32

New Product Watson to Launch Nulecit , a generic version of Ferrlecit

SEVENTH ANNUAL CONFERENCE

More Coverage: ✜ MTM program a boon to cancer patients

✜ Tips for enhancing rituximab safety, efficacy

See page

✜ Navigating cancer pain and drug dependency

11 12 22

�

would include stat and “now” doses, first doses and loading doses, one-time doses, PRN medications and drugs Scan for more ISMP information on administered at specifimpact of ic times to ensure opti30-minute rule mal peak-trough serum levels. ISMP made it clear, however, that “for now, hospitals will still be held accountable” for complying with the 30-minute rule.

Widespread Support for More Flexible Approach The ISMP guidelines were developed with input from an advisory panel made up of almost two dozen representatives from pharmacy, nursing and medicine. Organizations including the Joint Commission, the American Nurses Association, the American Association for Respiratory Care, ASHP and APhA provided comments on ISMP’s draft document that helped to shape the final recommendations. CMS spokesman Tony A. Salters said the agency met with ASHP staff last fall and has had “ongoing discussions” on the issue with ISMP. “We have carefully reviewed both their draft and final recommendations and indicated in advance of receiving their final document that we might want to discuss concerns further, but nothing definite has been planned or scheduled yet,” he said in an email. The review is part of CMS’s plan to update its interpretive guidelines on hospital medication administration, which includes the 30-minute rule. Nurses’ concerns about pressures to conform to the rule were strongly expressed in an ISMP survey last year that drew more than 18,000 responses, the largest-ever outpouring of replies to a poll by the medication safety group. Many nurses reported that management pressures were forcing them to resort to risky shortcuts or even deceptions for the sake of appearing to comply—noting, for example, that a drug had been administered at a certain time when in fact it had been delayed or given earlier than scheduled or withdrawing medications long before scheduled administration to avoid traffic jams at the dispensing cabinet. Dr. Cohen said ISMP “has even run across situations where hospital management was actually taking disciplinary action against nurses who didn’t meet the rule.” Other unsafe practices resulting from time pressures that were reported by nurses in a September 2010 issue of the ISMP newsletter included the following: • Bypassing pharmacy review of orders • Administering medications before conducting a physical assessment of patients and/or checking vital signs,

Pharmacy Practice News • July 2011

Policy 7

Medication Safety lab values, weight and allergy status • Skipping bar code scanning • Scanning medications at the correct time using patient charts/extra ID bracelets but administering them when able.

Impact on Pharmacy The CMS 30-minute rule has a potentially negative impact not only on nurses and their patients but also on pharmacy practice. Dan Sheridan, MS, RPh, medication safety pharmacist at Marion General Hospital, in Marion, Ohio, noted that “a nurse who can’t get the medication administered within 30 minutes of the scheduled time will often call the pharmacy and ask to have the medication rescheduled. This adds complexity to the medication system and increases the risk of error.” If CMS does amend its interpretive guidelines to allow some drugs to be administered in a more flexible time frame, ISMP and ASHP emphasize that it should be up to individual hospitals to develop their own policies and procedures and determine which medications should be treated as time-critical ones. Bona E. Benjamin, RPh, director of medication-use quality improvement at ASHP, noted that “ASHP’s Best Practices encourage hospitals to develop policy for standard dosing times as well as the deviations that are allowable by policy. An effective survey method for assessing timely administration would be to look at whether the hospital is following its own policies.” Ms. Benjamin echoed Dr. Cohen, stating that while ASHP “supports CMS efforts to ensure timely medication administration, giving a dose outside of the 30-minute window doesn’t always mean that patient care is compromised. In fact, depending on the medication, there may be little or no correlation between the time a particular dose is given and patient outcome.”

The medical center’s medication timing policy was validated partly by a search of patient records for potential harms associated with “outliers”—drugs administered outside of 30 minutes as well as those given beyond the one-hour limit. Dr. Guglielmo said the pharmacy– nursing team that conducted the search found that in almost every case it did not matter clinically if a drug was given within 30 minutes. He added, however, that they had detected a potential for harm if the one-hour window was missed, “but even then not totally provable.”

UCSF’s one-hour policy conflicts with the CMS’s 30-minute rule and places the institution at risk for citation in the event of a Medicare audit. Dr. Guglielmo said if that occurred “we would say, ‘OK, but we’re going to disagree with you. This is not consistent with good practice, and in fact may harm [patients] because of the intense pressure on nurses to feel as if every single medication has to be given within a 30-minute window—which it does not.’” Dr. Guglielmo cited two examples to show why the 30-minute rule should

not apply to all medications: the first a one-daily order for a docusate stool softener, such as Colase, which could be administered two hours later than scheduled without any negative effect, and the other a fluoroquinolone, such as ciprofloxacin, which must be administered at a precise time to avoid any overlap with an antacid that would result in a “huge problem with significant outcomes. Those are two extremes that tell you why ‘one size fits all’ doesn’t work.” —Bruce Buckley and Joan Buckley, RN

WE’VE SPENT

18 YEARS

8 MONTHS AND12 DAYS

FIXATING ON ACCIDENTS THAT OCCUR

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

In Defiance of CMS, UCSF Extends Dosing Window Even before the ISMP weighed in on the 30-minute rule, some medical centers developed policies that give nurses a wider latitude for administering medications. The University of California, San Francisco (UCSF) Medical Center, for example, has extended the dosing window for most drugs to an hour before or after the scheduled time. B. Joseph Guglielmo Jr., PharmD, associate director of pharmaceutical services at the UCSF Medical Center, said the one-hour timing recommendation was developed by the institution’s pharmacy–nursing committee and approved as a policy at higher administrative levels, included the Pharmacy & Therapeutics Committee and the Executive Medical Board.

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8 Policy

Pharmacy Practice News • July 2011

Medication Safety

TPN POLICY continued from page 1

But it put particular pressure on the FDA to develop a more aggressive plan for guarding against future fatalities. “Since the early 1990s, [the] FDA has been aware of multiple problems with compounded preparations that have resulted in recalls, patient injuries and deaths,” the alert stated. “However, when we communicated with the FDA recently to discuss [the events in Alabama], no one could clearly articulate how the agency regulates compounding pharmacies.” In response to the alert, FDA spokeswoman Shelly Burgess said that the FDA has the authority to inspect pharmacies but defers to the states with respect to routine practice. “Compounding pharmacies are regulated by federal and state laws. [The] FDA makes every effort to cooperate with states in investigating compounding pharmacies and typically defers to state authorities for the dayto-day operation of traditional pharmacy compounding,” she said. But the FDA doesn’t appear to be deferring all aspects of sterile compounding oversight: Pharmacy Practice News has learned that guidance from the FDA is expected to be released later this year. The FDA’s Center for Drug Evaluation and Research Guidance Agenda for 2011 notes two forthcoming documents, “Good Pharmacy Compounding Practices for Sterile Drug Products” and “Outsourcer Pharmacy Operations Compliance Policy Guide” in the category “Current Good Manufacturing Practices (CGMPs)/ Compliance.” Forthcoming guidance from the Joint Commission is also anticipated, but will address sterile compounding, not outsourcing practices. “In order to improve evaluation of sterile compounding, the Joint Commission is updating its surveyor guidelines in this area, taking into account revisions to USP <797>,” said Paul M. Schyve, MD, the Commission’s senior vice president. “Once the guidelines are updated, they will be reissued to the surveyors. Updated guidelines will also be provided to the field.” Dr. Schyve added that by policy, the Joint Commission evaluates health care organizations against standards that have gone through the Commission’s own standard-setting process, “and not to standards from other organizations.”

State Boards of Pharmacy Wrestling With <797> How each state board reacts to the call for action will be up to them, said Carmen Catizone, MS, RPh, DPh, executive director of the National Association of Boards of Pharmacy in Mount Prospect, Ill. He added that state boards are already contending with implementing changes to USP Chapter <797>.

“Compounding pharmawith them, auditing them cies will be regulated regardand physically visiting them less, and they will still have to to understand what they are meet state requirements,” he doing, how they are doing it said. “If [ISMP] is mandating and why they are doing it,” Scan to access FDA and state board oversight, ASHP Foundation’s he said. “A lot of pharmacists there is a problem there with new web-based tool think that outsourcing limits for evaluating venresources to get out to every dors of sterile par- liability when it doesn’t.” pharmacy and check what they enteral products. Although monitoring outare doing, what procedures sourced services can be timethey use, their quality control, etc.” consuming, labor-intensive and expenMr. Catizone said that hospital phar- sive, such oversight is one of the responmacy directors and others who deter- sibilities of the profession, Mr. Kastango mine when and how to outsource ser- said. Likewise, pharmacists must know vices like sterile compounding share what they are monitoring, he added, in accountability. “If there is an error stressing that it is important for pharlike the one in Alabama, and a hospi- macy directors not only to understand tal is contracting with a compounding USP Chapter <797> but to know what pharmacy, both [the hospital and the their state boards require of vendors, compounding pharmacy] are going to as well. “We go to vendors because be responsible for that error,” he said. they present themselves as skilled and “Whatever the standards are that the knowledgeable, but ignorance is no state and the hospital have set for phar- excuse for breaking a law,” he said. “For macy, the director should make sure that you to be able to go to any vendor, you the contracted pharmacy meets those have to have confidence in what you are standards. Directors need to ask ques- asking for.” tions and remember that they are not Mr. Kastango said that compounding obligated to do business with someone.” pharmacies should provide meaningful Eric S. Kastango, MBA, RPh, FASHP, responses to hospitals with whom they member of the 2010-2015 USP Sterile wish to work. “Ask the vendor what that Compounding Expert Committee and vendor is doing to protect your patients president of Clinical IQ, a pharmacy con- and prevent an event like what happened sultancy in Florham Park, N.J., agrees in Alabama,” he said. “They should be that pharmacy directors must also step forthcoming in key performance indicaup. According to Mr. Kastango, who tors in their operations. The quality concontributed to the ISMP alert, hospitals trol measurements can’t be just a bunch and pharmacy directors are responsible of numbers meant to look important and for their choice of outsourced services. not give you a sense of what goes on.” “Hospitals should be qualifying their According to Bona E. Benjamin, vendors. They should be in contact BSPharm, director of medication-use

A List of Musts for Compounding Pharmacy Vendors

ealth systems that are considering using outside vendors for sterile compounding solutions can glean several useful tips from ASHP guidelines on the practice. One of the ASHP’s primary recommendations is to ask vendors to submit a request for proposal (RFP) that includes specific information on areas of operation that can have a direct impact on patient safety. For example, the RFPs should include: • Assurance that all pharmacists and pharmacy technicians employed at the compounding facility are licensed as required, with verification that they are in good standing on file and available for review • Documentation of the results of all accreditation or regulatory surveys conducted of the compounding pharmacy’s sites, including copies of any significant regulatory actions brought against the facility • Details on the facility’s quality management programs, including those targeted to cleaning and validation, staff training and competency assessment • A demonstrated commitment to continually integrating technology and knowledge to improve patient safety • A risk assessment program to ensure that medication errors are not introduced by new or increased outsourced compounding activities • Assurance that the compounded medications are compatible with the client’s medication administration devices (e.g., bar-code labeling, smart pumps, etc.) For more guidelines on contracting with an outsourcing compounding pharmacy, scan the 2-D bar code on this page.

quality improvement at the American Society of Health-System Pharmacists (ASHP), compounding pharmacies must also back their own work. “Obviously you can’t be there to watch them every day. They need to stand behind their products,” she said. “Although you need to do your due diligence in selecting the company, their best advertisement is that they can deliver the product they promised because if they can’t, others can.” Sterile compounding is an either/ or proposition, Ms. Benjamin added. “There are no shortcuts in this regard. A product is either sterile or it’s not,” she said. “Sterile compounding is a very high-risk procedure, given that the product is going directly into the body. It is labor-intensive, both in practice and in facilities management, and you would anticipate that this requires a high level of resources committed to education and quality control.”

Advocating for Oversight Ms. Benjamin said that ASHP offers guidance for pharmacy directors tasked with outsourcing sterile compounding as part of its best practice recommendations. “‘ASHP Guidelines on Outsourcing Sterile Compounding Services’ goes into detail about what to look for to make sure that a company is reputable and reliable.” The ASHP Research and Education Foundation also offers help on the outsourcing front. Late last month, the group announced a new web-based tool for evaluating outside vendors of parenteral product preparation services. To access the tool, visit www.ashp foundation.org/SterileProductsTool or scan the 2D bar code on this page. Mr. Catizone encourages pharmacy directors who seek assistance to contact their state board of pharmacy, as well. “Most boards of pharmacy are receptive to pharmacists calling for guidance or education,” he said. “In situations where a pharmacy seeks to outsource, a discussion with the state board about what the hospital should [do to monitor] quality and what the pharmacy director should look for in a compounding pharmacy would be a great starting point.” —Terri D’Arrigo

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omputerized prescribing and error reporting systems combined to reduce the rate of medication mistakes in the psychiatric unit at an inner-city Baltimore hospital by more than 80%, report Johns Hopkins researchers. The findings, published in the March issue Practice, represent of the Journal of Psychiatric Practice the largest study to date evaluating such an intervention in the field and extend evidence of the benefit of electronic prescribing in reducing drug errors across all areas of medicine ((J Psychiatr Pract 2011;17:81-88). “Whenever there is a human interface with medication, there is a possibility of error,” said Geetha Jayaram, MD, MBA, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, in Baltimore. Everything from indecipherable handwriting and inaccurate transcriptions, to miscalculations and administration mistakes, even

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16 Clinical

Pharmacy Practice News • July 2011

Medication Safety

Reducing ‘Alert Fatigue’ Helps Avoid Dangerous Distractions Denver—Eliminating insignificant alerts from medication order verifications may allow pharmacists to focus their attention on warnings that could actually impact patient safety, suggests a preliminary study presented at the American Society of HealthSystem Pharmacists Summer Meeting. In their poster (17-M), the researchers described how they reduced the rate of non–value-added, often annoying

alerts by about one-third. “It started with our staff telling us that they were so overwhelmed with the volume of alerts that they found themselves ignoring both important and unimportant ones,” said lead author Brian Pinto, PharmD, assistant director of medication policy and clinical informatics at The Johns Hopkins Hospital, in Baltimore. So Dr. Pinto and his team decided to implement strategies that

might prevent this “alert fatigue.” After collecting baseline frequencies, they enlisted pharmacists to mark alerts that they felt were least crucial. Highlighted alerts that subsequently were also deemed insignificant by a 30-member panel of clinical pharmacy specialists were programmed for suppression in the order-verification system. Based on the initial data, the researchers found a large number of alerts triggered by missing

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or invalid National Drug Code (NDC) numbers. After suppressing these messages, the total number of NDC alerts decreased from 1,977 in July 2010 to 285 in December 2010. But a number of alerts marked as unnecessary still remained, including 57 different drug interactions or allergy-alert pairs. The expert panel agreed on suppressing 55 of them. Although concurrent use of selective serotonin reuptake inhibitors and nonsteroidal anti-inflammatory agents can result in an increased risk for bleeding, for example, the team decided that this common combination was not a serious enough threat to warrant an alert that could be distracting in many instances. In the end, the new filter trimmed the rate of alerts by one-third—from 150,902 of 176,595 orders (85%) to 107,770 of 206,124 orders (52%). The researchers do not yet have hard numbers on how this reduction impacted patient safety or workflow, but an ongoing informal survey suggested that pharmacists are satisfied with the adjustment. Furthermore, Dr. Pinto noted that there were no instances where review of a medication error found a relationship with an alert that had been suppressed.

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Jeremy Lee, PharmD, manager of clinical pharmacy services at Palomar Pomerado Health in Escondido, Calif., has led similar efforts to limit alerts to those that were deemed clinically significant. Before the initiative, 24 drug-interaction alerts were firing per 100 orders. That number is now down to one. Allergy alerts have never been a major problem at Palomar Pomerado Health, remaining at around one per 100 orders, but duplicate medication alerts continue to cause trouble: 40 alerts per 100 orders. The pharmacy has yet to identify an effective workaround strategy. “As far as drug-interaction alerts go, I know that our pharmacists are responding more consistently and reliably than they used to,” Dr. Lee said. “There’s a good sense that what we’ve put in place has dramatically changed care.” What’s more, Dr. Lee noted that satisfaction among the pharmacists has also improved since the initiative. “We don’t want to flash decision support in someone’s face,” added Dr. Pinto. “We want to build systems smart enough so that alerts don’t even have to show up. That’s the end game.” “I don’t think we’ll ever get away from these alerts, at least in the short term,” he said. “But this is a step toward improving the signal-to-noise ratio for our staff so that they can focus on important patientcare issues.” —Lynne Peoples

Pharmacy Practice News • July 2011

Clinical 17

Pain Medicine

Opioid Prescribing Patterns Hold Clues to Abuse, Misuse T

wo articles published in a recent issue of the Journal of the American Medical Association highlight potentially problematic prescribing patterns for opioids among younger patients and patients refilling prescriptions in the United States. The studies aimed to explain the increased use and abuse of opioids in recent years and make recommendations on how to resolve these complex issues. In a research letter, the team of authors from the University of Pennsylvania and the National Institute on Drug Abuse reviewed data from the Vector One: National database from SDI Health (Plymouth Meeting, Pa.), that gathers prescription information from more than half of the retail pharmacies in the United States (JAMA 2011;305:1315-1321). After analyzing the data, the researchers pointed to several possible contributors to the high rate of opioid analgesic abuse. Of all opioids prescribed, physicians wrote the most prescriptions (45.7% or 36.4 million) for patients between ages 40 and 59 years and for those between 10 and 29 years (11.7% or 9.3 million). The researchers described the younger group as “the most likely to abuse drugs and develop addiction.” More than half of the opioid prescrip-

tions were dispensed to patients who had already filled another opioid prescription in the past month. Most of the prescriptions (84.9%) were for products containing hydrocodone and oxycodone, and were administered over two to three weeks. During the past decade, there was a fivefold increase in patients admitted to substance abuse programs for opioid addiction, the researchers noted. While the authors acknowledge that opioids are among the most effective options for managing chronic pain, they note that recent increases in opioid prescribing and related “increases in abuse and overdoses” underscore the need for pain practitioners to understand the effects that current prescribing patterns have on patient health and the legal implications of these practices. “Given the known side effects from inappropriate prescribing, use and storage, we can expect even worse public health and safety problems if physicians, pharmacists, patients and the government do not work together to retain appropriate availability and reduce unwanted side effects,” said Thomas McLellan, PhD, one of the lead authors of the two articles and director of the Center for Substance Abuse Solutions in the Department of

Psychiatry, University of Pennsylvania School of Medicine, in Philadelphia. The second article, a commentary written by the same team of authors, offers recommendations for “best practices” for prescribing opioids (JAMA 2011;305:1346-1347). The authors support adopting guidelines developed by the American Academy of Pain Medicine as well as implementing standardized screening procedures and special provisions for managing pain in patients at highest risk for abuse and dependence. They also urge the pain community to agree on guidelines for the use of nonpharmacologic options and the administration of short- and long-acting opioids while also establishing “reasonable limits” on prescribed doses and duration of therapy. The authors also recommend that pain practitioners develop guidelines for urine screening, treatment agreements, patient contracts and state prescription drug monitoring programs (to “reduce doctor shopping”). Finally, they believe the pain community must develop standardized criteria for refilling and/or discontinuing opioid prescriptions. According to Dr. McLellan, pain specialists and primary care physicians have had “constructive” solutions for managing the risk for abuse and misuse of opioids; however, he added, “for the

most part” these procedures have not been implemented.

Pharmacists Advocate A Team Approach Susan Y. Kim, PharmD, and Ilene B. Anderson, PharmD, senior toxicology management specialists at the California Poison Control System, in San Francisco, called the problem of prescription opiate and opioid abuse “a new epidemic.” Although abuse of these potent pain medications “has emerged as a key drug problem in all age groups,” the abuse is a particular concern among teenagers and young adults, the toxicologists reported in the January 2011 online edition of the American College of Chest Physicians’ Pulmonary, Critical Care, Sleep Update. Given the inherent toxicities of opioids and their associated medical and psychiatric adverse effects, the authors added that “it is important to maintain clinical vigilance” for the signs of opioid abuse. Those signs include a history or evidence of exposure (e.g., access to a prescription opioid by the presence of a labeled bottle or via pharmacy records); presentation of classic clinical symptoms (coma, apnea and miosis); rapid reversal of symptoms via naloxone administration; and a positive urine drug test. —Brian P. Dunleavy

In Brief

Overdoses of Popular Painkiller Send Thousands to ER Each Year

Study: ‘No Safe Window’ for NSAID Use in Heart Disease Patients

on–abuse-related overdoses of acetaminophen products have led to more than 78,000 emergency department (ED) visits per year, and the majority of these overdoses are intentional, according to a new study from the Centers for Disease Control and Prevention (Am J Prev Med 2011;40:585-592). The study analyzed data from the National Electronic Injury Surveillance System from Jan. 1, 2006, through Dec. 31, 2007, to estimate the number of annual ED visits that occurred nationwide for non–abuse-related acetaminophen overdoses. ED visits related to abuse of acetaminophen products were not included in the study. The study found three main causes for acetaminophen overdose among ED patients. Most overdoses (69.8%) were selfharm attempts, with the highest rate occurring among patients aged 15 to 24 years. Unsupervised ingestion by children younger than 6 years accounted for 13.4% of the overdose-related ED visits. The remaining 16.7% of

overdoses were attributed to accidental misuse of over-the-counter products in order to achieve greater pain relief. “Because these data are based on ED records, it is often difficult to determine exactly what motivated the patient—if they had a premeditated plan to end their life with an overdose or if the overdose was an impulsive act,” Daniel Budnitz, MD, medical officer at the Division of Healthcare Quality Promotion, said in a press release. Taken correctly, acetaminophen is safe and effective, but the margin between a therapeutic and a dangerous dose is actually quite small. A toxic dose depends on the person’s age, weight and liver function, but in general, people should not take more than 4 g of acetaminophen per day, and taking 7 g or more can lead to a severe overdose if not treated. People who take acetaminophen continually should probably alternate with another pain medicine, like ibuprofen. Individuals who have taken an overdose of acetaminophen should call the National Poison Control Center (1-800-222-1222), follow their advice and, if directed, go to the ED for an evaluation. The good news is that with prompt treatment, most patients fully recover. —PPN Staff

he short-term use of nonsteroidal antiinflammatory drugs (NSAIDs) could pose serious danger to individuals with preexisting heart disease, according to a new study. Most NSAIDs were associated with a significantly increased risk for recurrent myocardial infarctions and death, said researchers. Despite contraindications in patients with existing cardiovascular disease, many are still given short-term courses of NSAIDs. Based on their results, the researchers did not recommend the use of NSAIDs, either short- or long-term, for patients who had previous heart attacks. “Our results indicate that there is no apparent safe therapeutic window for NSAIDs in patients with prior heart attack,” said Anne-Marie Schjerning Olsen, MB, lead author of the study and research fellow at Copenhagen University in Hellerup, Denmark.

The study (Circulation 2011:123:2226-2235) included a group of patients (n=83,677) older than age 30 years who had suffered heart attacks during a 10-year period. Researchers reported a 45% increase in risk for death and recurrent heart attacks within as little as one week of NSAID therapy. The number increased to 55% after three months of treatment. Although almost all NSAIDs were linked to an increased safety risk, the traditional NSAID diclofenac was associated with an almost three-times-higher risk than any of the other NSAIDs studied. Researchers also noted that the use of over-the-counter NSAIDs was unlikely to have a major impact on the study results. Researchers suggested that in the event that NSAID therapy is necessary, doctors should limit use to the “absolute minimum” in patients with prior heart disease. —PPN Staff

Clinical 19

Pharmacy Practice News • July 2011

Educational Review

Sedation in the ICU: Shifts and Strategies PETER J. PAPADAKOS, MD Director, Division of Critical Care Medicine Professor, Anesthesiology, Surgery, and Neurosurgery Associate Director, Kessler Regional Trauma Center University of Rochester School of Medicine and Dentistry Rochester, New York

FRANK COMPOLO, MD Department of Anesthesiology University of Rochester School of Medicine and Dentistry Rochester, New York Dr. Papadakos is on the speakers’ bureau of Hospira.

ver the past decade, intensive care units (ICUs) worldwide have adopted the goal of maintaining an optimal level of comfort and safety for critical care patients.1,2 Guidelines and protocols for the

sedation of ICU patients now also are mandated by accreditation agencies. As a result, sedation and pain management are being tracked as vital signs throughout a patient’s hospital stay.

Recently, clinicians have been faced with multiple shortages of sedative drugs, most notably propofol, which have significantly affected protocols in ICUs throughout the world. Our growing understanding of the importance of delirium in critically ill patients, and how it affects outcomes, also has influenced how clinicians plan ICU sedation and has led to shifts in how patients are evaluated and how they are treated, pharmacologically or otherwise. The large number of modern sedatives and analgesics has given critical care practitioners the ability to titrate specific agents for specific patient types, allowing patients to be comfortable throughout their stay in the ICU. This wide selection of drugs also has reduced the length of hospital stays and permitted patients to wean from therapy earlier, enabling them to participate in physical and occupational therapy. As the customized care of patients

continues to evolve, a common language is mandated for the titration and use of sedative agents. With this language also comes the development of protocols and guidelines to better use these drugs and to maximize the unique pharmacodynamic profile of each drug for individual patients. No longer is it necessary to be trapped by the all-or-none effect of very long-acting compounds that depress respiration and prolong the ICU stay. Titratable sedation also may modulate the immune system. Evidence now shows that high levels of anxiety and pain may influence morbidity and mortality, and specific compounds may modulate the release of cytokines and vasoactive compounds.1,2

Evaluation for Agitation And Anxiety Agitation and anxiety are common in ICU patients of all ages, occurring

at least once in 71% of patients admitted to a medical-surgical ICU.3 Agitation can be caused by multiple factors, such as extreme anxiety, delirium, adverse drug effects, and pain. Inadequate pain control is a significant factor in the development of agitation in critically ill patients, predominantly in the postoperative period. Insufficient pain management often results from suboptimal dosing of opioids because of concerns about respiratory depression and the development of dependence. Normally, these side effects are unlikely to develop over the short term if the medication is properly titrated to patient comfort. Hypoxemia has long been associated with agitation. It is crucial for ICU staff to monitor the oxygen levels of all patients. A partial pressure of oxygen of 60 mm Hg or lower (or oxygen saturation <90%) can contribute to agitation secondary to hypoxemia. Continues on page 20

20 Clinical

Pharmacy Practice News • July 2011

Educational Review Continued from page 19

Hypotension also can lead to agitation due to hypoperfusion of the brain. Common metabolic problems such as hyperglycemia and, especially, hypoglycemia can promote severe agitation. Uremia and elevated levels of heavy metals (eg, lead, mercury) have been identified as causes of significant agitation. Sepsis also is a common cause of agitation and must be immediately ruled out. The trauma patient with a closed head injury may have minor to severe agitation. Patients without traumatic head injury, including those with subarachnoid bleeds, also may present with agitation. Thrombotic stroke may cause agitation, and patients with brain neoplasms, brain seizures, infections such as meningitis, or air embolism also may have associated persistent and severe agitation. One of the most common problems confronting providers of critical care is a patient’s withdrawal from alcohol or other agents, including cocaine, opioids, and sedatives such as benzodiazepines; all of these substances contribute to brain injury and agitation.4 Withdrawal in cigarette smokers, who can suffer agitation from lack of nicotine, should be ruled out. Another common cause of agitation in the ICU patient is significant ventilator desynchronization in patients on mechanical ventilation. This is frequently the result of poorly set ventilators that delay response to the patient’s efforts at spontaneous breathing. The problem is becoming less common because of the availability of advanced computer-controlled ventilators and the use of graphic displays to titrate ventilation. Patients who undergo short- or long-term intubation also become agitated because of the stimulus of the endotracheal tube itself. Patients who are alert and intubated may become frustrated by their inability to communicate with staff and family and descend into a cycle of continued agitation. The ICU itself, with its high levels of technology, lights, noise, and continuous stimuli, can significantly contribute to further agitation. Numerous drug interventions, drug reactions, and drug–drug interactions, as well as drug withdrawal, all increase the incidence of patient agitation in the modern ICU. The occurrence of undesirable drug–drug interactions always should be considered when multiple drugs are being used for pain, anxiety, infection, and cardiac arrhythmias (a brief list of medications associated with agitation appears in Table 1). Even after the withdrawal of a pharmacologic compound suspected of increasing

agitation, a positive response may not be seen for several days while the drug and its metabolites clear from the patient’s system. A differential diagnosis of agitation begins with a review of the patient’s disease process, mechanism of injury, laboratory values, treatments, baseline medications, and history of chronic diseases (eg, hepatic or renal). Only after this type of rapid evaluation can the process move toward proper treatment for agitation.

Evaluation and Titration Of Sedative Agents ICU patients typically demonstrate a complex disease state and a rapidly changing spectrum of hemodynamic parameters, so the requirements to treat agitation fluctuate over time. Bedside clinicians must frequently reassess and redefine the goals of therapy, to evaluate ICU patients and their levels of sedation in real time. Tools and scales to monitor agitation in the ICU should be simple to apply yet should describe clearly graded changes between levels of sedation to allow the titration of both pharmacologic and nonpharmacologic interventions, depending on the patient’s condition. Many scales and tools for the evaluation of ICU patients described in the literature assess the level of consciousness with descriptive responses to interventions. Most ICUs use modifications of these scales and tools to develop customized unitbased scales, protocols, and guidelines. This customization is highly important to facilitate acceptance of the guidelines by all members of the health care team.

Sedation Scales The most commonly used sedation scale is the Ramsay Sedation Scale, which identifies 6 levels of sedation ranging from severe agitation to deep coma (Table 2).5 Despite its frequent use, the Ramsay Scale has some shortcomings when applied at the bedside of patients with complex problems. For example, a patient who appears to be asleep with a sluggish response to glabellar tap (Ramsay 5) also may be restless and anxious (Ramsay 1). The Ramsay Scale is simple, however, and is widely used throughout the world. The Riker Sedation-Agitation Scale (SAS) was the first scale formally tested and developed for reliability in the ICU (Table 3).2,6 The SAS identifies 7 symmetric levels, ranging from dangerous agitation to deep sedation. This scale provides descriptions of patient behavior that can assist the

Table 1. Medications Associated With Agitation in ICU Patients

Table 2. Ramsay Scale For Assessing Level Of Sedation

Antibiotics

Level

Response

Acyclovir Amphotericin B Cephalosporins Ciprofloxacin Imipenem-cilastatin (Primaxin, Merck) Ketoconazole Metronidazole Penicillin Rifampin Trimethoprim-sulfamethoxazole

Patient awake and anxious, agitated, and/or restless

Patient awake, cooperative, accepting ventilation, oriented, and tranquil

Patient awake; responds to commands only

Patient asleep; brisk response to light glabellar tap or loud auditory stimulus

Patient asleep; sluggish response to light glabellar tap or loud auditory stimulus but responds to painful stimulus

Patient asleep; no response to light glabellar tap or loud auditory stimulus

Anticonvulsants Phenobarbital Phenytoin Cardiac drugs Captopril Clonidine Digoxin Dopamine Labetalol Lidocaine Nifedipine Nitroprusside Procainamide Propranolol Quinidine sulfate Corticosteroids Dexamethasone Methylprednisolone Opioid analgesics Codeine Meperidine Morphine sulfate Miscellaneous drugs Anticholinergics Benzodiazepines Hydroxyzine Ketamine Metoclopramide Nonsteroidal anti-inflammatory drugs Theophylline

bedside practitioner in distinguishing between levels. The Motor Activity Assessment Scale (MAAS), which is similar in structure to the SAS, uses patient behaviors to describe the different levels of agitation.7 The MAAS identifies 7 levels, ranging from unresponsive to dangerously agitated (Table 4). Ely et al described a newer assessment tool for the ICU, the Confusion Assessment Method for the ICU (CAM-ICU).8 This tool is being validated in critically ill patients with delirium. It is used in combination with the Glasgow Coma Scale to evaluate highly complex, agitated

Based on reference 5.

patients. The CAM-ICU is simple to apply at the bedside and has been found to have high levels of reliability, sensitivity, and specificity. There is hope that real-time, computer-based monitors of brain function may remove human variability from the evaluation of patients with agitation. One such monitor that is popular in the operating room is the Bispectral Index (BIS, Covidien). This objective monitor is especially helpful for the deeply sedated patient receiving neuromuscular blockade. The BIS monitor provides discrete values from 100 (completely awake) to less than 60 (deep sedation) to 40 or below (deep hypnotic state or barbiturate coma) by incorporating several electroencephalographic components.9 Although the technique has been shown to be valid in the operating room, it has not been studied to any great extent in the ICU. This device should be carefully evaluated in the wide spectrum of critically ill patients in all types of ICUs.

Establishing and Implementing Sedation Guidelines/Protocols One of the most important goals for any ICU is the development of protocols and guidelines for the use of pain medications and sedative drugs. The development of such protocols requires multidisciplinary input and should be unit-specific. All staff, including physicians, nurses, and pharmacists, need to agree on which monitoring scales and tools to use and then ensure that they are

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ExactaMix® 1200 Compounder

RapidFill™ Automated Syringe Filler

Address: 9540 S. Maroon Circle, Suite 400, Englewood, CO 80112 Phone: 800-567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: marketing@baxa.com Web Site: www.baxa.com/exactamix Product Description: Product Cost: Varies by contract; call for pricing. Product Specifications: Bar-code verification, 12-ingredient ports, closed system with no sterility breaks, accurate delivery with secondary check, easy setup, high-speed delivery, electronic Y-site for high-use ingredients and lockout for incompatible ingredients as well as air occlusion detection. Disposables available on group purchasing organization contracts.

IV Automated Devices

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: info@baxa.com Web Site: www.baxa.com Product Description: The RapidFill Automated Syringe Filler reduces costs from premade syringes. RapidFill automates filling, capping, labeling and bar coding of sterile batch syringes—800/hour. It is designed to fit in the hood, and colored labels are available. Disposables are available on group purchasing organization contracts.

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SPRING/SUMMER

Other Pharmacy Automation

Other Information Systems

Talyst

Baxa Corporation DoseEdge® Pharmacy Workflow Manager

AutoCarousel / AutoCarousel HD Address: 11100 NE 8th St. Suite 600, Bellevue, WA 98004 Phone: 425-289-5400 Fax: 425-289-5401 Email: info@talyst.com Web Site: talyst.com

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: info@baxa.com Web Site: www.baxa.com

Product Description: Provides maximum medication storage in an organized, accessible and compact footprint. Its vertical design provides secure, automated storage and accurate retrieval. AutoCarousel decreases required storage space by 30% to 50% and enables customers to easily store, track and access medications.

Other Pharmacy Automation

Product Description: DoseEdge Pharmacy Workflow Manager is the first and only completely integrated system for managing IV and oral dose preparation. DoseEdge provides real-time status of incoming and in-process doses, bar-code drug verification, dose tracking and automatic dose calculation. It offers a best-practices approach for pharmacy workflow and remote inspection of pharmacy preparation steps. Also available: DoseEdge TPN for managing the parenteral nutrition compounding process, including manual additions. Visit www.baxa.com/doseedge for more information.

Productivity Software

Talyst

AutoCool

AutoPharm Enterprise

Address: 11100 NE 8th St. Suite 600, Bellevue, WA 98004 Phone: 425-289-5400 Fax: 425-289-5401 Email: info@talyst.com Web Site: talyst.com

Product Description: Delivers access-controlled refrigerated storage and automated dispensing for valuable refrigerated medications. It’s flexible, scalable and can be installed in remote locations. It provides pharmacy-grade refrigeration with passwordprotected access and enables perpetual inventory management with par-levels and order preparation.

Product Description: A powerful software platform designed to deliver improved patient safety through better medication inventory control and workflow management. AutoPharm Enterprise has multi-facility capabilities, batch dispensing, manages code (crash) carts and improved order routing. It works throughout health care systems to automate medication ordering, receiving, stocking, picking, bar coding and return processes.

Information Systems

Productivity Software

12 9

Lab Monitoring Software Cooper-Atkins Corporation TempTrak™ by Cooper-Atkins® Wireless Temperature Monitoring System Address: 33 Reeds Gap Road, Middlefield, CT 06455 Phone: (860) 347-2256 Fax: (860) 347-5135 Email: healthcare@cooper-atkins.com Web Site: www.cooper-atkins.com Product Description: TempTrak™ by Cooper-Atkins® Wireless Temperature Monitoring System offers 24/7 remote temperature, humidity, door open/close and pressure differential monitoring, stores data indefinitely and provides real-time alerts through pop-up message, email, voice alert and page. Designed exclusively for the health care environment, TempTrak™ monitors more than 60,000 pieces of equipment in more than 1,000 locations worldwide!

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Talyst AutoSplit 340B Address: 11100 NE 8th St. Suite 600, Bellevue, WA 98004 Phone: 425-289-5400 Fax: 425-289-5401 Email: info@talyst.com Web Site: talyst.com Product Description: AutoSplit® 340B is the industry leader in 340B purchase order splitting. The automated system provides full audit trails for all eligible 340B dispenses and splits. AutoSplit is easy to implement, and maximizes 340B savings while reducing program administration hours. It works with multiple wholesalers and has exportable reports to help maintain regulatory compliance.

Medication Management Systems

IV Protective Devices

Baxa Corporation

Drug Delivery Systems

Tamper-Evident Luer Lock Tip Caps

CareFusion

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: info@baxa.com Web Site: www.baxa.com

Pyxis MedStation™ system Address: 3750 Torrey View Court, San Diego, CA 92130 Phone: 858-617-2000 Email: communications@carefusion.com Web Site: www.carefusion.com

Product Description: Tamper-Evident Luer Lock Tip Caps are latex-free—no natural-rubber latex components—and made of non-DEHP materials. A three-part cap requires the user to break off the outer sleeve to dispense medication. A red ring remains, indicating the outer sleeve has been tampered with. The caps are sold in sterile packs of 10 for convenient use. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

Product Description: A leading solution in automated dispensing, the Pyxis MedStation™ system supports decentralized medication management. By combining proven Pyxis® technologies with actionable intelligence, CareFusion helps nurses and pharmacists improve workflow efficiency, medication safety and patient care.

Oral & Enteral Devices

Other IV Devices

Baxa Corporation

ExactaMed® Oral Syringes

DiscPac™ Self-Righting Luer Tip Caps

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: info@baxa.com Web Site: www.baxa.com

Product Description: ExactaMed® includes market-leading syringes and accessories for accurate and safe filling and delivery of oral medication. Unique tip design, gray piston and blue printing provide clear differentiation from IV syringes. They are the only complete range of dispensers—from 0.5 to 60 mL—that ensures precise delivery to as low as 0.01 mL. Also available: specialty dispensers for enteral, vaginal and topical medications. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

Product Description: DiscPac Self-Righting Luer Tip Caps secure easily to any size Luer syringe. Available in 12 colors, the caps are packaged individually or in convenient DiscPacs of 25 and 100. They are latex-free—no natural-rubber latex components—and made of non-DEHP material that withstands freezing. DiscPacs may be closed and stored in the hood for later use. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

IV Devices

Other IV Devices

Fluid Dispensing Systems

Baxa Corporation Repeater™ Pump Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: info@baxa.com Web Site: www.baxa.com Product Description: Tired of reconstituting, pooling and then filling syringes, dispensers and elastomeric devices? The Repeater Pump automates fluid transfer needs with high flow rates, variable speeds and delivery accuracy to as low as 0.2 mL. Disposables available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

Baxa Corporation ExactaMix® EVA Bag Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: info@baxa.com Web Site: www.baxa.com Product Description: ExactaMix EVA Bags offer better bag clarity for ease of visual inspection, attached bag clamp for convenient closure and covered addition port to keep the area protected until used. New lay-flat tube material minimizes the risk of particulates in the bag. EVA construction provides cleaner disposal for incineration. Manufacturing in North America reduces shipping time. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

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Medication Errors

Drug Name Preparer

Preparation Date/Time

Expiration Date/Time

Concentration

Codonics Safe Label System is a solution for safe, compliant, fast labeling of medication anywhere syringes are prepared. ™

SLS improves the syringe preparation workflow by automatically printing full color labels, critically important in the operating room or anywhere syringes are prepared, containing The Joint Commission required elements and ASA color and content guidelines. SLS seamlessly introduces patient safety into the workflow utilizing barcode technology. Anyone preparing syringe medications in the Pharmacy, Operating and Perioperative Rooms, or procedural settings such as the Endoscopy Suite or Cardiac Cath Lab can confirm that they have correctly selected the intended drug before drawing it up and administering it. SLS safety starts in Pharmacy. Pharmacy creates and controls the drug formulary for Codonics SLS 500i Safe Label Systems in a safe and secure fashion via its Administration Tool, making clinical pharmacists part of the perioperative/operating room team. All drug records in the system’s formulary can be edited in Pharmacy to add specific information for the use of that drug, consistent with the hospital’s policies. SLS utilizes standardized barcode technology as well as visual and audible confirmations acting as a double-check for the staff preparing and labeling syringes. Printed on each label is a 2D barcode that enables the syringe to be scanned into an Anesthesia Information Management System (AIMS) or at the bedside in the ICU. This standardization of drug labeling immediately improves patient safety, significantly decreases medication errors, and provides Pharmacy with documentation of the drugs used at each preparation station.

Call 800.444.1198 / 440.243.1198 or visit www.safelabel.com

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The Pharmacist’s News Source Hematology/Oncology Pharmacy Edition

Volume 38 • Number 5 • May 2011

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Psychiatric Medication in this issue Error Rates Slashed Via Clinical Hem/Onc Pharmacy e-Prescribing Initiative Japan nuclear crisis shakes U.S. drug supply.

omputerized prescribing and error reporting systems combined to reduce the rate of medication mistakes in the psychiatric unit at an inner-city Baltimore hospital by more than 80%, report Johns Hopkins researchers. The findings, published in the March issue of the Journal of Psychiatric Practice Practice, represent the largest study to date evaluating such an intervention in the field and extend evidence of the benefit of electronic prescribing in reducing ( Psydrug errors across all areas of medicine (J chiatr Pract 2011;17:81-88). “Whenever there is a human interface with medication, there is a possibility of error,” said Geetha Jayaram, MD, MBA, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, in Baltimore. Everything from indecipherable handwriting and inaccurate transcriptions, to miscalculations and administration mistakes, even

Opti

mize d for wide scr disp een lays

•

see DRUG ERRORS, page 71

Critical Care Statins in the ICU: ready for prime time?

Pain Medicine Pain contracts: are they really worth the hassle?

•

see ACADEMY, page 64

Helping Cancer Patients Quit Smoking Pays Off

28 52

Operations & Mgmt

Leadership in Action It shouldn’t be lonely at the top.

Technology

Telepharmacy Rural health-system reaps benefits of round-the-clock drug order review.

Policy

FDA Watch

Online Academy Prepares Future Pharmacy Leaders n advanced e-learning program offers pharmacists the opportunity to build the skills needed to be tomorrow’s clinical and management leaders, while also earning advanced credit toward master’s degree programs. The program is the result of an alliance between the ASHP Foundation’s Center for Health-System Pharmacy Leadership and GlobalHealth Education, an online educational services firm based in West Palm Beach, Fla. The initiative is an extension of efforts that began in 2008, when the center enrolled its first Pharmacy Leadership Academy (PLA) class. That first class came about in response to research that suggested a dramatic crisis in leadership within health-system pharmacy. “The world has only gotten more complicated

A call to action for the profession

Finally, a new drug for melanoma approved.

Educational Reviews

Drug Interactions in Post-Kidney Transplant Patients See page

Optimizing Warfarin Therapy Insert after page

Quality-of-Life Implications for Patients With Hereditary Angioedema Who SelfAdminister C1 Inhibitor

•

see QUIT SMOKING, page 9

In ER-positive breast cancer …

•

see BIOMARKERS, page 23

See page 32

New Product Watson to Launch Nulecit , a generic version of Ferrlecit

SEVENTH ANNUAL CONFERENCE

More Coverage: ✜ MTM program a boon to cancer patients

✜ Tips for enhancing rituximab safety, efficacy

See page

✜ Navigating cancer pain and drug dependency

11 12 22

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SPRING/SUMMER

Other IV Devices

Baxa Corporation RapidFill™ Connectors Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: info@baxa.com Web Site: www.baxa.com Product Description: RapidFill Connectors enable connections of male Luer syringes, tube sets, repeating syringes, bag ports and other containers. They are available with caps, allowing intermittent fills and capped storage. The connectors are latex-free—no natural-rubber latex components—and made of non-DEHP materials. Available 50 per case. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

For additional information about the products listed in this Buyer’s Guide, please fill out and return the reader service card on page 3 or visit our advertisers’ Web sites by scanning the following 2D bar codes with your smart phone:

Baxa http://www.baxa.com/ PharmacyProducts/

CareFusion Other IV Devices

http://www.carefusion.com/medicalproducts/medication-management/ medication-technologies/ pyxis-medstation-system.aspx

Baxa Corporation Supor® Syringe Filters Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: info@baxa.com Web Site: www.baxa.com Product Description: Supor sterile syringe filters assure quality control during sterile drug preparation. The filters feature double-Luer design for secure attachment and rapid filtration and high throughput, with low protein binding and broad drug compatibility. They allow for fast and effective filtration. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

Cooper-Atkins http://www.cooper-atkins.com/ TempTrak.asp

Talyst http://talyst.com/acutecare/

Other IV Devices

Baxa Corporation TwoFer™ Needles Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) Email: info@baxa.com Web Site: www.baxa.com Product Description: TwoFer dual-purpose Luer-lock needles allow for vented and non-vented vial additions and withdrawals. Huber points minimize the risk for coring. Reconstitution and fluid transfer applications can be performed without changing needles. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

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Pharmacy Practice News • July 2011

Educational Review

Table 3. Riker Sedation-Agitation Scale Score

Diagnosis

Description

Dangerously agitated

Pulls at endotracheal tube; tries to remove catheters; climbs over bed rail; strikes at staff; thrashes from side to side

Very agitated

Does not calm down despite frequent verbal reminding of limits; requires physical restraints; bites endotracheal tube

Agitated

Anxious or mildly agitated; attempts to sit up; calms down in response to verbal instructions

Calm and cooperative

Calm; awakens easily; follows commands

Sedated

Difficult to arouse; awakens to verbal stimuli or gentle shaking but drifts off again; follows simple commands

Very sedated

Arouses to physical stimuli but does not communicate or follow commands; may move spontaneously

Unable to be aroused

Minimal or no response to noxious stimuli; does not communicate or follow commands

resources in a busy hospital. It is important that pharmacologic colleagues—hospital pharmacists and PharmDs—be involved in the development of sedation guidelines. Pharmacists can provide guidance and educational input regarding specific pharmacodynamic profiles of individual agents. The participation of pharmacists on rounds and as members of the ICU team improves care, especially in complex cases. The implementation of guidelines and protocols has the added benefit of decreasing the use of sedative drugs, thereby enhancing hospital finances. Sedatives and narcotic agents are the most commonly prescribed drugs in the ICU and may account for a major percentage of patients’ pharmacy charges.

Review of Agents Commonly Used in Sedation

Based on references 2 and 6.

applied reliably across disciplines. It is key for staff to agree on documentation, frequency of assessment, predefined end points of therapy, and evaluation of patient outcomes. Tools to evaluate sedation and pain should be added to flow sheets placed at the bedside. The use of these types of protocols with documentation in daily practice can foster communication between disciplines and shifts. Each hospital should develop guidelines based on current pharmacologic and pharmacokinetic recommendations and supported by national standards.1,2 Several studies have shown that when ICUs institute protocol-driven sedative use, patients spend less time on mechanical ventilation and

have shorter stays in the ICU and the hospital.10 Another easy bedside strategy for optimizing outcome in patients receiving therapy for agitation is to implement a daily schedule for the reassessment and interruption of sedation infusions.11 This practice is common in the trauma–burn ICU at the University of Rochester in Rochester, NY, where daily interruptions of sedative infusions are found to decrease the duration of mechanical ventilation and decrease time in the ICU. A “sedation holiday” improves clinicians’ ability to perform daily neurologic examinations, thereby reducing the need for diagnostic studies to evaluate unexplained alterations in mental status.12 This practice also allows the maximal use of bed

Analgesics and sedatives are the mainstays of supportive patient care in the ICU, where they are the most commonly used drugs. Over the past few years, several novel, highly titratable agents have been introduced that have greatly altered patient care. The pharmacology of several of these widely used agents, along with that of classic drugs with long-use profiles, is reviewed in Table 5. Opioids Opioids are the main agents used for analgesia in the ICU. Analgesia greatly affects the need for sedation and other therapies. Unrelieved pain induces a powerful stress response characterized by tachycardia, increased myocardial oxygen consumption, hypercoagulability, immunosuppression, and persistent

Table 4. Motor Activity Assessment Scale Score

Description

Definition

Unresponsive

Does not move with noxious stimulus

Responsive only to noxious stimuli

Opens eyes or raises eyebrows or turns head toward stimulus or moves limbs with noxious stimulus

Responsive to touch or name

Opens eyes or raises eyebrows or turns head toward stimulus or moves limbs when touched or name is loudly spoken

Calm and cooperative

Does not require external stimulus to elicit movement; adjusts sheets or clothes purposefully; follows commands

Restless but cooperative

Does not require external stimulus to elicit movement; picks at sheets or clothes or uncovers self; follows commands

Agitated

Does not require external stimulus to elicit movement; attempts to sit up or moves limbs out of bed; does not consistently follow commands

Dangerously agitated, uncooperative

Does not require external stimulus to elicit movement; pulls at tubes or catheters, thrashes from side to side, strikes at staff, or tries to climb out of bed; does not calm down when asked

Based on references 7 and 16.

Clinical 21

catabolism.13 Effective analgesia also can diminish pulmonary complications in postoperative patients. Opioids are lipid-soluble and bind to opiate receptors in the central nervous system (CNS) and peripheral nervous system. At low doses, opioids provide analgesia but not anxiolysis, whereas at higher doses, they act as sedatives. All the opioids share therapeutic properties, but they vary in potency and pharmacokinetics. Although opioids can be given via several routes, the IV method is the most common in the ICU. It is important to consult with anesthesiologists when developing pathways for novel uses of these agents, such as epidural placement. When given intravenously in therapeutic doses, opioids cause sedation by clouding the sensorium, but they do not possess amnestic properties.14 Comparative trials of opioids have not been performed in critically ill patients. The selection of a specific agent depends on its pharmacology and potential for causing adverse effects. For opioids, desirable attributes include a rapid onset of effect, ease of titration, lack of accumulation of the parent drug or its metabolites, and low cost. Morphine sulfate is the preferred opioid analgesic in patients with stable hemodynamics. Its relatively low lipid solubility may result in a delayed onset of action. Morphine also induces the release of histamine, increasing the likelihood of hypotension secondary to vasodilation. Morphine-6-glucuronide, a metabolite of morphine, is excreted in the urine and may accumulate in patients with renal failure. The opiate activity of this metabolite is several times greater than that of morphine, and its accumulation in patients with renal failure has been reported to prolong narcosis. Fentanyl has the most rapid onset and shortest duration of action of the opioids, but repeated dosing may cause accumulation and prolonged effects. Fentanyl, a synthetic narcotic analgesic, is up to 100 times more potent than morphine, is highly lipid-soluble, and has a rapid onset of action because it quickly crosses the blood–brain barrier. Fentanyl has no active metabolites and is not associated with histamine release or venodilating effects. Because of these characteristics, fentanyl has become a widely used agent in the ICU. It is ideal for use in patients with unstable hemodynamics. Fentanyl should be administered by continuous infusion for sustained effect because of its short duration of action.15 Remifentanil (Ultiva, Abbott), Continues on page 22

22 Clinical

Pharmacy Practice News • July 2011

Educational Review Continued from page 21

Sedatives

Analgesic-Sedative

Analgesics

Table 5. Pharmacology of Selected Analgesics and Sedatives Infusion Dose Range (Usual, Continuous)

Agent

Equianalgesic Distribution Dose (IV) Half-life

Metabolic Pathway

Active Metabolites (Effect)

Adverse Effects

Intermittent Dosea

Acetaminophen

Conjugation

325-650 mg PO q4-6h; avoid >4 g/d

Codeine

120 mg

Demethylation Yes (analgesia, sedation) and glucuronidation

Lacks potency, histamine release

Not recommended

Fentanyl

200 mcg

1.5-6 h

Oxidation

Rigidity with high doses

0.35-1.5 mcg/kg IV q0.5-1h

0.7-10 mcg/ kg/h

Hydromorphone 1.5 mg

2-3 h

Glucuronidation None

10-30 mcg/kg IV q1-2h

7-15 mcg/kg/h

Ibuprofen

1.8-2.5 h

Oxidation

None

Risk for bleeding, GI and renal adverse effects

400 mg PO q4-6h

Ketorolac

2.4-8.6 h

Renal

None

Risk for bleeding, GI and renal adverse effects

15-30 mg IV q6h; decrease if age >65 y or weight <50 kg or renal impairment; avoid using >5 d

Infusion not FDA–approved

Meperidine

75-100 mg

3-4 h

Demethylation and hydroxylation

Yes (neuroexcitation, Avoid with MAOIs especially with renal and SSRIs insufficiency or high doses)

Not recommended

Morphine

10 mg

3-7 h

Glucuronidation Yes (sedation, especially with renal insufficiency)

Histamine release

0.01-0.15 mg/kg IV q1-2h

0.07-0.5 mg/kg/h

Remifentanil (Ultiva, Abbott)

3-10 min

Plasma esterase

None

0.6-15 mcg/ kg/h (0.1 mcg/ kg/min)

Dexmedetomidine (Precedex, Hospira)

~6 min

Hydroxylation, methylation, and glucuronidation

None (glucuronidation); undetermined for P-450–mediated pathways

Hypotension, transient hypertension, bradycardia

Intermittent dosing not FDA-approved

0.2-0.7 mcg/kg/h

Diazepam

30-66 min

Hepatic microsomal enzymes

Yes

CNS depressant, “paradoxical” reactions

5 mg as needed q2-5 min; maximum dose 0.25 mg/kg

2 mg/kg/d

Lorazepam

3-20 min

Glucuronidation None

Respiratory depression

2 mg as needed q2-5 min; maximum dose 1 mg/kg

2-4 mg (0.0440.05 mg/kg)

Methohexital (Brevital, JHP)

4 h (for adults; may be up to 5 h in younger patients)

Demethylation and oxidation

Cardiac and respiratory depression, neurologic and emergence delirium

1% solution (10 mg/mL) 1-1.5 mg/kg induction, then 20-40 mg as required (for adults)

2% solution (2 mg/mL) 6 mg/min (for adults)

Midazolam

6-15 min

Hydroxylation

Yes

Respiratory depression, respiratory arrest, hypotension

25% of induction dose

0.02-0.10 mg/kg/h (1-7 mg/h)

Propofol

2-3 min

Glucuronidation None

Apnea, hypotensionb

Increments of 20-50 mg as needed

100-200 mcg/kg/min

No metabolite, parent accumulates

CNS, central nervous system; D5W, 5% dextrose in water; GI, gastrointestinal; MAOIs, monoamine oxidase inhibitors; NA, not applicable; SSRIs, selective serotonin reuptake inhibitors a

More frequent doses may be needed for acute pain management in mechanically ventilated patients.

Strict aseptic technique required.

Continues on page 26

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P11-3131E-May, 11

Where does your thrombin come from?

Graphics are for illustrative purposes only. Not intended to depict actual manufacturing process or application method. Thrombin products are for topical use only.

INDICATION

RECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical.

References: 1. RECOTHROM [package insert]. Seattle, WA: ZymoGenetics, Inc. 2. Evithrom [package insert]. Somerville, NJ: Ethicon, Inc. 3. Thrombin-JMI [package insert]. Bristol, TN: King Pharmaceuticals, Inc. RECOTHROM is a registered trademark of ZymoGenetics, Inc. ©2011 ZymoGenetics, Inc. All rights reserved. RT396-00, January 2011

IMPORTANT SAFETY INFORMATION FOR RECOTHROM

Contraindications • Topical use only – DO NOT INJECT directly into the circulatory system • Do not use for the treatment of massive or brisk arterial bleeding or in patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins Warnings and Precautions • Potential risk of thrombosis if absorbed systemically • In patients with known hypersensitivity to snake proteins, there may be potential for allergic reaction

RECOTHROM is recombinant human thrombin RECOTHROM is human thrombin produced via recombinant DNA technology using a genetically modied Chinese hamster ovary (CHO) cell line1 Other thrombins are derived from human or bovine plasma2,3 – In a phase 3 study comparing RECOTHROM to bovine thrombin, the overall incidence of adverse events was similar between treatment groups – RECOTHROM has not been compared to human plasma-derived thrombin in clinical trials

Know your thrombin inside and out Visit RECOTHROM.com

Adverse Reactions • The serious adverse event that occurred in ≥1% (n=6/583) of patients exposed to RECOTHROM in completed clinical trials was atrial brillation. The most common adverse events reported in these trials (N=583) were incision site pain (51%), procedural pain (30%), and nausea (28%). Adverse events reported in these trials were consistent with those commonly observed in surgical patients

Please see Brief Summary of full Prescribing Information on following page.

26 Clinical

Pharmacy Practice News â&#x20AC;˘ July 2011

Educational Review Continued from page 22

a newer agent, has not been widely studied in ICU patients. The drug has a very short half-life and may be best used in patients requiring serial examinations or neurologic evaluations. Because of its short duration of action, continuous infusion is necessary for pain management.16 Hydromorphone is a highly potent opioid with no active metabolites. It can be used in the ICU but has not found broad-based application in this setting.

Meperidine is not recommended for repeated use; it has an active metabolite that causes neuroexcitation (apprehension, tremors, delirium, and seizures) and may interact with antidepressants (contraindicated with monoamine oxidase inhibitors and best avoided with selective serotonin reuptake inhibitors). Because of risks from multiple interactions with other medications, meperidine should not be used in the ICU. Certain adverse effects of opioid analgesics occur frequently in ICU

patients. Of greatest concern are respiratory, hemodynamic, CNS, and gastrointestinal effects. Respiratory depression is a concern in spontaneously breathing patients or in those receiving partial ventilatory support. Opioids also may increase intracranial pressure in patients with traumatic brain injury, although the data are inconsistent and the clinical significance is unknown.17 Nonopioids Gabapentin. Increasing evidence

suggests that non-benzodiazepine g-aminobutyric acid (GABA)-ergic compounds have promise for the treatment of alcohol withdrawal syndrome. GABA represents the major inhibitory neurotransmitter of the CNS. Ethanol, benzodiazepines, and some anticonvulsants directly affect GABA receptors, inducing similar anxiolytic, sedative-hypnotic, and anticonvulsant effects. Benzodiazepines (see below) are widely used to treat alcohol withdrawal syndrome and continue to be considered the drugs of choice for this condition. Because of their addictive potential and lack of safety when combined with alcohol, benzodiazepines usually are not recommended for maintenance treatment. A 2009 study compared gabapentin with lorazepam in a double-blind randomized clinical trial. Gabapentin was well tolerated and decreased symptoms of alcohol withdrawal in an outpatient population. Gabapentin reduced the probability of drinking during alcohol withdrawal and in the postwithdrawal week compared with lorazepam.18 A more recent study showed that gabapentin loaded up to 3,200 mg in the first 24 hours was helpful in reducing less severe and less complicated acute alcohol withdrawal syndrome. 19 Gabapentin is structurally related to GABA but does not bind to GABAa or GABAb receptors and does not appear to influence GABA synthesis or uptake. Binding sites have been located throughout the brain, corresponding to the presence of voltagegated calcium channels possessing the a2 d1 subunit. This channel appears to be located presynaptically and is thought to modulate the release of excitatory neuroÂtransmitters involved in epileptogenesis and nociception. 20 Gabapentin is not highly proteinbound, is excreted renally, and is absorbed mainly from proximal small bowel. Its half-life is 5 to 7 hours.20 The most common adverse reactions to the drug (occurring in fewer than 10% of patients) relate to the CNS and include somnolence, dizziness, ataxia, and fatigue. Gabapentin may enhance the effects of other CNS depressants, including herbal agents such as valerian and St. Johnâ&#x20AC;&#x2122;s wort. There is no labeled use or dosage recommendation for alcohol withdrawal. The daily dose range for labeled and unlabeled use of gabapentin (seizures and neuropathic pain, respectively) is adjusted based on creatinine clearance (CrCl) as follows: CrCl greater than or equal to 60: 300 to 1,200 mg 3 times daily; CrCl 30 to 59: 200 to 700 mg twice daily; CrCl 15

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Clinical 27

Educational Review to 29: 200 to 700 mg daily; CrCl 15: 100 to 300 mg daily with dose reduction in proportion to reductions in clearance. For hemodialysis, the dose ranges between 125 and 350 mg after each 4 hours of hemodialysis. Benzodiazepines are the most widely used sedative drugs in medicine.21 They are sedative and hypnotic—but not analgesic—agents that block the acquisition and encoding of new information and potentially unpleasant experiences (anterograde amnesia), but they do not induce retrograde amnesia. They have an opioid-sparing effect by moderating the anticipatory pain response.22 Benzodiazepines vary in potency, onset, duration of action, uptake, and number of active metabolites. The 2 predominant mechanisms of action of benzodiazepines in the nervous system involve activity at GABA receptors. Potentiation of GABA-mediated transmission by benzodiazepines is apparently responsible for somnolent, anxiolytic, and anticonvulsant effects, whereas the amnestic property appears to correlate with GABA agonist activity in the limbic cortex.2,15 Benzodiazepines are metabolized in the liver, where they are extensively cleared. The effects of these drugs may be prolonged in critically ill patients (because of reduced metabolism) or in patients with liver disease. A prolonged and continuous infusion of benzodiazepines should proceed with caution; an accumulation of the parent drug or active metabolites may produce inadvertent and prolonged oversedation, as is seen in elderly patients. It is therefore paramount that these drugs be titrated carefully and used in low doses, or the patient will be somnolent for several days after the infusion is stopped. Benzodiazepines should be titrated to a predefined end point, often by using a series of loading bolus doses. Hypotension may develop in hemodynamically unstable patients with the initiation of sedation. Intermittent or “as needed” doses of diazepam, lorazepam, or midazolam may be adequate to maintain sedation because of the relatively long half-life of these drugs.21,23 The clinical practice guidelines of the Society of Critical Care Medicine (SCCM) recommend lorazepam for the sedation of most patients, administered by either intermittent IV dosing or continuous infusion.1,2 Lorazepam, an intermediate-acting benzodiazepine, is less lipophilic than diazepam and, thus, has lower potential for accumulation. Lorazepam is associated with a stable hemodynamic profile, even when opioids are concurrently administered. It has no

prolonged infusions of this drug.25 The other commonly prescribed benzodiazepine is midazolam, more widely used in the operating room than in the ICU. Midazolam is a short-acting, water-soluble benzodiazepine that is transformed

active metabolites, and its metabolism is less affected by advanced age or liver dysfunction than that of midazolam.24 Lorazepam, however, should be used with caution; propylene glycol toxicity, marked by acidosis and renal failure, has occurred with high doses or

into a lipophilic compound in the blood. Midazolam exhibits doserelated hypnotic, anxiolytic, amnestic, and anticonvulsant actions. This drug produces dose-related respiratory depression, and larger doses may cause hypotension and vasodilation. Midazolam is metabolized in the liver to an active compound that is less potent and more transient than the parent compound. The SCCM guidelines recommend midazolam for the rapid sedation of actively agitated Continues on page 28

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28 Clinical

Pharmacy Practice News • July 2011

Educational Review Continued from page 27 1

patients for short-term use only; it is associated with unpredictable awakening and prolonged time to extubation when infusions continue for longer than 48 to 72 hours. Paradoxical agitation has been observed with the use of benzodiazepines during light sedation and in the elderly; this may be the result of drug-induced amnesia or disorientation. The effects of these drugs can be reversed with the benzodiazepine-receptor antagonist flumazenil. However, the routine use of flumazenil is not recommended after prolonged benzodiazepine therapy; there is a risk for inducing withdrawal symptoms and increasing myocardial oxygen consumption with as little as 0.5 mg of flumazenil.26 A starting dose of 0.15 mg of flumazenil is recommended and is associated with fewer withdrawal symptoms. Propofol has a rapid onset of action, within 1 to 2 minutes after a single IV dose, and a short duration of action, only 10 to 15 minutes, when discontinued.12,27 This is a result of its rapid penetration of the CNS and subsequent redistribution. Therefore, in the ICU, propofol is used by continuous infusion for sedation. Long-term infusions result in accumulation within lipid stores, a prolonged elimination phase, and a half-life of 300 to 700 minutes. Note, however, that subtherapeutic plasma concentrations of the drug are maintained after discontinuation because of rapid clearance; this limits the clinical significance of the drug’s half-life value. Although the mechanism of action of propofol still is not completely understood, the drug appears to activate the GABA receptor within the CNS. Propofol alters the sensorium in an extremely rapid dose-dependent manner, from light sedation to general anesthesia, making it a highly useful drug. It also is a potent respiratory depressant, causing a reduction in systemic vascular resistance and possible hypotension, especially when given as a bolus. Propofol should be administered with caution in hypovolemic patients. It has highly interesting effects on neurophysiology, parallel with the patient’s level of arousal. Propofol decreases cerebral metabolism, resulting in a coupled decline in cerebral blood flow and decrease in intracranial pressure. One of the most important benefits associated with propofol is a decrease in weaning time from mechanical ventilation. A large Spanish study using a cost-of-care approach, compared propofol and midazolam with regard to ICU costs for prolonged sedation of critically ill patients and weaning

time from mechanical ventilation.28 Although the 2 drugs provided equivalent sedation, propofol was associated with a shorter weaning time than midazolam, resulting in a more favorable economic profile. Because of its associated rapid wake-up time, propofol is considered the fundamental drug in many fast-track surgical programs, including cardiovascular surgery.12 Within a year of its introduction in the United States in 1990, reports appeared of clusters of infections in surgical patients treated with propofol.29 The majority of cases were due to contamination of the drug resulting from poor aseptic techniques. To prevent contamination, the additive ethylenediamine tetraacetic acid (EDTA) was included to help inhibit the growth of microorganisms. EDTA, at a concentration of 0.005%, has no effect on the physical or chemical stability of the emulsion compound. In the years following the introduction of the EDTA-containing formulation, the incidence of fevers and infections was reduced to zero. EDTA is a chelator of various ions, including calcium. In a randomized multicenter trial, patients were treated with either the original propofol formulation or the formulation with EDTA.30 The EDTA-containing formulation had no effect on calcium or magnesium homeostasis, renal function, or sedative efficacy compared with the original formulation. One of the interesting aspects of propofol with EDTA is its ability to modulate the systemic inflammatory response. In a study of surgical ICU patients, those receiving propofol with EDTA had significantly lower mortality rates at 7 and 28 days than patients receiving the original formulation.31 This potential positive effect of propofol with EDTA may be related to the ability of EDTA to bind cations. The EDTA-containing formulation of propofol increases the excretion of zinc; this, in turn, can diminish the inflammatory response to stress by decreasing the release of cytokines involved in inflammation (eg, tumor necrosis factor) and the generation of free radicals and other oxidants. The authors of this review are part of a group in Rotterdam, the Netherlands, that has investigated the release of cytokines and the transmigration of bacteria in an animal model, as modulated by various sedative agents. The full scope of the use of sedative agents to modulate the systemic inflammatory response is a highly interesting avenue of research for the future. Propofol is not recommended for pediatric patients in the ICU because of reports of metabolic acidosis with

accompanying lipemic serum, bradyarrhythmias, and fatal myocardial failure with excessively high doses.32 In adults with massive head trauma, prolonged use of propofol at very high doses may have contributed to cardiac failure33; however, these were highly complex cases with a high mortality index. The SCCM guidelines recommend propofol as the agent of choice for rapid awakening and early extubation.1 Because propofol is formulated as a lipid emulsion, triglyceride concentrations should be monitored after 2 days of propofol infusion. The total caloric intake from the lipids should be included in the nutritional support prescription and may decrease hospital costs for added nutritional support. Fospropofol (Lusedra, Eisai Inc.) is a prodrug that is hydrolyzed to yield propofol, which then interacts with the GABAa receptor, the presumed mechanism of propofol’s sedative/ hypnotic effect. No data are available on the use of fospropofol use for sedation in the ICU. Most studies of fospropofol concern its use in procedural sedation for various endoscopic procedures. Indeed, its sole indication is as a sedative/hypnotic for monitored anesthesia care in adult patients undergoing diagnostic or therapeutic procedures. There are no absolute contraindications to its use.34,35 The onset of effect of fospropofol is delayed compared with propofol due to the need for conversion to its active form. This lag may create a risk for dose stacking, which could result in deeper sedation than intended.34,35 The most common adverse reactions to fospropofol are paresthesia and pruritis.34,35 The drug is in pregnancy category B, and it is not known whether it crosses the placenta. Propofol, however, does cross the placenta and enters breast milk.34,35 Fospropofol is 98% protein-bound. It is completely metabolized by plasma alkaline phosphatases to propofol, formaldehyde (which is rapidly converted to formate), and phosphate. Although formate accumulation is the main mechanism of the toxicity seen with methanol ingestion, there have been no reports of toxicity due to fospropofol.36 There are no dosage adjustments recommended with hepatic or renal impairment, but limited data regarding this are available.34,35 Haloperidol , a butyrophenone neuroleptic drug, is the agent of choice for the treatment of delirium in critically ill patients. Patients treated with haloperidol generally appear calmer and are better able to respond appropriately to commands.12 Haloperidol does not cause major respiratory

depression. The drug, however, cannot be used alone in intubated critically ill patients. The adverse effects associated with haloperidol include occasional hypotension resulting from the a-adrenergic–blocking properties of the drug. Although it is rare with IV use, haloperidol may cause extrapyramidal effects such as drowsiness, lethargy, a fixed stare, rigidity, and akathisia. A highly dangerous side effect is neuroleptic malignant syndrome (NMS), with a mortality rate of 20% to 30%. NMS develops slowly over 24 to 72 hours and can last up to 10 days after discontinuation of the drug.37 The incidence of NMS may be higher when haloperidol is given by continuous infusion, which is not recommended. Dexmedetomidine (Precedex, Hospira), a selective a2-adrenergic receptor agonist, exhibits sympatholytic, sedative, and analgesic effects and has 8 times the affinity for the a2-adrenergic receptor as clonidine. Dexmedetomidine is approved for continuous IV sedation of initially intubated and mechanically ventilated patients in the intensive care setting for use for up to 24 hours, as well as in nonintubated patients before or during surgery. Its combined sedative and analgesic effects make it a highly promising therapy. Dexmedetomidine acts at 2 adrenergic sites. It works by presynaptic activation of the a2-adrenoceptor, thereby inhibiting release of norepinephrine and terminating propagation of pain signals; it also affects postsynaptic activation of these receptors in the CNS. Dexmedetomidine inhibits sympathetic activity, resulting in a decrease in blood pressure and heart rate. Together, these 2 effects can produce sedation, anxiolysis, sympatholysis, and analgesia.38 Dexmedetomidine has several advantages as a sedative in the ICU. Because the drug does not cause respiratory depression, a patient can be extubated without prior discontinuation. This property also makes it ideal for use in extubated patients. The drug provides great flexibility. It also may be ideal for use in weaning off mechanical ventilation. Another advantage of dexmedetomidine is the easy awakening of treated patients, making it useful for those with head injury.39 Because dexmedetomidine lowers the requirement for opioids, it can decrease opioid side effects. At the University of Rochester, the drug is widely used in burn patients, allowing complex wound care without the need for intubation. One of the greatest challenges in

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Clinical 29

Educational Review administering sedatives to patients who have a history of alcohol or drug abuse is to maintain the correct balance—avoiding both excessive sedation and agitation/withdrawal syndromes. The a2-adrenergic receptor properties of dexmedetomidine may be highly useful in this patient population. We have had great success in weaning patients with dexmedetomidine in the ICU—especially those with heavy alcohol or cocaine use. Further studies in this large population are necessary to map out the physiologic effects of sedation. Dexmedetomidine in the neurologic ICU offers a unique quality of sedation described as similar to normal sleep. Several investigators have noted that their patients were in a tranquil state but were able to understand and communicate their needs on verbal stimulation by the medical staff (including through the use of pen and paper).40 This particular profile of sedation may allow a more accurate evaluation of the neurophysiologic status of mechanically ventilated patients, which is difficult to accomplish with any other available sedative agents. Thus, dexmedetomidine may be the preferred sedative for neurosurgical patients who require a real-time assessment of their neurologic status. Another interesting population for further investigation is patients with head injuries, many of whom are highly agitated and expressing sympathetic outflow. With dexmedetomidine, we have been able to blunt the response of these patients and increase their rate of successful extubation. Dexmedetomidine has decreased the length of ICU stay and the rate of tracheotomies in patients with closed head injuries.41 A 2009 trial of dexmedetomidine versus midazolam for sedation in the ICU concluded that although no difference in time-to-targeted sedation was observed, at comparable sedation levels, patients treated with dexmedetomidine spent less time on a ventilator, experienced less delirium, and developed less tachycardia and hypertension.42 Because elimination is primarily hepatic, dexmedetomidine dosing should be lowered in patients with hepatic dysfunction. Also, the inappropriate use of dexmedetomidine may induce or aggravate cardiac conduction defects. Dexmedetomidine should not be used in hypovolemic or bradycardic patients, or in patients with low cardiac output or heart conduction blocks. The administration of this compound for more than 24 hours to critically ill patients has been found to be

safe and effective in the ICU.43 An initial loading dose of 1 mcg/kg over 10 minutes can be prescribed; however, this dose is not frequently used because it may cause transient hypotension or hypertension. These phenomena occur, depending on whether vasodilatation (central a2a-receptor stimulation) or vasoconstriction (peripheral a2b-receptor stimulation) predominates. The usual maintenance dose is 0.2 to 0.7 mcg/kg per hour, with increases no more frequently than every 30 minutes. Doses up to 1.4 mcg/kg per hour have been reported.42 For patients older than 65 years, the suggested loading dose is 0.5 mcg/kg over 10 minutes with a maintenance infusion of less than 0.6 mcg/ kg per hour. No specific guidelines exist for altering the dose for elderly patients or patients with hepatic or renal impairment.44 Dexmedetomidine is a promising agent with multiple actions that reduce analgesic and other sedative requirements, and it produces a cooperatively sedated patient. It may open a whole new arena in the sedation of extubated patients who have high levels of anxiety. The compound may also enhance our ability to evaluate lung function and perform bronchoscopy in nonintubated patients, critically ill patients, and patients with moderate to severe chronic obstructive pulmonary disease or emphysema.45 Dexmedetomidine needs to be further studied and its place in the ICU identified by well-designed research to evaluate both its shortand long-term effects. Methohexital (Brevital, JHP Pharmaceuticals) is a short acting IV barbiturate anesthetic. The literature is not robust regarding use of the drug for ICU sedation. Continuous IV infusion should use a 0.2% solution with a dose of 5 to 120 mcg/kg per minute for maintenance of anesthesia.46 Use for Wada testing is an unlabeled indication. Dosages should be lowered in patients with hepatic impairment and renal impairment may prolong or potentiate its hypnotic effect.46 Several adverse reactions of methohexital are known, but their frequency has not been defined. Contraindications to its use include hypersensitivity to methohexital (or any component formulation) or other barbiturates and porphyria (latent or manifest).46 Extravasation or intra- arterial injection may cause necrosis.

Many drug reactions are associated with methohexital. Methohexital is pregnancy category B, it crosses the placenta, and it enters breast milk. It is metabolized via a hepatic route and excreted in urine.46 Quetiapine. Oral atypical antipsychotics have drawn recent interest for the treatment of critically ill patients with agitation due to delirium. Few trials have compared the efficacy and safety of these agents with haloperidol, but a recent prospective randomized trial revealed that quetiapine added to as-needed haloperidol resulted in faster resolution of delirium, less agitation, and a greater rate of transfer-to-home or rehabilitation. The dosing recommendation for quetiapine by this study was 50 mg twice daily, increased as needed daily in 50-mg increments to a maximum dose of 400 mg per day.47 A 2007 study concluded that 25 to 100 mg per day of quetiapine improved delirious conditions within 24 hours of treatment, was well tolerated, and had a low propensity to induce extrapyramidal side effects.48 Quetiapine is a dibenzothiazepine atypical antipsychotic. Its antipsychotic activity is believed to be mediated via dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonism. Other CNS antagonist sites are the 5HT1A, dopamine D1, histamine H1, and a1- and a2-adrenergic receptors. Quetiapine does not appear to have affinity for benzodiazepine or muscarinic M1 cholinergic receptors, although norquetiapine, an active metabolite, does have affinity for M1 receptors.49 The main indication of quetiapine is for the treatment of patients with schizophrenia and acute manic or depressive episodes associated with bipolar disorder. Treatment for delirium in the critically ill patient is an unlabeled use. Significant adverse reactions include central (somnolence, headache), cardiovascular (orthostatic hypotension, tachycardia), and metabolic (hyperglycemia) effects.49 A boxed warning cautions about an increased risk for death compared with placebo in elderly patients with dementia-related psychosis treated with antipsychotic agents.49 Quetiapine is rapidly absorbed, is approximately 80% protein-bound, and is metabolized primarily by cytochrome P 4503A4 (CYP3A4) hepatic

enzymes with a half-life of 6 hours. The metabolite N-desalkyl quetiapine has a half-life of 9 to 12 hours. Excretion occurs renally, mainly as its metabolite and less than 1% as unchanged parent compound. Fecal excretion is approximately 20%.

Conclusion The most important aspect of ICU sedation is understanding the drugs given to patients and their specific advantages and disadvantages. Each drug is ideal for a specific use. It is crucial for the clinician to develop guidelines and pathways for the administration of these drugs within a specific environment. Each unit should develop protocols that grade effect based on the type of patient population in the unit. Newer drugs like dexmedetomidine should be introduced and studied in controlled trials in specific populations. In this way, protocols can be developed that enable patients to be comfortable and anxiety-free in the ICU. Poor levels of sedation should be a thing of the past. The immunomodulating properties of sedative drugs also must be explored because these properties may greatly affect outcome. An increased understanding of sedative drugs will improve clinicians’ ability to use multiple drugs at specific times during the patient’s hospital stay.

References 1. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30(1):119-141. 2. Cohen IL, Abraham E, Dasta JF, Gallagher TJ, Papadakos PJ, Pohlman AS. Management of the agitated intensive care unit patient. Crit Care Med. 2002;30(suppl):S97-S123. 3. Fraser GL, Prato BS, Riker RR, Berthiaume D, Wilkins ML. Frequency, severity, and treatment of agitation in young versus elderly patients in the ICU. Pharmacotherapy. 2000;20(1):75-82. 4. Hassan E, Fontaine DK, Nearman HS. Therapeutic considerations in the management of agitated or delirious critically ill patients. Pharmacotherapy. 1998;18(1):113-129. 5. Hansen-Flaschen J, Cowen J, Polomano RC. Beyond the Ramsay scale: need for a validated measure of sedating drug efficacy in the intensive care unit. Crit Care Med. 1994;22(5):732-733. 6. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999;27(7):1325-1329. 7. Devlin JW, Boleski G, Mlynarek M, et al. Motor Activity Assessment Scale: a valid and reliable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit. Crit Care Med. 1999;27(7):1271-1275. 8. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill Continues on page 30

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patients: validation of the confusion assessment method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29(7): 1370-1379. 9. Riker RR, Fraser GL. Monitoring sedation, agitation, analgesia, neuromuscular blockade, and delirium in adult ICU patients. Semin Respir Crit Care Med. 2001;22(2):189-198. 10. Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. 1999;27(12):2609-2615. 11. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):1471-1477. 12. Lund N, Papadakos PJ. Barbiturates, neuroleptics, and propofol for sedation. Crit Care Clin. 1995;11(4):875-886. 13. Lewis KS, Whipple JK, Michael KA, Quebbeman EJ. Effect of analgesic treatment on the physiological consequences of acute pain. Am J Hosp Pharm. 1994;51(12):1539-1554. 14. Levine RL. Pharmacology of intravenous sedatives and opioids in critically ill patients. Crit Care Clin. 1994;10(4):709-731. 15. Shapiro BA, Warren J, Egol AB, et al. Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Society of Critical Care Medicine. Crit Care Med. 1995;23(9):1596-1600.

Cuena-Boy R, Ayensa-Rincón A. Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs. Crit Care Med. 1997;25(1):33-40.

and alfentanil in head trauma patients: a study on cerebral hemodynamics. Crit Care Med. 1999;27(2):407-411. 18. Myrick H, Malcolm R, Randall PK, et al. A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009;33(9):1582-1588. 19. Bonnet U, Hamzavi-Abedi R, Specka M, Wiltfang J, Lieb B, Scherbaum N. An open trial of gabapentin in acute alcohol withdrawal using an oral loading protocol. Alcohol Alcohol. 2010;45(2):143-145. 20. Gabapentin. www.UpToDate.com. 21. Watling SM, Dasta JF, Seidl EC. Sedatives, analgesics, and paralytics in the ICU. Ann Pharmacother. 1997;31(2):148-153. 22. Gilliland HE, Prasad BK, Mirakhur RK, Fee JP. An investigation of the potential morphine-sparing effect of midazolam. Anaesthesia. 1996;51(9):808-811. 23. Watling SM, Johnson M, Yanos J. A method to produce sedation in critically ill patients. Ann Pharmacother. 1996;30(11):1227-1231. 24. Shafer A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit Care Med. 1998;26(5):947-956. 25. Young C, Knudsen N, Hilton A, Reves JG. Sedation in the intensive care unit. Crit Care Med. 2000;28(3):854-866. 26. Kamijo Y, Masuda T, Nishikawa T, Tsuruta H, Ohwada T. Cardiovascular response and stress reaction to flumazenil injection in patients under infusion with midazolam. Crit Care Med. 2000;28(2):318-323.

29. Bennett SN, McNeil MM, Bland LA, et al. Postoperative infections traced to contamination of an intravenous anesthetic, propofol. N Engl J Med. 1995;333(3):147-154. 30. Abraham E, Papadakos PJ, Tharratt RS, Hall JB, Williams GJ. Effects of propofol containing EDTA on mineral metabolism in medical ICU patients with pulmonary dysfunction. Intensive Care Med. 2000;26(suppl 4):S422-S432. 31. Herr DL, Kelly K, Hall JB, et al. Safety and efficacy of propofol with EDTA when used for sedation of surgical intensive care unit patients. Intensive Care Med. 2000;26(suppl 4):S452-S462. 32. Mirenda J, Broyles G. Propofol as used for sedation in the ICU. Chest. 1995;108(2):539-548. 33. Cremer OL, Moons KG, Bouman EA, Kruijswijk JE, deSmet AM, Kalkman CJ. Long-term propofol infusion and cardiac failure in adult head-injured patients. Lancet. 2001;357(9250):117-118. 34. Fospropofol [product information]. Woodcliff Lake, N.J.: Eisai Inc. 35. Fospropofol. www.UpToDate.com. 36. Fechner J, Schwilden H, Schüttler J. Pharmacokinetics and pharmacodynamics of GPI 15715 or fospropofol (Aquavan injection)—a water-soluble propofol prodrug. Handb Exp P harmacol. 2008; (182):253-266.

16. Tipps LB, Coplin WM, Murry KR, Rhoney DH. Safety and feasibility of continuous infusion of remifentanil in the neurosurgical intensive care unit. Neurosurgery. 2000;46(3):596-602.

27. Bailie GR, Cockshott ID, Douglas EJ, Bowles BJ. Pharmacokinetics of propofol during and after long-term continuous infusion for maintenance of sedation in ICU patients. Br J Anaesth. 1992;68(5):486-491.

37. Padegal V, Venkata B, Papadakos PJ. Neuroleptic malignant syndrome and malignant hyperthermia. In: Kruse JA, Fink MP, Carlson RW, eds. Saunders Manual of Critical Care. Philadelphia, PA: WB Saunders; 2002:301-303.

17. Albanese J, Viviand X, Potie F, Rey M, Alliez B, Martin C. Sufentanil, fentanyl,

28. Barrientos-Vega R, Mar Sánchez-Soria M, Morales-García C, Robas-Gómez A,

38. Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: a novel sedative-

analgesic agent. Proc (Bayl Univ Med Cent). 2001;14(1):13-21. 39. Chhangani SV, Papadakos PJ. The use of dexmedetomidine for sedation in patients with traumatic brain injury. Anesthesiology. 2002;97(ASCCA suppl):B20. 40. Bekker A, Sturaitis MK. Dexmedetomidine for neurological surgery. Neurosurgery. 2005;57(1 suppl):1-10. 41. Barreiro TJ, Papadakos PJ. Current practices in intensive care unit sedation. In: Papadakos PJ, Szalados JE, eds. Critical Care, the Requisites in Anesthesiology. Philadelphia, PA: Elsevier Mosby; 2005. 42. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301(5):489-499. 43. Rodrigues MG, Salgado DR, Paiva RNA, Chindamo G, Martins LC, Verdeal JCR. Use of dexmedetomidine beyond 24 hours in the intensive care unit. Crit Care. 2003;7(suppl 2):95. 44. Dexmedetomidine. www.UpToDate.com. 45. Abouzgheib W, Littman J, Pratter M, Bartter T. Efficacy and safety of dexmedetomidine during bronchoscopy in patients with moderate to severe COPD or emphysema. J Bronchol. 2007; 14(4):233-236. 46. Methohexital. www.UpToDate.com. 47. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010;38(2):419-427. 48. Maneeton B, Maneeton N, Srisurapanont M. An open-label study of quetiapine for delirium. J Med Assoc Thai. 2007;90(10):2158-2163. 49. Quetiapine. www.UpToDate.com.

Coming this Fall in our Special Edition … Guidelines for the Prevention Of Medication Errors This review compiles the errors received by the Institute for Safe Medication Practices over the previous year and offers tips on how to avoid them.

Immune Globulins: Therapeutic, Pharmaceutical, Cost and Administration Considerations In this perennial favorite, Jerry Siegel, PharmD, includes information on dozens of product selection factors to help match the right immune globulin to the right patient.

Compatibility of Commonly Used IV Drugs These organized concise charts allow clinicians to quickly and conveniently access compatibility data on more than 75 commonly used medications.

Antimicrobial Efficacy In this popular reference, pharmacists from Hartford Hospital’s Center for Anti-Infective Research describe potential in vivo activity of various antimicrobial agents when the infecting organism has been identified.

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PREMIXED AMIODARONE. Indications and Usage NEXTERONE (amiodarone HCl) Premixed Injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. Use NEXTERONE for acute treatment until the patient's ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

Important Risk Information NEXTERONE (amiodarone HCl) Premixed Injection is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE, including iodine • Cardiogenic shock • Marked sinus bradycardia • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available • NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. • Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported in 16% (288/1836) of patients treated with intravenous amiodarone. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In some cases, hypotension may be refractory and result in a fatal outcome. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including: vasopressors, positive inotropic agents and volume expansion. • In 4.9% (90/1836) of patients in clinical trials, drug-related bradycardia that was not dose-related occurred while patients were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. • Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. • The most common adverse reactions leading to discontinuation (1-2%) of intravenous amiodarone therapy are hypotension, asystole/cardiac arrest/pulseless electrical activity, VT, and cardiogenic shock. • Other important adverse reactions are torsade de pointes (TdP), congestive heart failure, liver function test abnormalities, pulmonary disorders, and thyroid abnormalities. • Drug Interactions: Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. Please see brief summary of Full Prescribing Information on the following pages.

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NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use Brief Summary of Prescribing Information. See PI for Full Prescribing Information. 1 INDICATIONS AND USAGE NEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information]. Use NEXTERONE for acute treatment until the patient's ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary. 4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage (bleeding), fever, arthralgias (joint pains), eosinophilia (abnormal blood counts), urticaria (hives), thrombotic thrombocytopenic purpura, or severe periarteritis (inflammation around blood vessels). • Cardiogenic shock. • Marked sinus bradycardia. • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available. 5 WARNINGS AND PRECAUTIONS NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. 5.1 Hypotension Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information]. In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information]. 5.2 Bradycardia and Atrio-ventricular Block In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. 5.3 Liver Enzyme Elevations Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment. Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information]. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE.

5.4 Proarrhythmia Like all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7) in full prescribing information]. Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias. 5.5 Pulmonary Disorders Early-onset Pulmonary Toxicity There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings have included pulmonary infiltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. ARDS Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary Fibrosis Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone). 5.6 Loss of Vision Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE. 5.7 Long-Term Use There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone. 5.8 Thyroid Abnormalities Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in full prescribing information]. Hyperthyroidism and Thyrotoxicosis Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear.

Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism.

Table 4 lists the most common (incidence â&#x2030;Ľ2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related. Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN

The institution of antithyroid drugs, Î˛-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE. Hypothyroidism Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients. 5.9 Surgery Perform close perioperative monitoring in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics. 5.10 Corneal Refractive Laser Surgery Advise patients that most manufacturers of corneal refractive laser surgery devices contraindicate corneal refractive laser surgery in patients taking amiodarone. 5.11 Electrolyte Disturbances Correct hypokalemia or hypomagnesemia whenever possible before initiating treatment with NEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

CONTROLLED AND OPEN-LABEL STUDIES (> 2% INCIDENCE) Study Event

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole Fever

Body as a whole 24 (2.9%)

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

Cardiovascular System Bradycardia Congestive heart failure Heart arrest Hypotension Ventricular tachycardia

Cardiovascular 49 (6.0%) 18 (2.2%) 29 (3.5%) 165 (20.2%) 15 (1.8%) Digestive System 35 (4.2%) 29 (3.5%)

Cardiovascular 41 (4.0%) 21 (2.0%) 26 (2.5%) 123 (12.0%) 30 (2.9%) Digestive System 29 (2.8%) 43 (4.2%)

Cardiovascular 90 (4.9%) 39 (2.1%) 55 (2.9%) 288 (15.6%) 45 (2.4%)

Digestive System Liver function tests normal Nausea

Digestive System 64 (3.4%) 72 (3.9%)

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of amiodarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever Cardiovascular: hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri Pancreatic: pancreatitis

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days.

Renal: renal impairment, renal insufficiency, acute renal failure

The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%).

Vascular: vasculitis

Respiratory: bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and /or mass, pleuritis Thyroid: thyroid nodules/thyroid cancer

Baxter Healthcare Corporation Deerfield, IL 60015 Baxter, Galaxy and the Sphere Graphic are registered trademarks of Baxter International Inc. NEXTERONE is a registered trademark of Prism Pharmaceuticals, Inc.

Sourced from: 07-19-65-459 Rev. November 2010

36 Operations & Management

Pharmacy Practice News • July 2011

Leadership

Academy Strives To Build Next Generation of Leaders F

ive years after the ASHP Foundation’s Center for Health-System Pharmacy Leadership established the Pharmacy Leadership Academy (PLA)— with the aim of fending off an impending crisis in the field—the program continues to build an alumni base that is taking on larger leadership roles and spreading skills among colleagues. What’s more, institutions of higher learning now recognize the PLA as worthy of graduate credit. “The PLA was launched in 2006 as a result of a study conducted by Sara J. White, that projected that 80% of pharmacy directors plan to retire in the next decade, and more than half indicated they did not know of anyone qualified to replace them,” noted Stephen J. Allen, RPh, MS, FASHP, executive vice president of the ASHP (American Society of Health-Systems Pharmacy) Foundation. “If they did take over, they were less than fully prepared and notably challenged. Other pharmacists would then witness their colleagues struggling and were less inclined to consider this as a career advancement opportunity.” The solution, as Mr. Allen and the ASHP Foundation team saw it, was a program that could complement schools of pharmacy and residencies, which build essential clinical skills but may not emphasize leadership areas. “We need to do a better job of developing dynamic leaders in our profession who can stand in front of administrators and clinicians and represent pharmacy,” said Michael O’Neal, RPh, manager of pharmacy procurement at Vanderbilt University Medical Center, in Nashville, Tenn., and recent PLA graduate. “We are advancing along with medicine. In fact, a lot of the advancements in medicine are pharmacy-related.” The PLA program is focused on filling this leadership gap, working to assist pharmacists in applying their leadership learning in advancing safe and effective medication use in health systems. But the ASHP Foundation also acknowledged a third category of key skills that remained unaddressed: management. “So when opportunity came along for us to partner with academic institutions that could provide that last slice of the triad and build various academic avenues for pharmacists to take depending on their pursuit, it just seemed like a nobrainer,” said Richard Walling, BSPharm, MHA, director of the Center for HealthSystem Pharmacy Leadership. “A 2010 survey of pharmacy directors and assistant directors indicated that advanced degrees (MHA, MBA, MPH) are the most desirable and well-recognized means of advancing in health systems.”

System in Boise, Idaho. Ms. Heckathorn described the day when the CEO of her health system approached her in the cafeteria. “He sat down with me to pick my brain regarding a new business venture,” she recalled. Because she was in Scan to access more details on the midst of the PLA program, PLA program she shared with him some of the tools she was learning. Alliance With GlobalHealth “At the end of our discussion, he asked Education me to serve on the infusion center’s Thanks to a new alliance with team,” added Ms. Heckathorn. “Then GlobalHealth Education, an online he paused and asked me if I would educational services firm based in like to lead the team. I know that I am West Palm Beach, Fla., completing the improving my performance, but this is program will earn participants gradu- definitely a milestone in my career.” A total of 81 students are enrolled in the 2011 PLA class. The series of nine online courses over 15 months cover a range of topics from change and innovation to financial management—all taught by renowned pharmacy practice leaders.

‘I find that I am learning skills to help motivate staff and appropriately delegate and understand the politics of hospital institutions.’

—Karen Riley, PharmD, BCPS

ate credits that can be applied to online master’s programs in health care administration, management, public policy or pharmacy at Simmons College, New England College or the University of Florida. (Mr. Walling expects more schools to be added over the next year.) Graduates of the classes of 2007 through 2010, before the agreement, can take two capstone courses that will bring them up to speed with students going through the revamped program. These additions will qualify them to apply for credit after acceptance into a master’s program. Meanwhile, a growing number of alumni—and their home departments— are already reaping the benefits of the continuing education. “My life has changed dramatically since joining the PLA,” noted Debbie Heckathorn, RPh, director of pharmacy at Elks Rehab

Before she knew it, she was also appointed to represent the hospital employees on a systemwide performance review committee, lead a team in charge of quality and compliance, and sit on a disaster planning council. The CEO even asked Ms. Heckathorn if she planned to take over his position. She has a few steps to take first, including an MHA. “The PLA opens the door and I’m going to walk on through,” she said. Ms. Heckathorn is not keeping all of the skills to herself. “If I can teach someone else how to use a tool, and he uses it successfully, that means I really do understand what I’m learning.” Other PLA graduates are also spreading the wealth and making broad changes at their home institutions. “I find that I am learning skills to help motivate staff and appropriately delegate and understand the politics of

hospital institutions,” said Karen Riley, PharmD, BCPS, clinical pharmacy manager of education and quality assurance at Hotel-Dieu Grace Hospital in Windsor-Essex, Ontario, Canada, and PLA participant. “I have also been trying to make changes behind the scenes by planting the seeds of change in my director’s mind.”

A Team Approach Janice Glascock, PharmD, assistant director of clinical and educational services for the Department of Pharmaceutical Services at Emory Hospitals, in Atlanta, has taken it even further. She is a graduate of the 2009 PLA class, and recently went through the capstone coursework along with another PLA graduate, Chad Hatfield, PharmD, BCPS, who plans to take advantage of the MHA. They also recruited two colleagues who have not completed the PLA to join them: Julie Temples, RPh, and Collin Lee, PharmD, BCPS. The group ended up collaborating on a course project that prompted a proposal for a new department-wide leadership training program. “We recently went through the transition to CPOE [computerized provider order entry] and updated drug distribution practices that have impacted our workflow processes,” Dr. Glascock said. “We need to make some major changes, and we felt that getting our leaders to embrace leadership principles would help us move through those changes more quickly.” They borrowed a series of readings and ideas focused on self-awareness and negotiation from the PLA curriculum that they now aim to cover during monthly meetings. Also included in their proposal, which is currently under consideration, is departmental funding for one person to go through the PLA annually. Patricia A. Marken, PharmD, professor of pharmacy practice and administration at the University of MissouriKansas City, and member of the board of directors for the American Association of Colleges of Pharmacy (AACP), suggested that the PLA is a great improvement on the traditional continuing education (CE) model. “Rather than just doing random CE to learn a little more about whatever new drug is out there, this program actually advances a skill set,” she said. “That’s the better model for maintaining our practice, and that’s why you’re seeing these programs coming together.” Dr. Marken noted that the AACP also offers a leadership program, which is aimed more at pharmacists in academia who want to become chairs or deans. But the specific coursework and

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Pharmaceutical Issues in Patients Receiving

Enteral Nutrition JOSEPH I. BOULLATA, PHARMD, RPH, BCNSP Associate Professor, Pharmacology & Therapeutics University of Pennsylvania, School of Nursing Pharmacy Specialist, Clinical Nutrition Support Services Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

n important area of clinical practice that traditionally has received less attention among many pharmacists is

nutritional pharmacotherapy, including the use of enteral nutrition (EN).

Over the past few years, drug administration with EN has been a focus of a number of pharmacy publications1-4 and was included in a national patient safety campaign highlighting pharmacists.5 This increased emphasis in this area coincided with the publication of the first national practice recommendations for EN.6 These comprehensive guidelines prepared by the American Society for Parenteral and Enteral Nutrition (ASPEN) are intended for an interdisciplinary audience and include sections on ordering, labeling, formula safety, enteral access, administration, monitoring, and medication administration. This document has a number of implications for pharmacists that serve as the focus of this review.

The EN System The EN process can be considered parallel to the drug use process, starting from a decision to use the specialized therapeutic intervention and the ordering process to preparation, labeling/dispensing, administration, and monitoring. That is, EN is not just a food substitute but an important therapeutic intervention for all health care providers to take into account. The overlapping route for drug administration in patients requiring EN is particularly significant to pharmacists, who can bring expertise in pharmaceutics, physiology, and pharmacotherapy.

ENTERAL NUTRITION EN products are specially formulated nutrient products intended for administration into the gastrointestinal (GI) tract through an enteral access device, also commonly referred to as an enteral feeding tube (EFT). The majority of the EN products used in adults are sterile liquids,

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

packaged either in individual cans or, more commonly, in ready-to-hang containers. More specifically, these are pharmaceutically dispersed systems (colloidal dispersions). In rare cases, a patient may need a specialized powdered EN formula that requires reconstitution with sterile water in the pharmacy using aseptic technique and applying a short beyond-use date.6 The dozens of EN products available vary in their ingredients, nutrient content, nutrient source, and osmolality. These products are regulated by the FDA as medical foods, ie, they are formulated to be administered enterally under the supervision of a physician based on a medical evaluation. Medical foods are exempt from food labeling, dietary supplement labeling, and drug labeling requirements. Many patients in hospitals and other health care institutions, as well as patients at home, receive EN for a variety of indications to meet some or all of their metabolic needs for energy, protein, and micronutrients. The therapy may be administered continuously or intermittently. Continuous infusion into the stomach or small bowel requires a feeding pump, whereas pump-assisted feedings are not always necessary for intermittent administration into the stomach.

ENTERAL ACCESS Patients unable to take food or medication by mouth will have an EFT in place. The tubes can vary in material, diameter, length, and size of opening(s) at the distal end. The type of tube placed will depend on the patient and the expected duration of forced feeding. Tubes placed through the nose (naso-), or less frequently the mouth (oro-), are used for short-term feeding, whereas percutaneous (-ostomy) tubes are for long-term needs. The

P H A M A C Y P R A C T I C E N E W S â&#x20AC;˘ J U LY 2 0 1 1

confirmed location of the distal tip in the stomach (gastric) or small bowel (duodenum, jejunum) provides a more valuable description for the pharmacist than the tube’s brand name or manufacturer. After the position of the EFT within the GI tract is confirmed, it may be used for feeding and/or medication administration. Intragastric administration (via nasogastric or gastrostomy tube) more closely resembles oral administration, for which the drug product was approved by the FDA. The GI milieu at the distal end of the feeding tube needs to accommodate drug dissolution, permeability, and absorption. It is important to use the ideal site to maximize bioavailability. It also is critical to dilute high-osmolality liquid drug products prior to administration to prevent GI complaints and malabsorption, especially if the drug is introduced directly into the small bowel. Aside from the position of the tube’s distal end within the GI tract, the size of the EFT is also important for drug administration. An EFT with a diameter of 10 French or less (1 Fr = 0.33 mm) is more likely to become obstructed and is best avoided for drug administration. Even at adequate sizes, if these devices are not routinely flushed with water, they are significantly more likely to become clogged with EN formula and/or drug residue. Inappropriate techniques of drug preparation and administration also contribute to EFT obstruction. Prevention remains the key because, short of replacing the tube, effective methods of resolving clogs have not been well studied.7

Preparation and administration of a drug via EFT most often are carried out by nurses or caregivers, although in some institutions a pharmacist may take the responsibility for preparing a dosage form for EFT administration, within norms of compatibility and stability. Although most caregivers are confident that they prepare and administer drugs appropriately, surveys suggest that errors such as not flushing tubes before and between administering medications, administering multiple medications mixed together, crushing of modified-release tablets, not diluting medications before administering, and not adhering to institutional guidelines occur fairly commonly.6,8-14 A prospective observational study suggests that such medication errors may occur with about 60% of doses, highlighting the need for pharmacists to be vigilant.15 Consequences of inappropriate drug preparation and administration include reduced efficacy, toxicity, and clogged tubes. Best practices for drug administration through an EFT are listed in Table 2.6 In the absence of drug-specific data, the rationale for some recommendations is based on pharmaceutical principles.16 Responsibility should be shared by prescribers, pharmacists, and nurses; inappropriate prescriber orders put the nurse in a difficult position if the pharmacist does not clarify them.

also should be avoided for this route of administration. A listing of the many oral dosage forms that should not be crushed or opened is readily available through the Institute for Safe Medication Practices.17 These dosage forms are implicated not only in interactions and excessive bolus drug doses but also in exposing caregivers (including via inhalation) to cytotoxic and teratogenic products. Appropriate tablets can be pulverized to a fine powder (triturated) and diluted in water, as can the solid contents of immediate-release capsules. Medication that is in a powdered form—either from pulverized tablets, capsule contents, or dry powder products intended for reconstitution—needs to be diluted to ensure delivery through the EFT. Dilution may be necessary for liquid medication (ie, solutions, suspensions) to reduce viscosity or osmolality. Reducing viscosity, the resistance to flow, allows the full drug dose to reach the distal end of the EFT. Not diluting a suspension that is being administered through an EFT could result in a significant decrease in drug delivery and bioavailability.18,19 Consistent delivery through an EFT requires adequate drug dilution and flushing.20-23 The simplest fluid for diluting powdered or liquid medication is water. The U.S. Pharmacopeia requires that purified water be used for preparation of drug dosage forms.24 Chemical contaminants in drinking water (tap, bottle, well) raise the risk for drug interactions when it is used to dilute medication prepared for administration by tube; this may, in turn, alter drug bioavailability.25,26 Although the real potential for acute drug– drug and drug–chemical interactions when contaminated waters are combined with medication has not been evaluated, the practice recommendations attempted to err on the side of safety and recommend purified water (eg, sterile water for irrigation, USP).6 Such use of the precautionary principle (ie, action based on scientifically plausible risk) serves patients well until more data are generated. More data are needed regarding appropriateness of medication dilution and the potential for drug interactions. Dilution with 30 to 60 mL of water appears adequate for powdered medication.21-23,27 The volume required to dilute liquid medication depends on the degree of viscosity and/or osmolality. Diluting viscous suspensions in a volume of at least 1:1 seems adequate for some drugs.18,20 High-osmolality medication can result in localized adverse effects at the mucosa or create an osmotic effect throughout portions of the bowel. The higher the osmolality, the greater the volume of diluent required to lower the osmolality.27 For example, a 500-mg dose of acetaminophen using a liquid product with an osmolality of 6,000 mOsm/ kg would require about 100 mL of water dilution to reduce the osmolality toward physiologic values. The case could be made that crushing an acetaminophen tablet to a fine powder and dispersing in a smaller volume of water would be more practical than using a liquid formulation.28

PREPARATION

ADMINISTRATION

Very few data support the admixture of a drug to an EN formula or to other drugs prior to administration. Modifiedrelease dosage forms (eg, delayed-, sustained-release)

Administration of medications through EFTs remains a time-consuming and complex issue in practice that can benefit from a pharmacist’s input (Table 1). Drugs should

Drug Preparation and Administration

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be administered after first stopping EN (if administered continuously) and flushing the tube. If more than one drug is due at the same time, each medication should be administered separately with the tube flushed between each to ensure removal of any residual drug or excipient. A volume of at least 15 mL is suggested, but the patient’s volume status and any restrictions should be considered. The tube should be flushed again after drug administration is complete, and the EN should be restarted. The time lapse between stopping the feeding, administering the drug, and restarting the feeding will depend on any potential for drug–nutrient interaction in the GI lumen.2,6 Although a number of surveys have focused on nurses’ inappropriate technique in preparing and administering medication through EFTs, prescribers’ and pharmacists’ responsibilities also need to be considered. According to one study, patients with “NPO” (nothing by mouth) orders who are unable to take medication by mouth are still prescribed drugs orally more than 80% of the time; this often is not corrected by the pharmacist reviewing the orders and, therefore, places the nurse in the precarious position of committing a wrong route medication error.29 In this same study of drug administration in enterally fed hospitalized patients, less than 20% of drugs administered directly into the small bowel were considered appropriate.29 Therapeutic alternatives or a different route of administration may need to be considered.

Order Review ENTERAL NUTRITION Even if EN is not dispensed by the pharmacy, putting EN orders (and the EFT description) on the patient’s drug profile is vital and analogous to including parenteral nutrition (PN) orders (and IV access). A quick review of the EN order should note that it is complete. This entails all the essential elements—patient identifiers (eg, name, medical record number), EN product/formula type (eg, either generic or brand name), route of administration (eg, gastric) and access device (eg, gastrostomy), administration method (eg, continuous), and volume or rate (eg, 30 mL/h × 20 h).6,30 These minimum data should be reflected on the generated labels affixed to the product.6,30 Although the pharmacy department is less often responsible for procuring and dispensing these products, the complete patient-specific label should be provided by the responsible department. A quick check of product dosing should note that the patient will be receiving 20 to 30 kcal/kg, 1 to 1.5 g/kg protein, and 30 to 40 mL water daily, varying with his or her clinical status; this also may vary if the patient is being transitioned from PN or to an oral diet.30 The volume of water delivered is less than the final EN volume, considering that the water content varies with the formula from approximately 70% to 85%. Any additional volume requirement will need to be met by enteral water flushes or IV fluids. A review of the EN orders with enteral drug orders is analogous to the pharmacist’s responsibility to review PN orders for both clinical and pharmaceutical appropriateness.31

Table 1. Strategies for Medication Preparation and Administration • Do not add medication to the EN formula • Do not mix medications together • Use only immediate-release drug dosage forms (solid or liquid) • Dilute each medication with purified water before administration • Administer each medication separately through an appropriate access site • Use clean oral/enteral syringes to measure, prepare, and administer medication • Flush the feeding tube with purified water before and after each medication • Flush the tube with purified water (at least 15 mL) and restart the feeding in a timely manner • Consult with a more educated pharmacist as needed Based on reference 6.

MEDICATION Pharmacists play a critical role in supporting prescribers and nurses in addressing issues with drug administration in the patient with an EFT.32 Pharmacists evaluating enteral drug orders in a patient receiving EN should go through a systematic evaluation of the drug orders (Table 2). They need to be aware of the patient’s GI status, the EN regimen, and the location of the EFT to identify inappropriate administration routes, potential interactions, and other administration route issues. A drug ordered by the prescriber to be administered “PO” (orally) in the patient with NPO orders is a conflict that needs to be resolved by the pharmacist. If the drug is intended for administration through the EFT, the order should be changed so as not to constitute a medication error when the nurse administers it by the “wrong route.” An important consideration for pharmacists reviewing such orders is deciding whether the drug and its formulation are appropriate for EFT administration. Given the risks for physicochemical incompatibility and instability, drugs should not be admixed together. Potential drug– nutrient interactions that result from a physical, chemical, physiologic, or pathophysiologic relationship between a drug and EN also need to be considered.6 An interaction is considered to be clinically significant if it influences therapeutic response (or compromises nutrition status) with clinical consequences related to altered drug (or nutrient) disposition. For example, the bioavailability of some drugs may benefit from administration in close proximity to EN, whereas that of other drugs may be significantly reduced. In the latter case, administration of drug should be temporally separated from administration of EN. These factors should be considered with other factors for drug administration via EFT (eg, flushing protocol, appropriate drug dilution, location of EFT distal tip).

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Table 2. Drug Order Evaluation In Enterally Fed Patients Identify the patient’s current enteral status • “PO” or “NPO except medications” or “NPO”? • What is the patient’s current EFT site? • What is the patient’s current EN order? Review oral/enteral drug orders • Ordered PO or via an EFT? • Does it match the patient’s current PO status? • Is the drug dosage form appropriate for EFT administration?

10. Schmieding NJ, Waldman RC. Nasogastric tube feeding and medication administration: a survey of nursing practices. Gastroenterol Nurs. 1997;20(4):118-124. 11. Belknap DC, Seifert CF, Peterman M. Administration of medications through enteral feeding catheters. Am J Crit Care. 1997;6(5):382-392. 12. Seifert CF, Johnston BA, Rojas-Fernandez C. Drug administration through enteral feeding catheters. Am J Health-Syst Pharm. 2002;59(4):378-379. 13. Seifert CF, Johnston BA. A nationwide survey of long-term care facilities to determine the characteristics of medication administration through enteral feeding catheters. Nutr Clin Pract. 2005;20(3):354-362. 14. Boullata JI, Hudson LM, Spencer CT, et al. Drug administration by feeding tube: results of a practice-based survey. Nutr Clin Pract. 2007;22: Abstract 126.

• Are the drug and the formulation appropriate based on the distal end of the EFT?

15. Bertsche T, Niemann D, Mayer Y, Ingram K, Hoppe-Tiche T, Haefeli WE. Prioritising the prevention of medication handling errors. Pharm World Sci. 2008;30(6):907-915.

• Is EN administered continuously or intermittently?

16. Boullata JI. Drug administration through an enteral feeding tube: the rationale behind the guidelines. Am J Nurs. 2009;109(10):34-42.

• Should the EN be held for a period of time around any of the ordered drugs? So ordered?

17. Mitchell JF. Oral dosage forms that should not be crushed. http:// www.ismp.org/Tools/DoNotCrush.pdf. Accessed June 9 2011.

• Resolve any inappropriate orders with prescriber and nurse EFT, enteral feeding tube; NPO, nothing by mouth; PO, by mouth

Conclusion The pharmacist is in an important position to ensure optimal use of drugs, including those administered to patients receiving EN. The ASPEN practice recommendations can guide drug preparation and administration through EFTs and the development and implemention of institution-specific EN protocols. Clinical observations and research findings related to inappropriate drug preparation and administration, especially if they refute or substantiate current recommendations, should be documented and shared to educate others. Nutritional pharmacotherapy is another area in which pharmacists can advance patient care and clinical practice.

References 1.

9. Mateo MA. Nursing management of enteral tube feedings. Heart Lung. 1996;25(4):318-323.

Williams NT. Medication administration through enteral feeding tubes. Am J Health-Syst Pharm. 2008;65(24):2347-2357.

2. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT. Recommendations for the use of medications with continuous enteral nutrition. Am J Health-Syst Pharm. 2009;66(16):1458-1467.

18. Clark-Schmidt AL, Garnett WR, Lowe DR, Karnes HT. Loss of carbamazepine suspension through nasogastric feeding tubes. Am J Hosp Pharm. 1990;47(9):2034-2037. 19. Ashley ESD, Varkey JB, Krishna G, et al. Pharmacokinetics of posaconazole administered orally or by nasogastric tube in healthy volunteers. Antimicrob Agents Chemother. 2009;53(7):2960-2964. 20. Seifert CF, McGoodwin PL, Allen LV Jr. Phenytoin recovery from percutaneous endoscopic gastrostomy Pezzer catheters after long-term in vitro administration. JPEN J Parenter Enteral Nutr. 1993;17(4):370-374. 21. Yuk JH, Nightingale CH, Sweeney KR, Quintiliani R, Lettieri JT, Frost RW. Relative bioavailability in healthy volunteers of ciprofloxacin administered through a nasogastric tube with and without enteral feeding. Antimicrob Agents Chemother. 1989;33(7):1118-1120. 22. Healy DP, Brodbeck MC, Clendening CE. Ciprofloxacin absorption is impaired in patients given enteral feedings orally and via gastrostomy and jejunostomy tubes. Antimicrob Agents Chemother. 1996;40(1):6-10. 23. Cohn SM, Sawyer MD, Burns GA, Tolomeo C, Milner KA. Enteric absorption of ciprofloxacin during tube feeding in the critically ill. J Antimicrob Chemother. 1996;38(5):871-876. 24. United States Pharmacopoeia Convention. United States Pharmacopoeia/National Formulary, Edition 34/29. Rockville, MD: United States Pharmacopoeia Convention, Inc; 2011. 25. Boullata JI. Enteral nutrition practice: the water issue. Support Line. 2010;32(3):10-17. 26. Benotti MJ, Trenholm RA, Vanderford BJ, Holady JC, Stanford BD, Snyder SA. Pharmaceuticals and endocrine disrupting compounds in U.S. drinking water. Environ Sci Technol. 2009;43(3):597-603. 27. Rollins CJ. Drug-nutrient interactions in patients receiving enteral nutrition. In: Boullata JI, Armenti VT, eds. Handbook of Drug-Nutrient Interactions. 2nd ed. New York, NY: Humana Press; 2010:367-410.

3. Boullata JI. Medication administration through feeding tubes [letter]. Am J Health-Syst Pharm. 2010;67(1):23.

28. White R, Bradnam V, eds. Handbook of Drug Administration via Enteral Feeding Tubes. 2nd ed. London, England: Pharmaceutical Press; 2011.

4. ISMP. Medication Safety Alert. Preventing errors when administering drugs via an enteral feeding tube. May 6, 2010. http://www.ismp.org/ Newsletters/acutecare/articles/20100506.asp. Accessed June 9, 2011.

29. Boullata J, Aloupis M, Fodero K, et al. Appropriateness of drug administration in enterally fed patients. Crit Care Med. 2009;37(suppl): Abstract 122.

5. American Society for Parenteral and Enteral Nutrition. Patient safety initiatives: Be A.W.A.R.E., 2010. http://www.nutritioncare.org/ WorkArea/showcontent.aspx?id=4520. Accessed June 9, 2011.

30. Boullata J, Carney LN, Guenter P, eds. A.S.P.E.N. Enteral Nutrition Handbook. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2010:205-235.

6. Bankhead R, Boullata J, Brantley S, et al, and A.S.P.E.N. Board of Directors. Enteral nutrition practice recommendations. JPEN J Parenter Enteral Nutr. 2009;33(2):122-167. 7.

Dandeles LM, Lodolce AE. Efficacy of agents to prevent and treat enteral feeding tube clogs. Ann Pharmacother. 2011;45(5):676-680.

8. Leff RD, Roberts RJ. Enteral drug administration practices: report of a preliminary survey. Pediatrics.1988;81(4):549-551.

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31. Canada T, Crill C, Guenter P, eds. A.S.P.E.N. Parenteral Nutrition Handbook. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2009:129-161. 32. Langebrake C, Hilgarth H. Clinical pharmacists’ interventions in a German university hospital. Pharm World Sci. 2010;32(2):194-199.

Dr. Boullata reports no relevant conflicts of interest.

Pharmacy Practice News • July 2011

Operations & Management 37

Leadership in Action

Leadership in Pharmacy: More Nuggets T

his month’s column continues with my favorite leadership “nuggets.” Most are based on the book “Leadership Gold,” by John Maxwell (Nashville, TN: Thomas Nelson Publishers; 2008). Let’s see how they can apply to the profession of pharmacy.

‘As a leader, you should always challenge people to move out of their comfort zones, but never out of their strength zones.’

Hire the Right People Of course, we always try to make the perfect hiring decisions. However, most of us have had the experience of hiring someone who just doesn’t turn out to be the right fit. Perhaps you have vowed to help the person become successful in the position. This happened to me several years ago when I was a new manager. I hired a pharmacy technician who turned out to be very abrasive in his interactions with people, both internally and externally. I committed to work with this individual and assured everyone that he was “going to make it.” Sadly, after working with him for six months, we finally concluded together that he was just not cut out to be a pharmacy technician. We mutually agreed that it wasn’t going to work and we parted company. The important lesson I learned was that there are times when no matter what efforts are made with the intention of “changing” someone, no change will come. Sometimes, the person is just not the right fit for the job. Although easier said than done, we need to do what it takes to hire good people who are the right fit for each position. We need to find those self-motivated pharmacy

—John Maxwell

everything; therefore they must surround themselves with people who complement one another—clinical experts, information technology experts, managerial experts and so on. Knowing what motivates each of these individuals helps to define their roles and find their niches within the department. Maxwell states: “As a leader, you should always challenge people to move out of their comfort zones, but never out of their strength zones.” There are certain parts of our characters that represent our choices and our efforts—responsibility and attitude, for example. Because our strengths in these areas depend on the amount of effort we put into them, we can always improve them. Some other areas are based more on natural skills. These natural skills can be improved, too, although perhaps not as dramatically. This is why it is important to hire the right people.

Focus on the Important Items

employees who want to learn and grow and have the innate skills required for the job. We cannot force people to be who they are not.

Know the DNA of Your Staff Of course, no two people are alike. We all have different skills, abilities, knowledge, training, experience and DNA. Our jobs as leaders are to place the right people in the right positions and maximize their particular strengths. Wise managers realize that they cannot know

We’ve been taught to prioritize and concentrate on the important items on our lists. As busy pharmacy leaders, this is becoming increasingly difficult as our responsibilities continue to pile up. I would like to encourage all leaders to get out of the crisis-management mode that we often find ourselves embroiled in. If you believe in Pareto’s 80/20 principle, then you will want to concentrate on the top 20% of your activities that provide 80% of your impact. You may want to ask yourself how many of the items on your list are important to someone else, but not to you. Can you bounce issues and tasks back to others? There are three questions that can help you focus when your priorities feel fuzzy. First, what gives you the greatest return?

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

Ernest R. Anderson Jr., MS, RPh

Second, what is the most rewarding? And third, what is required? We all are looking for results and efficiency. Some of the keys to success include providing systems and structures, prioritizing planning and vision and simplifying through standardization (to minimize variation and to maximize other’s strengths, empowering everyone to take responsibility and action).

We All Make Mistakes We’re all human, therefore we make mistakes. We all recognize this fact. What we also need to recognize is how to handle our mistakes. Good leaders need to acknowledge their mistakes to people above and below them in the hierarchy. We also need to learn from our mistakes in order not to repeat them. When we admit to mistakes, particularly to those we lead, we are acknowledging our weaknesses. By doing so, we invite others to honestly share, too, without fear of retribution. Fear immobilizes people and teams. I often say to those who report to me: “Let me know when I am doing something wrong, if I am going in the wrong direction or if I am missing something.” This requires abundant trust, in both directions. Accepting negative feedback constructively is the sign of a mature leader. This is the price of progress. Avoid taking criticism personally or defensively. Thank the person and work to improve. Do not rule

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see MORE NUGGETS, page 53

Leadership advanced degree component, she added, are unique to the PLA. Vanderbilt’s Mr. O’Neal, who now plans to pursue a dual MHA and MBA, pointed to other opportunities for pharmacists to enhance their leadership skills, including the Pharmacy Leadership Institute held at Boston University once a year. “But the PLA is the first I’ve seen that is so comprehensive, where you have classmates collaborate and share ideas,” he said. Another unique aspect of the PLA is its target audience: not students or residents, but career pharmacists who have spent years, even decades, in the field. “We’re still a huge group of pharmacists that needs to be invested in,” noted Mr. O’Neal. And with all the programs available

‘Rather than just doing random CE to learn a little more about whatever new drug is out there, this program actually advances a skill set. That’s the better model for maintaining our practice ….’ —Patricia A. Marken, PharmD

online, career pharmacists don’t have to leave work to go back to school. Roger Woolf, PharmD, administrative director at Virginia Mason Medical Center, in Seattle, has put five individuals through the PLA. One went on to complete an MHA certificate; two are currently in the MHA degree program at the University of Washington; and a third will start next year. “At the

time the leadership academy was initiated, I had a relatively young management team but one with strong potential for assuming leadership roles,” he said. “They all will continue to expand their leadership roles in health care.” But Dr. Woolf notes that the PLA is not the end-all answer to health-system pharmacy’s leadership dilemma. “The PLA does not automatically prepare

individuals for a formal leadership role,” he said. “It does, however, provide some background knowledge and an introduction to the concepts that new leaders need to develop. To be most effective, the PLA program also has to be paired with mentoring and coaching as the participants are allowed to integrate their new knowledge and projects into their day-to-day work.” A rolling application process is under way for the PLA class of 2012. Requirements, costs and other details can be found on the ASHP Foundation Web site (www.ashpfoundation.org). —Lynne Peeples The sources in this story did not report any relevant conflicts of interest.

Hem/Onc Pharmacy

Pharmacy Practice News • July 2011

In Focus

Yervoy Part of a One-Two Melanoma Data Punch at ASCO Chicago—One year ago, the monoclonal antibody ipilimumab generated big news as an agent that could provide a survival benefit in second-line therapy for metastatic melanoma. At this year’s annual meeting of the American Society of Clinical Oncology (ASCO), two Phase III latebreaker trials (LBA4 and LBA5) demonstrated that ipilimumab and a new agent, vemurafenib, improved survival in advanced melanoma, this time in firstline treatment. Vemurafenib, an inhibitor of BRAF kinase, is effective when advanced metastatic melanoma is positive for the V600EBRAF mutation.

Crystallographic structure of BRAF.

‘For a two- to four-year remission of metastatic melanoma, a lot of severe toxicity becomes quite acceptable. It certainly beats dying.” —Steven Vogl, MD Ipilimumab (Yervoy, Bristol-Myers Squibb) received regulatory approval in March 2011. If vemurafenib (Roche) receives regulatory approval, clinicians will have two highly active therapies from which to choose, at least for those advanced melanomas with the V600E BRAF mutation, a mutation present in about half of these cancers. This is an impressive leap forward, but the ASCOinvited discussant of these two studies, Kim Allyson Margolin, MD, Division of Medical Oncology, University of Washington, Seattle, cautioned that the clinical choice between these two agents is not yet straightforward. The decision for those with a V600E BRAF-positive melanoma is between “starting with a drug that has a rapid onset and very early evidence of anti-tumor activity but potentially limited duration of control, versus starting with an agent that has a slower mecha-

nism-dependent onset but may provide a plateau of long-term disease control in a substantial proportion of patients,” explained Dr. Margolin, referring to ipilimumab and vemurafenib, respectively. “Unfortunately, we cannot yet, in either case, further subset the patients to preidentify those with a therapeutic index that would be superior to the overall pooled results for each drug that we heard about today.”

Ipilimumab Data In the Phase III study of ipilimumab, which binds to cytotoxic T lymphocyteassociated antigen 4 (CTLA-4), 502 patients with metastatic melanoma previously untreated for advanced disease were randomized to 10 mg/kg ipilimumab or placebo. Both groups received 850 mg/m2 dacarbazine (DTIC). The therapies were administered at weeks 1, 4, 7 and 10 and then DTIC was given every three weeks through week 22. This was followed by maintenance ipilimumab at the same dose or placebo administered every 12 weeks. With up to four years of follow-up, investigators identified a 28% improvement in overall survival (OS) (hazard ratio [HR], 0.72; P=0.0009) among those randomized to the ipilimumab arm. The rates of survival were superior at year 1 (47.3% vs. 36.3%), year 2 (28.5% vs. 17.9%) and year 3 (20.8% vs. 12.2%). The median progression-free survival (PFS) was increased modestly (2.8 vs. 2.6 months), but it was highly statistically significant (HR, 0.76; P=0.006), and median PFS “may not tell the most important part of the story,” said Jedd D. Wolchok, MD, PhD, associate director, Ludwig Center for Cancer Immunology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York City. He presented the results on behalf of participating centers in 24 countries. Dr. Wolchok noted that objective response rates were not only higher in the ipilimumab arm but that durability of these responses, reflecting the biologic activity of the drug, was far longer (19 vs. eight months). Responses have now been observed in a small number of patients out to four years. Steven Vogl, MD, an oncologist who practices in White Plains and Bronx, N.Y., said he had “grave reservations” about the initial study that led to ipilimumab’s approval. His main concern? The absence of an interpretable control group—the monoclonal antibody was compared against the gp100 vaccine, rather than any accepted standard of care. He said the new data presented at ASCO has convinced him

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see MELANOMA DRUGS, page 40

Pharmacists Play Key Supportive-Care Role in Ipilimumab Therapy

pilimumab may be one of the few breakthroughs in melanoma therapy in the last generation, but if the monoclonal antibody’s considerable side effects are not managed effectively, its impact on the disease could be compromised, according to Jamie Poust, PharmD, BCOP, a hematology/oncology pharmacist who participated in clinical trials of the drug. Dr. Poust already has assumed an aggressive supportive-care role with ipilimumab (Yervoy, Bristol-Myers Squibb) at the University of Colorado Hospital, in Aurora, one of the top melanoma centers in the United States. Here are some of her top-line recommendations for managing patients on the chemotherapy: Educate physicians. The immune-mediated side effects caused by ipilimumab—for example, severe colitis and diarrhea—as well as hormone changes caused by the drug’s effect on the endocrine system “are a very different subset of adverse reactions that physicians are not used to seeing,” Dr. Poust said. “They have a much more complicated presentation, can be more severe, and can last longer than the side effects of other drugs they’re used to handling.” Because of that unfamiliarity, she added, “physicians understandably are not always comfortable managing these side effects. This is an opportunity for pharmacists to step in with education.” Dr. Poust suggested educating not just oncologists but also emergency department physicians who are often on the front lines of seeing patients with ipilimumab-related reactions. “Also, don’t forget about family physicians—they may be fielding calls from patients, who may say something as nonspecific as, ‘I’m feeling weird or awkward inside,’ or ‘I am really tired lately.’ That could be due to the drug’s endocrinopathy, and without your reaching out to them, the physician may not make the connection to the drug. So there should be a lot of direct involvement on that front by pharmacists.” Dr. Poust also stressed the importance of educating not just veteran physicians. “At our hospital, we also reach out to the medical residents. That’s something we learned when we had patients who were taking ipilimumab as part of the clinical trial who were admitted with adverse reactions to the drug. The residents need to be up to speed on these issues if they’re going to manage patients optimally.” Another education tip is to let all physicians and patients know that ipilimumab side effects can persist for up to two months after the drug is stopped. Thus, “it’s important that everyone take very thorough medical histories, so that any previous drug therapies such as impilimumab are noted.” Be vigilant for life-threatening side effects. Colitis and diarrhea “are one of the most problematic autoimmune side effects of ipilimumab,” Dr. Poust said. “We recently had a patient whose GI [gastrointestinal] problems were so severe that we had to treat them with high-dose steroids and infliximab [Remicade, Centocor Ortho Biotech], which blunts some of the T-cell activation that ipilimumab stimulates as part of its mechanism of action. If these GI side effects aren’t managed aggressively, they can rapidly become life-threatening.” Initiate early supportive care. “When we saw how quickly some of the adverse reactions to ipilimumab began to occur in the clinical trials, we started to give patients steroids earlier in the course of therapy, and that has made a big difference in outcomes,” Dr. Poust said. In fact, she noted, because of that aggressive strategy, very few of her patients have needed infliximab therapy. Don’t be surprised by an uptick in adverse drug reactions (ADRs). Now that ipilimumab has been approved and will be used on a more widespread basis, Dr. Poust noted, “I’m a little bit concerned that the incidence of adverse reactions may begin to climb.” This is likely to occur, she noted, because patients “are no longer being managed as aggressively as we would if we were paying close attention to them during a clinical trial of the drug, where patients have study coordinators monitoring them all the time. I am very curious to see what will happen to the number of ADRs that will be filed going forward. My guess is that we’ll see an increase, but the question is how much.” The bottom line with ipilimumab therapy? In Dr. Poust’s view, “it’s a bona fide treatment breakthrough,” but with significant management issues that pharmacists need to help the care team address proactively. “The infusion itself is not a problem—there are no infusion-related reactions to contend with, unlike what you would normally see with other monoclonals,” she said. “The challenge comes later, when the side effects really begin to crop up and clinicians’ education and close follow-up by the pharmacist can literally be lifesaving.” —David Bronstein

Hem/Onc Pharmacy

Pharmacy Practice News • July 2011

In Focus

MELANOMA DRUGS continued from page 38

that the drug has activity. “The biggest influence is not at the median, but in some long responders who live a long time, presumably doing well. I would love to see some work done on identifying, before the first dose, those likely to have long responses compared to the rest.” Such a study will save society a lot of money and spare toxicity for patients who will not derive benefit from the drug, he noted. “For a two- to four-year remission of metastatic melanoma, a lot of severe toxicity becomes quite acceptable,” Dr. Vogl added. “It certainly beats dying.” Jamie Poust, PharmD, BCOP, an oncology pharmacy specialist at the University of Colorado Hospital, in Aurora, who participated in the ipilimumab clinical trials that led to its FDA approval, said she agreed that the use of a vaccine as a comparator was problematic. “The early trial results were certainly interesting and encouraging,” she told Pharmacy Practice News. “But a vaccine is by no means definitive care in melanoma, and most of the clinical trials that have looked at vaccines for this malignancy over the past 10 years have not panned out. So those initial [ipilimumab] results didn’t have very much clinical relevance for our practitioners.” The ASCO data, in contrast, “hit the nail on the head, in terms of confirming the initial efficacy of the ipilimumab, and most importantly, it did so in a comparison against a treatment (dacarbazine) that is in fact consid-

ered the standard of care for metastatic melanoma. To see that the data are holding up and the drug is now producing durable responses for longer periods of time is really encouraging.” Once the latest ASCO data were released, she noted, “we felt that we were ready to finally present this drug to our Pharmacy & Therapeutics Committee. I actually presented it, and it got passed.” The challenge going forward, Dr. Poust said, is to continue to adequately manage the immunemediated side effects of ipilimumab— a role that she says pharmacists are “uniquely qualified” to play on the health care team (sidebar, page 38).

Vemurafenib Data In the Phase III trial of the oral agent vemurafenib, 675 patients with previously untreated unresectable stage IIIC or IV melanoma positive for V600EBRAF were randomized to 960 mg twice daily of vemurafenib or 1,000 mg/m2 DTIC given every three weeks. OS and PFS were co-primary end points. The randomization of patients was stratified by stage, geographic region and lactate dehydrogenase, a marker of poor prognosis. At the preplanned interim analysis, there was a 74% improvement in OS (HR, 0.26; 95% CI, 0.20-0.33; P<0.0001) and a 63% improvement in PFS (HR, 0.37; 95% CI, 0.26-0.55; P<0.0001). In the evaluable patients, the response rates also have been profoundly higher in the

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‘To see that [earlier ipilimumab] data are holding up and the drug is now producing durable responses for longer periods of time is really encouraging.’ —Jamie Poust, PharmD, BCOP

Above, melanoma cells and tumors.

vemurafenib arm (48.4% vs. 5.5%). The estimated six-month survival rates were 84% for vemurafenib compared with 64% for DTIC. Benefits were seen across all of the subgroups evaluated. The interim data led the independent Data and Safety Monitoring Committee to halt the control arm. “Due to these data, the DTIC cohort has been allowed to cross over to vemurafenib,” reported Paul B. Chapman, MD, an MSKCC attending physician. Presenting these data on behalf of a consortium of 104 participating centers around the world, Dr. Chapman indicated that the activity of the agent suggests it will be a major addition to options for control of advanced melanoma, a disease for which options have been extremely limited.

Adverse Events Adverse events (AEs) were not insignificant with either ipilimumab or vemurafenib. Ipilimumab, which has been given a black box warning by the FDA for severe and potentially fatal immune reactions, produced twice as many grade 3 or 4 AEs in combination with DTIC than DTIC with placebo (56.3% vs. 27.5%). The most common AEs were elevations in alanine aminotransferase (21.9% vs. 0.8%) and aspartate aminotransferase (18.2% vs. 1.2%). For vemurafenib, greater rates of arthralgia, rash, and diarrhea were observed in the experimental arm, but the most significant concern may be the greater rate of cutaneous tumors, particularly squamous cell carcinomas, observed in patients on vemurafenib relative to DTIC. These were excised when they occurred and may not pose a long-term risk, but caution is needed. “Experience in recognizing and managing the side effects and toxicities of both of these novel agents is required as well as a strong commitment to compliance, particularly in regard to reporting and managing of symptoms on the part of both the patient and the family,” suggested Dr. Margolin. According to data from the ipilim-

umab trial, it is not clear that the addition of DTIC added any therapeutic benefit, she said, but it did appear to increase the rate of hepatotoxicity. In particular, it was associated with an increased rate of grade 3 or greater liver enzyme elevations. However, rates of high-grade colitis, diarrhea and endocrinopathy were all lower than expected based on prior ipilimumab monotherapy studies. The relative clinical efficacy of ipilimumab in the absence of DTIC is unknown, but Dr. Margolin suggested that it is possible that higher doses provided as a monotherapy may increase response rates, but further study is needed. Dr. Vogl said clinicians need “some quickly done studies looking at dose of ipilimumab, combination with DTIC, rules for stopping and continuing the drug, and biomarkers to identify those likely to have long remissions.” He also voiced concern with the recommendation of continuing ipilimumab in the face of progressive disease. “I would like to know how many patients benefitted even if they had early progression, and if there was anything special about them,” he said. Overall, the introduction of two agents with activity against late-stage metastatic melanoma may make sequencing of agents “trickier,” according to Dr. Margolin. Although it might be reasonable to employ vemurafenib as a second-line agent in patients with the V600EBRAF mutation who have progressed on firstline ipilimumab, this has not been tested. Both agents may provide a basis on which to explore combinations in order to further extend OS. While Roche seeks approval of vemurafenib, the drug is available through a global Expanded Access Programme. —Ted Bosworth, with additional reporting by David Bronstein Dr. Wolchok disclosed he is a consultant to BMS and his study was sponsored by BMS. Dr. Chapman disclosed his study was sponsored by Roche and that he is a consultant to and has received research funding from Roche. Dr. Margolin had no relevant disclosures. Dr. Vogl owns stock in BMS. Dr. Poust disclosed no relevant conflicts of interest.

www.BioOncology.com

Taking a broader view — charting a unique course in cancer care

At Genentech BioOncology, not only are we leading the fight against cancer with innovative science, but we’re also dedicated to supporting patients and others within the oncology community. A commitment to patients — We created Genentech BioOncology™ Access Solutions®, a single source for all access and reimbursement issues, so healthcare providers can remain focused on patient care. Reducing barriers to treatment — We help make treatment possible for patients in financial need through our BioOncology Co-pay Card Program and ongoing charitable donations to various independent, nonprofit organizations in support of co-pay assistance. A commitment to care — Our first product was approved in 1985, and since then we have donated approximately $2.3 billion in medicine to uninsured patients through the Genentech® Access to Care Foundation and other donation programs. Our goal is to fundamentally change the way that cancer is treated by personalizing solutions to patient care.

Hem/Onc Pharmacy

Pharmacy Practice News • July 2011

In Focus

New Gold Standard Proposed for High-Risk GIST Three years of imatinib One year of imatinib

Recurrence-free Survival Rate, %

100 80 65.6

60 47.9

40 20 0

Figure 1. Five-year recurrence-free survival in GIST.

Three years of imatinib One year of imatinib

100

Overall Survival Rate, %

Chicago—A three-year course of therapy with imatinib (Gleevec, Novartis) after surgery soon may become the new standard of care for patients with resected gastrointestinal stromal tumors (GIST) who are at high risk for relapse. In this patient population, the threeyear course of therapy improved the five-year overall survival rate by roughly 10% compared with patients who received imatinib for one year, which is the current standard treatment. “I think that three years of imatinib will become the standard of care for adjuvant treatment of high-risk GIST for patients at risk for relapse,” said Heikki Joensuu, MD, professor of oncology at Helsinki University Central Hospital in Helsinki, at the recent American Society of Clinical Oncology (ASCO) annual meeting (abstract LBA1). Previous trials have shown that one year of adjuvant imatinib reduces the risk of GIST recurrence compared with placebo but have not yet demonstrated an improvement in survival. Approximately 85% of patients who have advanced GIST respond to imatinib, with partial remission or stable disease lasting a median of two years. High-risk GISTs, which are defined by clinical factors including size (>5 cm), high cell proliferation rate and/ or location, are associated with at least a 50% five-year risk for recurrence after surgery, said Dr. Joensuu. At the ASCO meeting, Dr. Joensuu presented results from a prospective, open-label, randomized Phase III study carried out in Finland, Germany, Norway and Sweden. The study randomly assigned 400 high-risk GIST patients to one year of imatinib (200 patients, median age 62 years) or three years of imatinib (200 patients, median age 60 years). All patients received imatinib 400 mg daily. After a median follow-up of 54 months in the intention-to-treat population, the results showed a significantly higher five-year recurrence-free survival in patients treated for three years compared with one year (65.6%

92 81.7

60 40 20 0

Figure 2. Five-year overall survival in GIST. vs. 47.9%; P<0.0001) (Figure 1). Similarly, the five-year overall survival rate was significantly higher for patients receiving imatinib for three years (92% vs. 81.7%; P=0.019) (Figure 2). “The longer treatment prevented recurrence of GIST in 54% of patients, and there were 55% fewer deaths in the three-year versus the one-year group,” Dr. Joensuu said. “Historically, 50% of GIST patients had died within five years. With imatinib, we are making substantial improvements.”

The treatment was well tolerated, with the most frequent side effects including anemia, eyelid swelling, fatigue, nausea and muscle cramps, which were usually mild. There were slightly more treatment discontinuations due to adverse events in the three-year group (14% vs. 8%) and slightly more grade 3/4 adverse events in the three-year group (33% vs. 20%). As in previous studies, few patients developed resistance to adjuvant imatinib. Only 2% of patients in the oneyear group and 6.1% of those in the three-year group stopped treatment because of GIST recurrence while receiving imatinib. “Compared to one year of adjuvant imatinib, three years of imatinib improves recurrence-free survival and overall survival as treatment of GIST patients who have a high estimated risk for recurrence after surgery,” Dr. Joensuu said. He noted that there are no data that these patients might survive longer if they received five years of adjuvant imatinib, but that studies analyzing GIST risk factors and addressing longer treatment times with adjuvant imatinib are currently under way. Clinicians need to follow these patients carefully to detect early recurrence, he said. “There is evidence that patients with small tumors will respond longer to imatinib than patients with bulky tumors,” said Dr. Joensuu. “If we can detect the tumor when tumor volume is small, there is less likelihood the patient will develop resistance to imatinib.” Charles Blanke, MD, chief of medical oncology at University of British Columbia, Vancouver, was asked to discuss the study at ASCO. “Three years of postoperative imatinib treatment represent the new gold standard for patients with resected, high-risk GIST,” Dr. Blanke said. “The overall survival advantage demonstrated means we cannot try to ‘catch up’ later in the advanced disease setting.” Dr. Blanke pointed out that imatinib is not a cure for advanced GIST. “Even

Endoscopic image of GIST in fundus of stomach, seen on retroflexion.

patients in complete remission at five years are not cured and need to stay on imatinib,” he said. “We also still don’t know how long to administer imatinib for GIST in the postoperative setting.” Dr. Blanke asked, “Should we treat longer than three years? Should we treat forever? There are many reasons to think that giving imatinib for a longer period would be better. For now, if I were a patient with resected GIST, I would request more. As a compliant oncologist, I personally will offer imatinib indefinitely. I reserve the right to change my mind, pending the longerterm overall survival results from SSG [Scandinavian Sarcoma Group] XVIII and the findings from the recently completed PERSIST-5 trial. But I don’t think GISTs are curable (with imatinib) even in the adjuvant setting.” At the moment, Dr. Blanke said, “Given the possibility that we need to treat for a very long term, coupled with the difficulty in patients taking long durations of the drug, I will recommend adjuvant imatinib to patients who have a 50% chance of recurrence following surgery.” He believes the number used to predict recurrence and then treat will be lower in the community. Drs. Joensuu and Blanke disclosed that they serve in a consultant or advisory role for Novartis. Dr. Joensuu has also received honoraria from the company.

—Mark Fuerst

FDA NEWS

Istodax Approved for PTCL

he FDA has granted accelerated approval for romidepsin for injection (Istodax, Celgene) for the treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication has been granted based on response rate; clinical benefit, such as improved overall survival, has not been demonstrated. The approval is based on results from two studies. One of the studies was a Phase II, multicenter, international,

open-label study of romidepsin in progressive or relapsed PTCL following prior systemic therapy. In the study, patients with histopathologically confirmed PTCL who failed or were refractory to prior systemic therapy received 14 mg/m2 of romidepsin as a four-hour infusion on days 1, 8 and 15 of a 28-day cycle for up to six cycles. Treatment could be extended for response or stable disease. Of 130 patients with histopathologically confirmed PTCL in the study, the overall response rate (ORR) was 26%, as assessed by an Independent Review

Committee (IRC). Thirteen percent of patients achieved a complete response (CR), the primary end point of the study, and another 13% achieved a partial response (PR). The median duration of response for all patients who responded was 12 months. The median duration of response for patients who achieved a CR has not been reached (median duration of follow-up: 8.2 months), and 82% of patients with a CR had not progressed as of the data cutoff for the IRC evaluation. In the study, 96.2% of patients evaluable for safety experienced at least one

treatment-emergent adverse event (AE), with the most common grade 3 or higher AEs reported as thrombocytopenia (24%), neutropenia (20%), infections (17%) and anemia (10%). In a second Phase II study of 47 patients with PTCL, CRs were observed in eight and PRs in nine of 45 patients, for an ORR of 38%. The median duration of overall response was 8.9 months (range, two to 74). Responses were observed in various subtypes, with six responses among the 18 patients with prior stem cell transplant.

44 Clinical

Pharmacy Practice News • July 2011

Medication Safety

TRANSPLANT continued from page 1

to 10 items, labeling them as definite (>9), probable (5-8), possible (1-4) or doubtful (0). During the three-month study period, 48 cardiac transplant patients were hospitalized. The mean time from transplant was 4.5 years. Mean number of medications on admission was 16, with an average of eight chronic diseases noted per patient. There were no differences in gender, age, admitting serum creatinine level, number of medications, number of chronic disease states or time from transplant. Drug-related problems accounted for 19 of 48 admissions (40%), 11 of which were considered preventable (58%), Dr. Repp reported. The types of drug-related problems included adverse drug reactions (32%), supratherapeutic dosage (32%), subtherapeutic dosage (16%), untreated indications (11%), nonadherence (5%) and drug interaction (5%). No admissions were attributed to improper drug selection or drug prescription without an indication. Pharmacologic classes implicated included immunosuppressants (63%), antimicrobials (11%), electrolytes/fluids (11%), anticoagulants (5%), antiseizure agents (5%) and other classes (5%). One preventable case involved a patient started on valganciclovir who developed gastrointestinal upset but presented only after becoming severely dehydrated, and as a consequence was found to have decreased renal function and reduced clearance of tacrolimus. This was classified as a supratherapeutic dose of tacrolimus and a preventable problem. A problem that was deemed unpreventable involved a patient with a complicated medical course and recent history of urosepsis and pneumonia. The patient, who was already on three immunosuppressive medications, was prescribed antibiotics and later admitted to the hospital for a Clostridium difficile infection that was most likely secondary to the immunosuppressant and anti-infective drug therapy. “It is unlikely that medication changes would have prevented this event,” Dr. Repp said. The drug problems documented in the study were associated with longer hospital LOS: mean 11.4 days versus 8.5 days for admissions not related to drugs, although the difference was not statistically significant (P=0.458). “When annualized, we determined that 44 hospitalizations or 500 hospital days could be prevented,” she said.

A Challenging Population The results underscore the challenge of treating these complicated patients. “In the general population, drug-related problems are less of a problem—they cause about 15% of all hospital admis-

‘We see twice the national average for drugrelated problems in our cardiac transplant patients because of polypharmacy.’ —Michael A. Shullo, PharmD

sions and approximately 30% are preventable,” Dr. Repp said. “Cardiac transplant patients, in contrast, are clearly at

an increased risk, based on our results, and it may be due to their complicated

medication regimens, which include drugs with narrow therapeutic windows.” The drug problems uncovered

Step up to a range of insulin delivery options.

As part of Eli Lilly and Company’s ongoing commitment, we provide healthcare facilities with a choice of vial sizes. Humalog® (insulin lispro injection [rDNA origin]), Humulin® R U-100 (regular insulin human injection, USP [rDNA origin]), and Humulin® N (NPH human insulin [rDNA origin] isophane suspension) are available in a smaller vial size.* The smaller vials are designed to give healthcare facilities ﬂexibility when evaluating insulin storage and distribution (ﬂoor stock vs individual patient supply), in addition to the 10 mL vial and Humalog® KwikPen™. • Humalog Smaller Vial* NDC Number - 0002-7510-17 • Humulin R U-100 Smaller Vial* NDC Number - 0002-8215-17 • Humulin N Smaller Vial* NDC Number - 0002-8315-17 * 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. Humalog should be used with longeracting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.

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

Pharmacy Practice News • July 2011

Clinical 45

Medication Safety in the study “also underscore the need for multidisciplinary care,” she stressed.

Polypharmacy Among Culprits Michael A. Shullo, PharmD, assistant professor at the University of Pittsburgh School of Pharmacy in Pittsburgh, and clinical pharmacist for the transplant service, said the findings are no surprise to him. “We see twice the national average for drug-related problems in our cardiac transplant patients because of polypharmacy,” he said. “Drug therapy has profound potential for multiple

interactions, and pharmacists must be diligent about verifying these adverse events.” Dr. Shullo said that although electronic medical records do capture drug-related problems, they do so “at a very sensitive level that often is not clinically relevant. In transplant, there are drug–drug interactions and there are dynamic interactions that are not captured nearly as well.” Patients may have a drug added to their treatment regimens without the knowledge of the transplant pharmacist,

Dr. Shullo continued. “At the University of Pittsburgh, the most common interaction is generally one caused by [someone] not on the transplant team, adding a product that normally would be good for patient care but is not so good for the transplant patient. We count on the dispensing pharmacist to be alert to things that do not seem right.” Dr. Repp agreed that the pharmacist’s role is crucial in this setting. In fact, “at Saint Luke’s, as a result of our research, we increased the number of pharmacists dedicated to [cardiac] polypharmacy, and

Humalog Important Safety Information, continued

Warnings, continued Starting or changing insulin therapy should be done cautiously and only under medical supervision.

Other Side Effects, continued 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 potassiumlowering drugs, or taking drugs sensitive to serum potassium level).

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. Because of the difference

Please see adjacent pages for Brief Summary of full Prescribing Information for Humalog. 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.

we provide a better continuum of care between inpatient and outpatient services. This position is still evolving and we have not re-measured to quantify its impact. But as Dr. Shullo pointed out, we not only need transplant pharmacists watching for drug-related problems, but community pharmacists as well. We all need to be diligent in identifying these problems.” —Caroline Helwick Drs. Repp and Shullo reported no relevant conflicts of interest.

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 Humalogtreatment 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 wellcontrolled 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. 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 longeracting 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) 5 x 3 mL cartridges3 NDC 0002-7516-59 (VL-7516) 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) 1

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]) 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 3 mL 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.

48 Technology

Pharmacy Practice News • July 2011

2011 unSummit

Post-Rollout, BCMA Vigilance Urged Louisville, Ky.—Implementing a bar code medication administration (BCMA) system is labor-intensive, but the real work starts after the technology rollout, Jerry Fahrni, PharmD, currently product manager at Talyst, in Bellevue, Wash., said at the 2011 unSummit for Bedside Barcoding meeting. “Like most people in health care, we implemented our BCMA system and then we forgot about it,” said Dr. Fahrni, a veteran of BCMA in his former post as IT pharmacy specialist at Kaweah Delta Medical Center, in Visalia, Calif. “I don’t think most people realize that it takes just as much work following implementation to optimize it, standardize it, and keep everything up and running smoothly.” Dr. Fahrni gave some suggestions for steps that stakeholders can take postimplementation to make sure their new BCMA system they have worked so hard to establish functions, so that it doesn’t start to “crumble before their eyes.”

First, Develop the Right Team “Everybody develops a team before BCMA implementation, but I think people fail to develop a team post implementation that will come back and make sure the system is working properly,” Dr. Fahrni said. The team should be interdisciplinary and involve pharmacists and nurses from all areas of the hospital. “We had nurses coming from the emergency department, from rehab, from our

mental health department, our intensive care unit, our obstetrics department, and they all had something to bring to the table,” Dr. Fahrni said. The role of the nurse as the end user of the technology should not be underestimated, he emphasized. “I can’t tell you the number of times I’ve sat down at meetings and saw nothing but administration, directors, sitting across the table from me. As great as that is, it doesn’t really help the process because they tend to be disconnected from what’s going on at the bedside, so it’s important that you get the bedside nurse in, free them up, give them the time to come in and sit down and talk with you.” The second thing that needs to be done is to go through all reports and data that are being generated by the new system on a regular basis. All too often, these data are ignored. Once a procedure is in place for reviewing the data, hold people accountable for the information that is brought to the fore and meet on a regular basis to discuss what is going on. “This keeps everyone on top of any problems that might be developing so that you can act on them right away,” Dr. Fahrni said. Next on the list is troubleshooting. Sometimes the problem can be with the hardware that is not functioning properly, the software, the product or the user. “The biggest problem we had was that some of the bar codes were difficult to scan. People would continue to scan

problematic bar codes until they got it instead of telling me. If you can’t scan the med in three attempts, then the bar code is no good and you need to figure out another way to handle that bar code.”

Create a Culture of Safety Even when hardware and software are running well, the human element can have a negative impact, especially when people have a poor attitude about bar coding. “When someone speaks negative thoughts, that can be contagious,” Dr. Fahrni said. “Working toward making all members of the health care team accountable for the success of BCMA is key. Change the culture of your organization, if necessary; you want to foster a culture that really believes in the value of safety.” He added that there should be zero tolerance for people who willfully disregard the BCMA system. “If it’s an honest mistake, you accept it as honest and move on. But don’t let a just culture be an excuse to ignore bad behavior. If somebody willfully disregards your system, they’re putting themselves, the hospital and the patient at risk.” Chris Urbanski, RPh, MS, director, pharmacy informatics and medication integration at Clarian Health Partners in Indianapolis, agrees that much work remains to be done once BCMA is implemented. “We tend to underestimate the resources needed to support systems like

this once they are live,” he told Pharmacy Practice News. “They tend to work extremely well for us in the test lab as well as during a pilot implementation, but once the implementation is widespread, there are lots of potential failure points. The end users cannot always interrupt their job of direct patient care to call the help desk to report a problem.” Mr. Urbanski said that his center has had to redeploy resources several times to nursing units for direct observation and discussions with staff to understand the issues that arise after they implemented BCMA. He also agreed that reviewing reports on a regular basis is important. “It is very helpful to look at these reports to look for trends that might suggest the system is not working as intended.” However, Mr. Urbanski cautioned that reports can be misleading. “Scanning compliance numbers might look appropriate but need to be validated to be sure users are not working around the system,” he said. In addition, Mr. Urbanski suggested that the nursing leadership should be charged with regular review of data for their respective areas “so follow-up can be sure and swift.” —Fran Lowry Dr. Fahrni disclosed that he is an employee of Talyst. Mr. Urbanski reported no significant financial relationships.

Automation

Ultrasound-Guided Pump Refill May Boost Patient Safety U se of an ultrasound-guided intrathecal pump may improve drug delivery and prevent the complications often associated with this procedure, according to a new study. Intrathecal drug delivery involves implanting a pump that can bring medication to a particular location. Although it may provide continuous and effective relief in patients with chronic pain, morbidity and even mortality may be associated with pump maintenance. Of particular concern is the “pocket fill,” which refers to misplacement of the needle during pump refill and may cause delivery of toxic doses of medication. Officially, eight deaths and 270 serious or life-threatening injuries requiring medical intervention have been reported due to pocket fills; the real numbers may be even higher. “In my hospital, there were five admissions last year of patients who experienced complications related to pocket fills. All events happened

at offices of outside providers, and patients were rushed to the emergency department,” said study co-author Michael Gofeld, MD, assistant professor of anesthesiology, pain medicine and neurological surgery at the University of Washington (UW) School of Medicine, in Seattle, and clinical director of the UW Center for Pain Relief. To determine the safety and efficacy of the real-time ultrasound-guided pump refill, Dr. Gofeld and colleagues performed a preclinical feasibility study, using unembalmed cadaver models with either an inverted or deeply implanted pump (Pain Med 2011;12:607-611). “Our goal was to find safe and reliable access to the pump in a difficult situation where the pump cannot be palpated,” Dr. Gofeld said. In the study, the team first tried to implant the pump in a cadaver with a heavy body frame, which is consistent with the typical clinical situation of a difficult pump refill. As expected, palpation of the pump was not possible. The

researchers then attempted ultrasoundguided access using two needles to replicate reservoir and pocket fill conditions. One operator performed the refills and another, the observer, assessed whether an inter- or intrapump fill had been done. The researchers studied sonographic images of those conditions and developed an ultrasound-guided technique for accessing the pump injection port. They found that clinicians who were inexperienced with ultrasound learned the procedure quickly, in about 30 minutes, and were able to distinguish reservoir from pocket fill after one or two 0.5-mL injections 100% of the time. “When the injection is done inside the pump through the port, you see it as a color cone. When it’s done outside the pump into the pocket, you don’t see any consistent column spread—it’s kind of speckled,” Dr. Gofeld explained. He noted that the feedback to his study has been “phenomenal,” adding that his team already has trained the physical medicine rehabilitation nurses

to use the new technique. “Several colleagues say that this technique should be accepted as a standard of care for difficult cases,” he said. “We don’t have any decent imaging alternatives in clinics and offices for difficult patients.” Timothy Deer, MD, president of the Center for Pain Relief, in Charleston, W.Va., agreed that the study findings are important for pain practitioners who deal with pump refills. “This is a small study, but it gives us a good indication of improving safety,” he said. “The problem associated with filling into the pocket is rare, but when it does occur, it’s deadly. That is why this study is very important to ensure safety in difficult patients.” —Laura Tendler Dr. Gofeld acknowledges receiving equipment support from Philips and Medtronic to complete the study. Dr. Deer is a consultant for St. Jude Medical, Codman, Azur and Medtronic.

ACHIEVED

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1 Quandt, W. and Drucker, L. Methodist Hospital System Reaps Financial Results with Shared Pharmacy Services. Pharmacy Practice News, July 2011. First quarter 2011 results. Reflects individual facility data. Your facility may or may not achieve similar results. © 2011 CareFusion Corporation or one of its subsidiaries. All rights reserved. MedStation and Pyxis are trademarks or registered trademarks of CareFusion Corporation or one of its subsidiaries. PHACTS and Pharmogistics are trademarks or registered trademarks of PHACTS, LLC or one of its subsidiaries. DI2905 (0611)

50 Technology

Pharmacy Practice News • July 2011

2011 unSummit

ACCOUNTABILITY continued from page 1

the successes but also the failures in improving patient safety in their hospitals, she stressed. A lack of accountability can have a very negative impact on the work the team is trying to do, and also on the morale of team members. “Often you have resentment among team members for various reasons. Some have different work ethics, or different ways of approaching things,

or just different standards of performance,” Dr. Miller noted. “Also, when you have a team without accountability, you just get average work and you begin to accept that mediocrity.” Teams that lack accountability miss deadlines and place undue pressure on

those team members who are willing to work hard to implement patient safety, she added.

Barriers to Success After BCMA was instituted in the HCA consortium of hospitals, Dr.

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Miller and her colleagues began to ask questions to find some of the barriers that were preventing the program from developing and moving forward. They found that team members were blaming each other, rather than taking responsibility for the success of the project as a whole. “Some told us it was pharmacy’s fault, some blamed the biomed people, some blamed the information technology staff. There were a lot of excuses, and it was a prime example of people not being held accountable and just finger pointing,” she said. But the multidisciplinary team began to work more cohesively after potential problems were identified. Also, specific responsibilities for each team member were elucidated. As these measures evolved and were adopted, team members began to feel comfortable with one another. “They felt comfortable questioning each other’s approach. They weren’t afraid of being wrong. Respect was established and everyone was held to the same standards. We made it possible for poor performers to feel pressure to improve, but in a respectful way,” Dr. Miller said.

Steps To Creating More Accountability Jon Lakamp, PharmD, vice president of pharmacy at Sisters of Mercy Health System, in St. Louis, and a co-presenter at the unSummit session, detailed more thoroughly how accountability can be established. He listed responsibilities for some of the key players on the BCMA team. As members became more accountable for their actions, compliance with bar-code scanning rose. At Sisters of Mercy hospitals, compliance was less than 90% when BCMA was first instituted. Two years later, it was 95% and continues to rise, he said. The first key player is the top executive. “The executive leader’s role involves setting expectations,” Dr. Lakamp said. “It’s all about assuring that the automation is sound and actually works, and communicating those expectations to the clinicians who are involved in direct patient care as well as to the staff who oversee the delivery of that care.” Next on the team is the medication safety leader, who can be a pharmacist, nurse or someone in charge of quality. “The medication safety leader’s role is all about defining best practices, outlining the exact process that is to be followed based on the safest methodologies documented in the literature, knowing what medications require independent double-checking, how to document that this checking has been done,” Dr. Lakamp said. “It’s establishing all policies and procedures behind utilizing the technology and putting the

Pharmacy Practice News • July 2011

Technology 51

2011 unSummit patient in the center of the process.” The middle manager has several important responsibilities. Perhaps the most important is being able to recognize and respond to health care staff who may be knowingly or unknowingly putting patients at risk. “If there are atrisk behaviors, the middle manager has to be able to appropriately respond. He or she may have to do some coaching or counseling and be prepared to take action in cases of reckless behavior, consistent with a ‘just culture,’” Dr. Lakamp said. The pharmacy department needs to confirm that all medications are available on a unit-dose basis, that the bar codes work and that verification processes are in place. Information technology needs to ensure that all equipment is running properly and reliably. “Some of the key roles for IT include making sure that back-end support systems are in place, that dictionaries are built, that bar codes are flowing into the right systems, and making sure that all systems are updated on a regular basis,” he said. Last but definitely not least is the patient. “We need to empower patients so that they feel free to speak up if they see something that doesn’t look quite right to them,” Dr. Lakamp said. “When we started a campaign to get our patients to hold our staff accountable, that was probably one of the most powerful tools that we had. When the patient asked the nurse why she wasn’t scanning a medication when the last three nurses did so, that was more impactful than having the nurse’s supervisor do the counseling, so setting the stage for having our patients hold us accountable definitely is a very key tool.” In an interview with Pharmacy Practice News, Dr. Lakamp emphasized that setting up a culture in which accountability is recognized as a key component is essential for success. “Make sure you’ve got the right systems in place, the right tools in place, and set the stage for the right path to follow, from the beginning. Make sure everyone on the team has performance goals and that they all feel accountable for implementing safe patient care.”

Setting the Stage Laura M. Lee, RN, special assistant to the deputy director for clinical care at the National Institutes of Health (NIH) Clinical Center in Bethesda, Md., agrees that accountability is important. “Setting the stage for assuring accountability starts at the leadership level of the organization,” she said. Ms. Lee is responsible for ensuring that patients participating in one of the more than 1,400 clinical research protocols at the NIH Clinical Center receive not only

‘When you have a team without accountability, you just get average work and you begin to accept that mediocrity.” —Karla M. Miller, PharmD, BCP

the highest-quality, but also the safest care. She also is responsible for designing and operationalizing the organization’s patient safety activities, coordinating the clinical center’s clinical quality and performance measurement activities, direct-

ing the patient perception survey process and ensuring compliance with accrediting organizations. “A first step toward creating a culture of accountability is to articulate clearly the strategic importance of an

initiative such as bar coding,” Ms. Lee told Pharmacy Practice News. “Equally important is assuring that the organization provides appropriate support, such as staffing, equipment and supplies and training, to those staff members who are responsible for implementing and maintaining these types of complex, critical patient safety initiatives.” —Fran Lowry Drs. Miller and Lakamp have disclosed that they have no relevant financial relationships.

For the treatment of iron deﬁciency anemia in chronic hemodialysis patients undergoing epoetin therapy

Now Available Nulecit

™

Available in a Vial • Convenient administration of regular low doses of IV iron with 62.5-mg single-dose vials1

AB-Rated by the FDA2 • Nulecit™ is therapeutically equivalent to branded sodium ferric gluconate complex in sucrose injection3

Optimized ESA Usage and Hospital Spending • Sodium ferric gluconate complex in sucrose injection* showed a mean reduction in ESA requirements by up to 60.2%4 • Sodium ferric gluconate complex in sucrose injection* provided signiﬁcant cost savings when used with ESA therapy5† − $1390 net cost savings per g/dL Hb increase over 12 weeks compared to ESA alone5‡

Stability Data Available6 • Data supports its stability in syringes and saline bags6 − Stability testing with syringes was conducted at room temperature for up to 2 days and at refrigerated conditions for up to 7 days − Stability testing with intravenous infusion bags containing 0.9% sodium chloride solution was conducted at room temperature for up to 1 day and at refrigerated conditions for up to 7 days

More Than 10 Years of Clinical Use7 • Sodium ferric gluconate complex in sucrose injection* is safe7 and effective8

Studies used Ferrlecit®. Nulecit™ is bioequivalent to Ferrlecit®. In anemic patients with high ferritin (500-1200 ng/mL), low TSAT (<25%), and receiving adequate ESA therapy. ‡ Economic model only included drugs and hospitalizations due to serious adverse events. In DRIVE (Dialysis Patients’ Response to IV Iron with Elevated Ferritin), patients were either given no iron (control group) or Ferrlecit® (sodium ferric gluconate in sucrose injection; 125 mg x 8); ESA dosage was raised 25% in each group at randomization with no further dose adjustments. DRIVE-II was a 6-week, observational extension of the DRIVE study designed to evaluate the sustained effects of IV iron administration on epoetin requirements, hemoglobin (Hb), and iron parameters under usual anemia clinical management. Investigators were not restricted in the type of iron product administered. *

†

For more information, please visit Nulecit.com. Important Safety Information • Sodium ferric gluconate complex in sucrose is contraindicated in non iron-deﬁcient anemias, in patients hypersensitive to sodium ferric gluconate complex in sucrose or its inactive components, or with evidence of iron overload • Hypersensitivity reactions have been reported with injectable iron products • Hypotension has been reported with rapid administration of IV iron • In a singledose, placebo-controlled safety study (n=1097), the most frequent adverse events occurring after sodium ferric gluconate complex in sucrose administration were hypotension, nausea, and vomiting and/or diarrhea • In multiple-dose studies (n=126), the most frequent adverse events, whether or not related to sodium ferric gluconate complex in sucrose administration were nausea, vomiting and/or diarrhea, injection site pain, hypotension, cramps, hypertension, dizziness, dyspnea, and chest pain Please see next page for references and brief summary of full Prescribing Information.

52 Technology

Pharmacy Practice News • July 2011

2011 unSummit

VA Initiative Slashes BCMA Scanning Errors Improvement yields more time for patient care Louisville, Ky.—When medication bar codes or wristbands fail to scan, a huge amount of time that would go toward providing patient care is lost. When the U.S. Department of Veterans Affairs (VA) realized this, it took immediate steps to figure out ways to minimize such failures. Ronald Schneider, RPh, MHA, phar-

macist consultant, and Jonathan Bagby, RN-BC, MSN, MBA, of the Department of Veterans Affairs in Washington, outlined details of a new program, called Managing Scanning Failures (MSF) at the 2011 unSummit for Bedside Barcoding meeting. “Bar code medication administration or BCMA has always been about

patient safety, but it was never designed to be faster,” said Mr. Schneider, who has been at the forefront of the VA’s renowned efforts for ensuring BCMA quality. “We didn’t even look at what we could do to make it fit into the workflow of the nurses and make it faster in the long run. We began asking if we could make scanning not only safer but faster,

References: 1. Nulecit™ full Prescribing Information, Watson Pharma, Inc. 2010. 2. US Department of Health & Human Services, US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (Database). Silver Spring, MD. http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=078215&Table1=OB_Rx. Accessed April 5, 2011. 3. US Department of Health and Human Services, Food and Drug Administration. Approved Drug Products with Therapeutic Equivalence Evaluations. 31st ed. 2011. 4. García Cortés MJ, Sánchez Perales MC, Borrego Utiel FJ, et al. Estudio de la eﬁcacia del hierro parenteral en pacientes en hemodiálisis tratados con eritropoyetina. Nefrologia. 1997;17:424-429. 5. Pizzi LT, Bunz TJ, Coyne DW, Goldfarb DS, Singh AK. Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney Int. 2008;74:1588-1595. 6. Data on ﬁle, Watson Laboratories, Inc. 7. Michael B, Coyne DW, Fishbane S, et al. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int. 2002;61:1830-1839. 8. Nissenson AR, Lindsay RM, Swan S, Seligman P, Strobos J. Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American clinical trial. Am J Kid Dis. 1999;33:471-482.

Rx Only

BRIEF SUMMARY See package insert for full Prescribing Information. INDICATIONS AND USAGE Nulecit™ (sodium ferric gluconate complex in sucrose injection) is indicated for treatment of iron deficiency anemia in adult patients and in pediatric patients age 6 years and older undergoing chronic hemodialysis who are receiving supplemental epoetin therapy. CONTRAINDICATIONS All anemias not associated with iron deficiency. Hypersensitivity to Nulecit™ or any of its inactive components. Evidence of iron overload. WARNINGS Hypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS. PRECAUTIONS General: Iron is not easily eliminated from the body and accumulation can be toxic. Unnecessary therapy with parenteral iron will cause excess storage of iron with consequent possibility of iatrogenic hemosiderosis. Iron overload is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias. Nulecit™ should not be administered to patients with iron overload. See OVERDOSAGE. Hypersensitivity Reactions: One case of a life-threatening hypersensitivity reaction was observed in 1,097 patients who received a single dose of sodium ferric gluconate complex in sucrose injection in a post-marketing safety study. In the post-marketing spontaneous reporting system, life-threatening hypersensitivity reactions have been reported rarely in patients receiving sodium ferric gluconate complex in sucrose injection. See ADVERSE REACTIONS. Hypotension: Hypotension associated with light-headedness, malaise, fatigue, weakness or severe pain in the chest, back, flanks, or groin has been associated with administration of intravenous iron. These hypotensive reactions are not associated with signs of hypersensitivity and have usually resolved within one or two hours. Successful treatment may consist of observation or, if the hypotension causes symptoms, volume expansion. See ADVERSE REACTIONS. Carcinogenesis, mutagenesis, impairment of fertility: Long term carcinogenicity studies in animals were not performed. Studies to assess the effects of sodium ferric gluconate complex in sucrose injection on fertility were not conducted. Sodium ferric gluconate complex in sucrose injection was not mutagenic in the Ames test and the rat micronucleus test. It produced a clastogenic effect in an in vitro chromosomal aberration assay in Chinese hamster ovary cells. Pregnancy Category B: Sodium ferric gluconate complex in sucrose injection was not teratogenic at doses of elemental iron up to 100 mg/kg/day (300 mg/m2/day) in mice and 20 mg/kg/day (120 mg/m2/day) in rats. On a body surface area basis, these doses were 1.3 and 3.24 times the recommended human dose (125 mg/day or 92.5 mg/m2/day) for a person of 50 kg body weight, average height and body surface area of 1.46 m2. There were no adequate and wellcontrolled studies in pregnant women. Nulecit™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: 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 Nulecit™ is administered to a nursing woman. Pediatric Use: Sodium ferric gluconate complex in sucrose injection was shown to be safe and effective in pediatric patients ages 6 to 15 years (refer to CLINICAL STUDIES section). Safety and effectiveness in pediatric patients younger than 6 years of age have not been established. Nulecit™ contains benzyl alcohol and therefore should not be used in neonates. Geriatric Use: Clinical studies of sodium ferric gluconate complex in sucrose injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In particular, 51/159 hemodialysis patients in North American clinical studies were aged 65 years or older. Among these patients, no differences in safety or efficacy as a result of age were identified. 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 REACTIONS Exposure to sodium ferric gluconate complex in sucrose injection has been documented in over 1,400 patients on hemodialysis. This population included 1,097 sodium ferric gluconate complex in sucrose injection-naïve patients who received a single-dose of sodium ferric gluconate complex in sucrose injection in a placebo-controlled, crossover, post-marketing safety study. Undiluted sodium ferric gluconate complex in sucrose injection was administered over ten minutes (125 mg of elemental iron at 12.5 mg/min). No test dose was used. From a total of 1,498 sodium ferric gluconate complex in sucrose injection-treated patients in medical reports, North American trials, and postmarketing studies, twelve patients (0.8%) experienced serious reactions which precluded further therapy with sodium ferric gluconate complex in sucrose injection. Hypersensitivity Reactions: See PRECAUTIONS. In the single-dose, post-marketing, safety study one patient experienced a life-threatening hypersensitivity reaction (diaphoresis, nausea, vomiting, severe lower back pain, dyspnea, and wheezing for 20 minutes) following sodium ferric gluconate complex in sucrose injection administration. Among 1,097 patients who received sodium ferric gluconate complex in sucrose injection in this study, there were 9 patients (0.8%) who had an adverse reaction that, in the view of the investigator, precluded further sodium ferric gluconate complex in sucrose injection administration (drug intolerance). These included one life-threatening reaction, six allergic reactions (pruritus x 2, facial flushing, chills, dyspnea/chest pain, and rash), and two other reactions (hypotension and nausea). Another 2 patients experienced (0.2%) allergic reactions not deemed to represent drug intolerance (nausea/malaise and nausea/dizziness) following sodium ferric gluconate complex in sucrose injection administration. Seventy-two (7.0%) of the 1,034 patients who had prior iron dextran exposure had a sensitivity to at least one form of iron dextran (INFeD® or Dexferrum®). The patient who experienced a life-threatening adverse event following sodium ferric gluconate complex in sucrose injection administration during the study had a previous severe anaphylactic reaction to dextran in both forms (INFeD® and Dexferrum®). The incidences of both drug intolerance and suspected allergic events following first dose sodium ferric gluconate complex in sucrose injection administration were 2.8% in patients with prior iron dextran sensitivity compared to 0.8% in patients without prior iron dextran sensitivity. In this study, 28% of the patients received concomitant angiotensin converting enzyme inhibitor (ACEi) therapy. The incidences of both drug intolerance or suspected allergic events following first dose sodium ferric gluconate complex in sucrose injection administration were 1.6% in patients with concomitant ACEi use compared to 0.7% in patients without concomitant ACEi use. The patient with a life-threatening event was not on ACEi therapy. One patient had facial flushing immediately on sodium ferric gluconate complex in sucrose injection exposure. No hypotension occurred and the event resolved rapidly and spontaneously without intervention other than drug withdrawal. In multiple dose Studies A and B, no fatal hypersensitivity reactions occurred among the 126 patients who received sodium ferric gluconate complex in sucrose injection. Sodium ferric gluconate complex in sucrose injection-associated hypersensitivity events in Study A resulting in premature study discontinuation occurred in three out of a total 88 (3.4%) sodium ferric gluconate complex in sucrose injection-treated patients. The first patient withdrew after the development of pruritus and chest pain following the test dose of sodium ferric gluconate complex in sucrose injection. The second patient, in the high-dose group, experienced nausea, abdominal and flank pain, fatigue and rash

following the first dose of sodium ferric gluconate complex in sucrose injection. The third patient, in the low-dose group, experienced a “red blotchy rash” following the first dose of sodium ferric gluconate complex in sucrose injection. Of the 38 patients exposed to sodium ferric gluconate complex in sucrose injection in Study B, none reported hypersensitivity reactions. Many chronic renal failure patients experience cramps, pain, nausea, rash, flushing, and pruritus. In the postmarketing spontaneous reporting system, life-threatening hypersensitivity reactions have been reported rarely in patients receiving sodium ferric gluconate complex in sucrose injection. Hypotension: See PRECAUTIONS. In the single dose safety study, post-administration hypotensive events were observed in 22/1,097 patients (2%) following sodium ferric gluconate complex in sucrose injection administration. Hypotension has also been reported following administration of sodium ferric gluconate complex in sucrose injection in European case reports. Of the 226 renal dialysis patients exposed to sodium ferric gluconate complex in sucrose injection and reported in the literature, 3 (1.3%) patients experienced hypotensive events, which were accompanied by flushing in two. All completely reversed after one hour without sequelae. Transient hypotension may occur during dialysis. Administration of Nulecit™ may augment hypotension caused by dialysis. Among the 126 patients who received sodium ferric gluconate complex in sucrose injection in Studies A and B, one patient experienced a transient decreased level of consciousness without hypotension. Another patient discontinued treatment prematurely because of dizziness, lightheadedness, diplopia, malaise, and weakness without hypotension that resulted in a 3 to 4 hour hospitalization for observation following drug administration. The syndrome resolved spontaneously. Adverse Laboratory Changes: No differences in laboratory findings associated with sodium ferric gluconate complex in sucrose injection were reported in North American clinical trials when normalized against a National Institute of Health database on laboratory findings in 1,100 hemodialysis patients. Most Frequent Adverse Reactions: In the single-dose, post-marketing safety study, 11% of patients who received sodium ferric gluconate complex in sucrose injection and 9.4% of patients who received placebo reported adverse reactions. The most frequent adverse reactions following sodium ferric gluconate complex in sucrose injection were: hypotension (2%), nausea, vomiting and/or diarrhea (2%), pain (0.7%), hypertension (0.6%), allergic reaction (0.5%), chest pain (0.5%), pruritus (0.5%), and back pain (0.4%). Similar adverse reactions were seen following placebo administration. However, because of the high baseline incidence of adverse events in the hemodialysis patient population, insufficient number of exposed patients, and limitations inherent to the cross-over, single dose study design, no comparison of event rates between sodium ferric gluconate complex in sucrose injection and placebo treatments can be made. In multiple-dose Studies A and B, the most frequent adverse reactions following sodium ferric gluconate complex in sucrose injection were: Body as a Whole: injection site reaction (33%), chest pain (10%), pain (10%), asthenia (7%), headache (7%), abdominal pain (6%), fatigue (6%), fever (5%), malaise, infection, abscess, back pain, chills, rigors, arm pain, carcinoma, flu-like syndrome, sepsis. Nervous System: cramps (25%), dizziness (13%), paresthesias (6%), agitation, somnolence. Respiratory System: dyspnea (11%), coughing (6%), upper respiratory infections (6%), rhinitis, pneumonia. Cardiovascular System: hypotension (29%), hypertension (13%), syncope (6%), tachycardia (5%), bradycardia, vasodilatation, angina pectoris, myocardial infarction, pulmonary edema. Gastrointestinal System: nausea, vomiting and/or diarrhea (35%), anorexia, rectal disorder, dyspepsia, eructation, flatulence, gastrointestinal disorder, melena. Musculoskeletal System: leg cramps (10%), myalgia, arthralgia. Skin and Appendages: pruritus (6%), rash, increased sweating. Genitourinary System: urinary tract infection. Special Senses: conjunctivitis, abnormal vision, ear disorder. Metabolic and Nutritional Disorders: hyperkalemia (6%), generalized edema (5%), leg edema, peripheral edema, hypoglycemia, edema, hypervolemia, hypokalemia. Hematologic System: abnormal erythrocytes (11%), anemia, leukocytosis, lymphadenopathy. Other Adverse Reactions Observed During Clinical Trials: In the single-dose post-marketing safety study in 1,097 patients receiving sodium ferric gluconate complex in sucrose injection, the following additional events were reported in two or more patients: hypertonia, nervousness, dry mouth, and hemorrhage. Pediatric Patients: In a clinical trial of 66 iron-deficient pediatric hemodialysis patients, 6 to 15 years of age, inclusive, who were receiving a stable erythropoietin dosing regimen, the most common adverse events, whether or not related to study drug, occurring in ≥ 5%, regardless of treatment group, were: hypotension (35%), headache (24%), hypertension (23%), tachycardia (17%), vomiting (11%), fever (9%), nausea (9%), abdominal pain (9%), pharyngitis (9%), diarrhea (8%), infection (8%), rhinitis (6%), and thrombosis (6%). More patients in the higher dose group (3.0 mg/ kg) than in the lower dose group (1.5 mg/kg) experienced the following adverse events: hypotension (41% vs. 28%), tachycardia (21% vs. 13%), fever (15% vs. 3%), headache (29% vs. 19%), abdominal pain (15% vs. 3%), nausea (12% vs. 6%), vomiting (12% vs. 9%), pharyngitis (12% vs. 6%), and rhinitis (9% vs. 3%). Postmarketing Surveillance: The following additional adverse reactions have been identified with the use of sodium ferric gluconate complex in sucrose injection from postmarketing spontaneous reports: dysgeusia, hypoesthesia, loss of consciousness, convulsion, skin discoloration, pallor, phlebitis, and shock. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. OVERDOSAGE Dosages in excess of iron needs may lead to accumulation of iron in iron storage sites and hemosiderosis. Periodic monitoring of laboratory parameters of iron storage may assist in recognition of iron accumulation. Nulecit™ should not be administered in patients with iron overload. Serum iron levels greater than 300 mcg/dL may indicate iron poisoning which is characterized by abdominal pain, diarrhea, or vomiting which progresses to pallor or cyanosis, lassitude, drowsiness, hyperventilation due to acidosis, and cardiovascular collapse. Caution should be exercised in interpreting serum iron levels in the 24 hours following the administration of Nulecit™ since many laboratory assays will falsely overestimate serum or transferrin bound iron by measuring iron still bound to the Nulecit™ complex. Additionally, in the assessment of iron overload, caution should be exercised in interpreting serum ferritin levels in the week following Nulecit™ administration since, in clinical studies, serum ferritin exhibited a non-specific rise which persisted for five days. The Nulecit™ iron complex in sucrose injection is not dialyzable. Sodium ferric gluconate complex in sucrose injection at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg caused deaths to mice, rats, rabbits, and dogs respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions. Individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events based on information from postmarketing spontaneous reports. These adverse events included hypotension, nausea, vomiting, abdominal pain, diarrhea, dizziness, dyspnea, urticaria, chest pain, paresthesta, and peripheral swelling. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Distributed by: Watson Pharma Inc. Corona, CA 92880 USA Manufactured by: Hikma Farmaceutica (Portugal), LDA Estrada Do Rio Da Mo, 8,8 AE 8B-Fervenca 2705-906 Terrugem SNT, Portugal January 2010 192147-1 PIN220-WAT/2

and if that would return time to nursing and to pharmacy to do what we should be doing, rather than problem-solving bar-code issues.” Most BCMA systems require the nurse to do additional steps to report scanning failures, said Mr. Bagby, nurse consultant for the U.S. Department of Veterans Affairs’ Bar Code Resource Office. “With the old process, if something didn’t scan, it wasted five seconds of the nurse’s time. With the new [MSF] process which we implemented in 2009, the time that it took to report something that didn’t scan was actually increased to 10 seconds, but in the long run, it made the process speedier.” With the MSF system, the nurse right-clicks to report a scanning failure. This communicates nonscanning medications to the pharmacy in real time and also allows scanning information to be stored for ad hoc reporting. Additionally, the data become extractable at a national level, something that is important for a national hospital system such as VA. “The new process delivers a headsup that something needs to be fixed, hopefully before the next dose is due, so the pharmacist can fix it. Or, if it’s a wristband, the BCMA coordinator can go and check out the printer and get that fixed, or they can reprint a band and have it done before the next time that wristband needs to be scanned,” Mr. Bagby explained. “So a stitch in time saves nine.”

By the Numbers When the MSF system was introduced, the medication scan rate was 96.1%, 16,533,002 medications were scanned per month, and 21,272 medications were reported as “unable to scan” daily throughout the entire VA system. VA has 153 medical centers using BCMA. With each “unable to scan” report taking 10 seconds, this amounted to 1,773 hours per month lost. “That’s a lot of hours we’re spending for people just to click a mouse button because they are unable to scan,” Mr. Bagby noted. After the MSF system had been in place for 16 months, the scan rate increased to 97.7% and medications “unable to scan” decreased to 12,430 per month. This amounted to 1,036 hours per month lost. The net result was 737

Pharmacy Practice News • July 2011

Technology 53

2011 unSummit hours per month returned to care. “We assume or would hope that this time was returned to patient care,” Mr. Bagby said, but he acknowledged that his research team did not track the specific impact of the gain in staff hours realized by the MSF system. The wristband scan success rate also climbed during this time. At baseline, before the system was implemented, the wristband scan success rate was 88.8%, and 5,311,798 wristbands were scanned in one month. There were 19,866 “unable to scans” per day. At 10 seconds each, this amounted to 55 hours per day, or 1,656 hours per month lost due to failure to scan wristbands. After the system was in place for 16 months, the scan rate had increased to 92.9%, the “unable to scan” total decreased to 11,471 per month, and at 10 seconds per “unable to scan” that amounted to 32 hours lost per day,

or 956 hours lost for patient care per month, for a net of 700 hours returned to patient care. When these improvements in barcode and wristband scanning were combined, the result was a net return of 1,437 hours for patient care since the MSF system was implemented. “This is strictly BCMA. You can imagine if you looked at all of your processes and implemented a similar system for all of them that you could drill down and start returning some of that wasted time back to the nurses,” Mr. Bagby said.

VA Effort Lauded Invited to comment on the VA’s latest efforts at improving BCMA by Pharmacy Practice News, Dennis A. Tribble, PharmD, FASHP, chief pharmacy officer at Baxa Corporation, said: “There can be no doubt that the folks at the VA have pioneered not only BCMA

in general, but also have led the way on building the infrastructure necessary to ensure that it works properly. The message that Ron and Jon brought to unSummit this year was clear—there is an ongoing obligation … to maximize the benefit of this program.” The next important milestone in deploying a BCMA program is to capitalize on the accumulated data in order to make the program more successful, Dr. Tribble added. “Ron’s statement about never intending BCMA to save time is quite telling. In many cases, safety initiatives must have value in their own right in order to get started. However, as their data showed, taking the extra effort to capture the data resulted in significant improvement in performance on the system.” Chris Urbanski, RPh, MS, director of pharmacy informatics and medication integration at Indiana University

Health in Indianapolis, told Pharmacy Practice News he was surprised that scanning compliance of drugs was higher than for patient wristbands. “We experience the exact opposite at our organization,” he said. Being able to develop and implement changes such as those accomplished by the VA is often difficult for organizations that use major electronic medical record (EMR) vendors, Mr. Urbanski added. “I hope the EMR vendors read this article and evaluate how they can improve scan issue reporting within their respective systems.” He added: “I applaud Ron, Jonathan, and the VA for their leadership with respect to BCMA.” —Fran Lowry Ron Schneider, Jonathan Bagby and Chris Urbanski reported no relevant financial relationships. Dr. Tribble disclosed that he is an employee of Baxa Corporation.

OPERATIONS & MANAGEMENT

Leadership in Action

MORE NUGGETS continued from page 37

by intimidation. This stifles people, and they will not look out for your best interest if you treat them this way. Go out of your way to invite opinions from others before rendering final decisions. Teamwork often produces the best decisions.

Don’t Reinvent the Wheel Pharmacy is a very sharing profession. Most pharmacists are always looking for best-practice models, and do so by exchanging positive and negative experiences with each other. This is a wonderful thing. We need to take advantage of others’ wisdom. Seeking out those who have something to teach us helps us to be

more efficient. By developing our knowledge bases and by learning from others, we enhance our productivity.

Time Management Is an Oxymoron We have all been to multiple timemanagement courses and walked away with new techniques on how to effectively manage our time. However, sometimes reality doesn’t match up with the promises made in these courses. The fact is, there are just 24 hours in a day. We really can’t manage our time, because we all get the same time in a day, but we can manage ourselves. Effective managers use their time wisely. Time is the most precious commodity that we have, and its effective use is

the key issue we each need to evaluate if we want to make a difference. How can we fulfill our visions? Sometimes we have to say “no” to make space for the items that are key to us fulfilling our missions. When we are vision- and mission-oriented in our goals, we think broadly about what we want to accomplish over time. As I think about broad goals in pharmacy such as the Pharmacy Practice Model Initiative (PPMI), I think to myself “we cannot accomplish this in a day.” We need to develop broad goals related to the PPMI and work on the specifics to move them in the right directions. If we get caught up in “the tyranny of the urgent,” we never reach the important goals. We need to allow people to do their jobs (and not micro-

manage), to look broadly and to create long-term goals. Maxwell states that life management begins with an awareness of time and of the choices we should make to be good time stewards. Benefits include: • Advancing your overall purpose in life • Underscoring your values and finding fulfillment • Maximizing your strengths • Maintaining happiness and health • Adding value to others When we can apply these principles to our lives, we are more effective. When we improve our effectiveness, the winners include ourselves, our employees and the profession of pharmacy in general.

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he science of pharmaceutical compounding poses unique challenges to pharmacists and nurses in both the hospital and community settings. Whether caring for people or animals, health care professionals have to meet the stringent requirements of USP Chapter <797> and other pertinent

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

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Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on 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 registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

February 2011

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