Pharmacy Practice News - April 2010 - Digital Edition by McMahon Group

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The Pharmacist’s News Source

pharmacypracticenews.com

Volume 37 • Number 4 • April 2010

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McMahon Publishing

Taxane a ‘Game Changer’ in this issue Front For Late Prostate Cancer Up Events NCI pharmacist supports FDA approval San Francisco—A drug that few oncologists have even heard of may soon provide an option for treating men with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxelbased chemotherapy. Cabazitaxel (Sanofi-aventis) improved median overall survival by approximately 2.4 months compared with standard therapy in this patient population, according to a study presented at the 2010 annual American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GCS) (abstract 9). “Cabazitaxel demonstrated a statistically and clinically significant overall survival improvement compared with mitoxantrone,” said Oliver Sartor, MD, Plitz Professor for Cancer Research at Tulane Cancer Center, New Orleans, who led the study. “The overall survival benefit was consistent across subgroups. The safety profile was predictable and manageable.” The news created quite a buzz at the ASCO-GCS

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see CABAZITAXEL, page 14

It’s Safe Handling Awareness Month: Do you know where your cytotoxic agents are?

Las Vegas—Bariatric surgical procedures can reduce serious cardiovascular and other health risks associated with obesity, but the anatomic changes in the gastrointestinal tract that the surgery creates also can make it more difficult for patients to take and absorb certain forms of medicine and essential vitamins. To avoid these complications, clinical pharmacists at two different hospitals collaborated with physicians, nurses and other health professionals in developing strategies to optimize medication therapy and nutritional absorption in patients undergoing bariatric surgery. The results of their efforts were detailed in separate poster studies at the American Society of Health-System Pharmacists Midyear Clinical Meeting. One study, carried out at the Department of Veterans Affairs (VA) Loma Linda Healthcare System, in California, was led by Susan Jacob, PharmD.

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see BARIATRICS, page 29

Economic Crisis Doesn’t Faze Two Health Systems One survival tactic racks up $4.2 million in cost avoidance through pharmacist interventions

Operations & Mgmt

Medication Safety More lean strategies to boost pharmacy performance.

Clinical

Hem/Onc Pharmacy Trastuzumab improves gastric cancer survival without compromising quality of life.

Educational Review Strategies for managing EGFR-induced dermatologic toxicity.

Policy

Research Ethics

Pharms Can Help Bariatric Team Optimize Nutrition And Medication Therapy

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Fospropofol studies pulled over problems with PK/PD data.

Opinion Recognizing—and fixing— the signs of job misery.

Las Vegas—In the current harsh economic climate, health care organizations ranging from large academic medical centers to small safety net hospitals have been challenged to find ways to bolster revenues and reduce losses in an effort to maintain vital patient services. However, survival tactics have sometimes resulted in staff reductions and service cutbacks, at the risk of patient safety. In response to a recent survey by the Institute for Safe Medication Practices, for example, four out of 10 pharmacists and nurses reported that the economy had had a negative impact on medication safety— and patient safety in general (https://ismp.org/pressroom/PR20100114.pdf ). Two reports from the American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting illustrate how some pharmacies have used very different strategies to help improve their institutions’ financial picture

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Better coverage urged for organ transplant drugs.

Educational Review

Prevention of Medication Errors

Insert after page

see SURVIVAL TACTICS, page 6

ACC late-breaker:

For BP, When Is Low Too Low? Atlanta—Getting systolic blood pressure down to below 130 mm Hg does not benefit patients with diabetes and documented coronary artery disease (CAD) and may actually be harmful, investigators said in a latebreaking trial at the 59th annual scientific session of the American College of Cardiology (ACC). “Current guidelines suggest that lower is better when it comes to managing

blood pressure in patients with diabetes and CAD,” said Rhonda M. CooperDeHoff, PharmD, MS, associate professor of pharmacy and medicine at the University of Florida, Gainesville. “However,” she added, “there really is no evidence-based information in the literature suggesting that less than 130 systolic is beneficial.” The finding that the more aggressive BP target can be harmful

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see INVEST, page 28

New Product American Health Packaging launches new unit-dose Indomethacin capsule and Potassium Chloride tablet See page

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

Lot number is imprinted for easier tracking

TALLman lettering, used when appropriate, helps reduce dispensing errors

Bar Coded with a scannable Standard RSS bar code

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

Manufacturing location of product

Expiration Date

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

8430 A

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

Up Front 3

Pharmacy Practice News • April 2010

Capsules

surf

The winners of the Pharmacy Practice News

APRIL 2010

watch

Readers’ Choice Award for the Best Clinical Abstract of 2009 are:

The five most-viewed articles last month on pharmacypracticenews.com: 1. Going Wireless With Medication Tracking

Gita Wasan Patel, PharmD,

2. The Missing Piece in the Pharmacy Practice Model

Nicki Roderman, MSN,

3. Pharmacists Lend a Hand in Earthquake-Ravaged Haiti

Hollie Gehring, MSN,

4. Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations

John Saad, MD, and

5. Software Helps Document Value of Clinical Pharmacy

William Bartek, MD,

Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

of the Medical Center of Plano, Texas.

heir abstract, “The Successful Implementation of a Collaborative Sepsis Bundle at a Community Hospital,” won a majority of the Reader’s Choice Award votes, with more than 55% of respondents choosing it as their favorite abstract of 2009.

‘Most physicians and other caregivers would admit that

pharmacists are uniquely qualified to [help manage targeted chemotherapy toxicities].’

See article, page 14

The Book Page

—William D. Figg, PharmD

Congratulations also go to Shawn Hansen, PharmD, cardiovascular pharmacotherapy specialist, Ministry Heart Care/St. Joseph’s Hospital, and clinical assistant professor of pharmacy, University of Minnesota and Wisconsin Schools of Pharmacy, both in Marshfield, whose name was selected from among our readers voting for their favorite abstract. He will receive $250.

MCMAHONMEDICALBOOKS.COM Atlas of Image-Guided Intervention in Regional Anesthesia and Pain Medicine James P. Rathmell

See page

The investigators won a 2009 Best Practices Award from the American Society of Health-System Pharmacists for this research, and were recognized at the Opening General Session of the ASHP’s 44th Midyear Clinical Meeting in Las Vegas.

EDITORIAL BOARD

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ADMINISTRATION

James O’Neill, Senior Systems Manager

Robert Adamson, PharmD, Livingston, NJ Ernest R. Anderson Jr., MS, RPh, Boston, MA

Volume 37 • Number 4 • April 2010 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN

Dan Radebaugh, Director of Production and Technical Operations

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

NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

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4 Up Front

Pharmacy Practice News • April 2010

Events

Awareness Campaign Promotes Safe Handling Reducing occupational exposure to hazardous drugs among the goals of outreach program

or years, professional organizations and the federal government have endeavored to raise awareness about risks associated with workplace exposure to hazardous drugs, such as antineoplastic agents. Yet many misconceptions linger about the hazards the drugs pose. Now, the private sector has stepped in to support the effort by establishing April as National Safe

Handling Awareness Month. The national awareness month is described by its organizers as “a national campaign aimed at furthering education surrounding the occupational risks associated with handling hazardous drugs and the U.S. guidelines that have been implemented to help prevent hazardous drug exposure.” The program, now in its second year, is supported entirely

by Carmel Pharma. Despite its industry roots, National Safe Handling Awareness Month earned the support of the International Society of Oncology Pharmacy Practitioners (ISOPP), and individuals who promote safe handling of hazardous agents praise the concept. “We’re comfortable endorsing this initiative because it is an opportunity to encourage safe handling awareness

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and also to broaden the distribution of our international standards,” said ISOPP President Carol Chambers, BScPharm. “We were looking at different places we could promote the standards, and it aligned beautifully with the concept of having a National Safe Handling Awareness Month.” She added that ISOPP does not endorse any products. The events planned for the month include speakers and lunch-and-learn sessions, but the keystone event will be a one-hour live, interactive webinar featuring a multidisciplinary panel of experts. “The panel will discuss the latest trends and best practices with regard to the safe handling of hazardous drugs in the practice setting,” as well as cost issues involved in implementing adequate safeguards, said Mike Johnston, chairman and CEO of STAT Educational Services and coordinator of the webinar. Mr. Johnston said he would like participants to walk away with a better understanding of the risks and how to reduce them, and a more thorough understanding of best practices. The April 20 event will be broadcast twice to accommodate different time zones. Its intended audience includes pharmacists, pharmacy technicians, nurses and health care risk managers. The emergence of the awareness month doesn’t surprise Ms. Chambers or some of her colleagues, who point to a pervasive—although mistaken—impression that the threat from hazardous drug contamination in the workplace has been essentially neutralized through engineering controls and institutional policies.

A Potentially Dangerous Knowledge Gap

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March 2010

Nothing could be further from the truth, according to Luci Power, MS, RPh, senior pharmacy consultant at Power Enterprises, in San Francisco. “The problem has been around for so long that people think it’s been solved, but the problem was never solved.” In fact, the dangers often come as a revelation to the very people who handle these hazardous drugs most frequently. “When we present to meetings about some of these drugs, people are often surprised,” said Thomas H. Connor, PhD, a research biologist at the National Institute on Occupational Safety and Health (NIOSH). “They say, ‘I had no idea of how toxic they can be.’” A number of the drugs, he pointed out, are known carcinogens and have harmful reproductive effects. A substantial body of evidence links workplace exposure to hazardous drugs with serious health risks, yet keeping

Up Front 5

Pharmacy Practice News • April 2010

Events the issue front and center and prompting widespread effective action has been a struggle. “It’s very scary how well this subject has been studied—about 30-something years,” said Ms. Power. “It’s not overnight data, which is something a lot of people don’t understand.” Furthermore, data continue to show that these hazardous agents are getting into places where they should not be despite engineering controls and practice guidelines. Dr. Connor recently completed a NIOSH study that revealed widespread workplace contamination from these drugs in pharmacy and nursing/patient areas. Another study, conducted at Massachusetts General Hospital, found contamination on computer keyboards, elevator buttons and flooring, some of which were hundreds of feet away from preparation areas intended to prevent the spread of harmful substances. (For more information on these studies, see Pharmacy Practice News January 2010, page 1.) One reason the problem persists is that in health care, the emphasis historically has been on patient safety concerns, whereas the funding priority for worker safety programs is lower, Dr. Connor said. Some of the engineering and process changes required to minimize the risk of exposure to hazardous drugs can be expensive. However, he pointed out that guidelines and policies that have been established over the last decade, such as the United States Pharmacopeia <797> regulation, which addresses a wide range of pharmacy policies and procedures, have resulted in safety improvements for workers. Another obstacle to safety improvements is the inability to establish a direct pathway between exposure and the effects, which may take years to manifest. For example, the chance that a person in North America will develop some type of cancer over his or her lifetime is about one in four, Ms. Chambers said, so the outcome is not unique to someone exposed to cytotoxic drugs. “You wouldn’t know for certain if someone’s cancer was caused by working at a cancer clinic.” In addition, no one knows if there are safe levels of exposure. However, recent data presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting may help to establish that pathway between exposure and effects. The data, presented by Melissa McDiarmid, MD, MPH, DABT, professor of medicine and director of the University of Maryland School of Medicine’s Occupational Health Program, in Baltimore, links exposure to certain cytotoxic agents, particularly the alkylating agents, with chromosomal abnormalities found in patients with therapy-mediated leukemias. Dr. McDiarmid and her colleagues used fluorescent in situ hybridization to evaluate the DNA from the

exposed workers, looking for irregularities in chromosomes 5, 7 and 11, the most common abnormalities found in patients with therapy-mediated myelodysplastic syndrome or acute myeloid leukemia. When the investigators assessed the contribution of drug-handling frequency to chromosomal abnormalities, they found that for each handling event, there was a

statistically significant increased frequency of damage to either chromosome 5 or chromosome 7 or to chromosome 5 alone (P=0.01). When they looked specifically at handling events with alkylating agents (cyclophosphamide and ifosfamide), they also found a significantly increased frequency of damage to chromosome 5 or 7 (P=0.001) and to chromosome 5 alone (P=0.01). In fact, said Dr. McDiarmid,

ERROR PREVENTION

they observed a “fivefold increase in the absolute value of the effect estimate” (the estimate of the insult to chromosome 5 or 7) for each handling event with alkylating agents compared with all agents. There is a “biological progression of evidence here,” Dr. McDiarmid said, “and we really do need to pay attention.” For more information about National Safe Handling Awareness Month, visit http://www.carmelpharmausa.com/ aware1. To register for the webinar, visit http://www.statce.com/shad2010reg. —Steve Frandzel

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PATIENT SAFETY

6 Operations & Management

Pharmacy Practice News • April 2010

Finance

SURVIVAL TACTICS

continued from page 1

and in the process maintain or even increase patient services. Pharmacists from St. Joseph’s Healthcare System in Paterson, N.J., and the University of Massachusetts (UMass) Memorial Healthcare in Worcester, reported the results of their efforts in ASHP posters and interviews with Pharmacy Practice News.

Inventory Turns

18.4

15 12.8 11.0

10 8.0

Safety and Savings Go Hand-in-Hand

0 April 07

August 07

December 07

June 08

December 08

Figure 1. 2007-2008 inventory turns.

‘Our profession needs to do a better job of marketing and enhancing our practice. I cannot think of a better way than partnering the pharmacist with the medical team and demonstrating firsthand our impact and worth.’ —Mitch G. Sobel, RPh, MAS

Inventory turns, Mr. Sobel noted, are a strong indicator “of how well your business is doing. The national benchmark is 12 times a year. We were able to get from eight turns a year to about 24.7 largely because of changes in operational practices and the addition of a progressive and innovative buyer for the pharmacy department.” “Instead of having enough medications sitting on the shelves for a month or more, we have enough for five days,” he said. “The par level is two and a half days. When we get to that point, we order enough to get us back

to five days again. Two and a half days is enough to get us through a holiday weekend.” The rollout of 86 automated dispensing cabinets (ADCs) was another key to bringing inventory costs in line. The new devices allowed nursing units to fill 90% of their patients’ medication requirements right on the floor, relieving pharmacists of a substantial portion of their distributive duties. The remaining 10% consisted of slowermoving, patient-specific medications manually filled in pockets corresponding to room numbers. In two years, the number of ADC transactions—refills

500,000 450,000 400,000 350,000

Dollarsa

Mitch G. Sobel, RPh, MAS, had two strategic goals in mind when he joined St. Joseph’s Healthcare System in Paterson, N.J., as a system director of pharmacy services in 2006. One was to make pharmacy operations—particularly medication distribution—more efficient and less costly. The second goal, tied closely to the first, was to improve the safety and quality of medication management by taking pharmacists out of the basement and assigning them to patient care units. By early last year, both goals had been achieved. Inventory turns had tripled (Figure 1). Average time from medication order entry to nurse administration had decreased from 95 to 23 minutes. Pharmacist interventions had more than doubled to nearly 55,000 per year, resulting in cost avoidance gains of $4.2 million (Figure 2). And St. Joseph’s pharmacists started filling clinical roles on the nursing care units. “In two and a half years, we have really been able to explode from a purely distributive model—an antiquated model of pharmacy practice—to a pharmacy practice of the future,” Mr. Sobel said. “The key to our success was the commitment to implementing clinical pharmacist specialists and services that addressed relevant patient care issues.” Pharmacist-driven initiatives focused on antimicrobial stewardship, anticoagulation management and education, emergency and critical care medicine, and pediatric medicine, Mr. Sobel noted. “We also focused on medication management and safety as a way of reducing expenses in medication usage, avoiding potential errors, and ultimately contributing to a decrease in length of stay through proper medication use,” he said. “Every pharmacist can contribute to the impact of clinical cognitive services, but our clinical pharmacist specialists are definitely the catalyst for change, innovation and progress.” The changes, driven by the health care system’s willingness to invest in new technology and clinical pharmacist positions, began with an effort to improve inventory turnover, enhance patient safety and increase pharmacist clinical interventions.

24.7

300,000 250,000 200,000 150,000 100,000 50,000 0 1/1/07

3/1/07

5/1/07

7/1/07

9/1/07 11/1/07 1/1/08

3/1/08

5/1/08 7/1/08

Figure 2. 2007-2008 pharmacists cost savings/avoidance. a

Each data point is a monthly amount, totaling $4 million in overall savings.

9/1/08 11/1/08

and removals—increased 10-fold, from 503,000 to 5.2 million. “Now that we were able to get the distributive function out of the pharmacists’ hands and into the machine, we used pharmacy technicians to handle the distributive functions of loading and filling,” Mr. Sobel said. “The pharmacist would check, but certainly that is a lot less activity than having to check every single bin for patients.” The savings in pharmacists’ time allowed for a greater concentration on clinical interventions. Mr. Sobel set a goal for each pharmacist of at least 300 interventions a year. “What I asked for was one intervention a day,” he said. “Every pharmacist can do that.” The result was an increase from approximately 26,000 to about 55,000 interventions per year. The efficiency gains allowed pharmacy to move pharmacists out of the basement and onto patient units and to hire additional clinical specialists. “Inserting clinical pharmacists into medical teams over time proves the value and necessity of a pharmacist contribution to patient care. The hospital staff cannot imagine giving up their pharmacist on the team. That’s better than saving dollars, because now you are impacting patients’ lives,” Mr. Sobel said. “You are supporting nursing and physicians and making the hospital look great. It’s such a tremendous ripple effect. Our profession needs to do a better job of marketing and enhancing our practice. I cannot think of a better way than partnering the pharmacist with the medical team and demonstrating firsthand our impact and worth.”

Disproportionate Share Hospital’s Approach UMass Memorial Healthcare, like many other academic medical centers, faced the challenge of continuing to provide full patient care services while trying to maintain financial stability in the midst of an economic downturn. As a disproportionate share hospital with a high percentage of low-income and indigent patients, UMass Memorial was able to take advantage of the favorable drug acquisition costs available to outpatient pharmacies under the federal 340B program. In their ASHP poster, pharmacists described how the use of the federal program at two outpatient pharmacies allowed the 834-bed health care system to fill the outpatient prescription medication needs of its indigent patient population and self-insured staff members while realizing ever-increasing net profits, which were then applied to help offset other money-losing inpatient services. “The net sum is that it has allowed us to maintain services in tough economic

•

see SURVIVAL TACTICS, page 8

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8 Operations & Management

Pharmacy Practice News • April 2010

Medication Safety

Centers Use Lean Methods To Boost Safety, Reduce Waste H ealth-system pharmacies straining under high volume demands and tight budgets might consider an unexpected lifeline—lean processimprovement methods developed by Toyota Motor Company—to improve patient safety and quality of care, while saving time and slashing waste in filling medication orders. These methods have proven effective for pharmacies at institutions such as Johns Hopkins Hospital, in Baltimore; The University of Minnesota Medical Center, in Fairview; and the MemorialCare Health System hospitals, in California. Just as lean principles helped Toyota sustain quality and become the largest automaker in the world, these same principles have helped these innovative pharmacies speed fulfillment times and operate at higher standards, with more efficiency, less stress and fewer chances for mistakes.

Lean Doesn’t Mean Skimping Toyota’s history of lean processes and its recent extensive recalls could lead people to wonder whether lean approaches might leave hospitals and health-systems vulnerable on safety issues. Jane Hodding, PharmD, executive director of Inpatient Pharmacy Services, at MemorialCare’s Long Beach Memorial Medical Center (LBMMC) doesn’t think so. “I’ve participated in several lean processes. The concepts are valid, and the outcomes are valid. I can’t speak to what went wrong at Toyota, but you don’t throw the baby out with the bath water. We’re intelligent people. We can understand and apply the concepts, and we can see the positive outcomes.” Regarding the processes put in place at her institution, she said, “I don’t see lean

As part of Long Beach Memorial Medical Center’s lean 5S process, the pharmacy stores supplies where they are used the most, arranging items according to job function and frequency of use.

making MemorialCare Health System vulnerable. Our goal is to make patients better. We see nothing in lean that would put patients at risk. We have to maintain the best care and safety standards, and be responsible stewards of our resources. Lean [management] helps us do that. We’ve seen it firsthand.”

Long Beach Memorial Medical Center At MemorialCare, “we’re sold” on lean principles, said Dr. Hodding. “We utilize our lean thinking in decision making, particularly as it affects use of technology. For example, in the pharmacy, we are using lean principles to determine how to best establish operations for an automated dispensing robot. Medication safety is always at the forefront of our lean thinking.” MemorialCare “brought lean management forward three years ago,” explained Dr. Hodding. “Each of our five hospitals is in various stages of lean expertise. We have a strategic focus to train our own lean fellows and all managers. We’ve made steady progress in that plan.” The health system implemented MC21 (MemorialCare for the

21st Century)—a system-wide initiative to improve patient care and implement, among other things, an electronic medical record system in all of its medical centers. The hospital’s pharmacies operate under “a developing lean culture,” said Dr. Hodding. Within its pharmacy operations, the Long Beach campus has an internal Centralized IV Admixture Service (CIVAS) that prepares all IV admixtures for the 462-bed center and the 326-bed Miller Children’s Hospital (MCH) on the same campus. They used a lean approach twice in 2009 to improve practices. Initially, a team of five pharmacists and seven technicians (from CIVAS, LBMMC satellite pharmacies and MCH) collaborated to identify areas of waste and process improvements using the lean tool called Rapid Process Improvement (RPI). This tool allowed the pharmacy to decrease staging times for IV admixture products by 50%. (“Staging time” is the time it takes the pharmacy to actually begin to make a product once they get the order. In clean rooms, this is primarily time spent meeting regulatory and safety requirements to ensure

that products made there start sterile and stay that way.) RPI also helped the medical center standardize work procedures in its pharmacies, including procedures for staging the drugs and supplies needed to make IV products, and recording the drug’s lot number, expiration date, patient name and other necessary data for each preparation, in case of a manufacturer recall or other historical need. Because CIVAS has so many recordkeeping requirements, it used the RPI process as an opportunity to shift from a paper-based methodology to one using a Microsoft Access database “to track every product we make, from a single syringe with a drug in it to an IV admixture,” said Dr. Hodding. A clean-room technician enters the data. “This reduces a lot of paper and helps us work faster. It also enhances communication between

What Is Lean?

linchpin of lean management is to identify value as customers see it, and eliminate production process steps that don’t add value. Value-creating steps should occur in tight sequence so product flows smoothly to customers. The lean management system creates a sense of team purpose that transforms business and cultures. Some of the catchy names of lean management include: Single-Piece Flow, Rapid Process Improvement, 5S, Value-Stream Mapping, Standardized Work, Lean Kaizen and more. All foster the delivery of greater customer value with less waste. A resource for readers to learn more is the Lean Enterprise Institute at http://www.lean.org.

Finance

SURVIVAL TACTICS continued from page 6

times that probably would have had to be cut,” said John P. Ryan, RPh, director of ambulatory care pharmacy. “And it’s maintained staff, when staff might not have been able to stay.” Opened in 2006, the outpatient pharmacy at UMass Memorial’s university campus increased its prescription count from approximately 50,000 in fiscal 2007 to over 90,000 two years later. Meanwhile, net profit more than doubled to $4.8 million. The outpatient pharmacy at the Hahnemann campus opened a year later. Its net profit reached $1.3 million in fiscal 2009. The profits, said Mr. Ryan, come from both the markup

‘The idea of the future is that we’re expanding into Medicare Part B billing for transplant and HIV medications.’ —John P. Ryan, RPh

on traditional third-party billing and a “cost-saving calculation based on what the medicine would have cost if the hospital had to pay for that benefit from an outside pharmacy.” He noted that it was “sometimes hard to talk about profits in a disproportionate share hospital,” but he added that it wasn’t about profits for the hospital but “more about available cash that allows the hospital to continue to operate and

continue its mission.” In addition to benefiting from the availability of low-cost medicines, patients also gain from mandatory pharmacist counseling services. “We have a counseling room and pharmacists have an appointment book,” Mr. Ryan said. “Any patient who wants to talk longer than 10 or 15 minutes has carte blanche to schedule hour-long appointments. We probably do about

three of those a week. It’s not huge, but it’s nice when it happens.” “The idea of the future is that we’re expanding into Medicare Part B billing for transplant and HIV medications,” he said. “We’re starting to look at what patients of the facility might need.” Another plan is focusing on readmissions. “We’re looking at those patients most likely to be readmitted within 30 days—cardiovascular is a key category—and we’re going to start running discharge programs for them. With more than 800 beds, there are a lot of discharges on any given day. We can’t do them all, so we’re looking at where we can have the highest impact.” —Bruce and Joan Buckley

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Operations & Management 9

Pharmacy Practice News • April 2010

Medication Safety the centralized IV room and pharmacists on the patient floors, because it tracks product status. We started with Access, but in the coming months, we’ll be looking into more proprietary software,” she added. Also, to reduce waste in a dynamic hospital environment “where medication needs change as patients’ conditions change,” CIVAS went to shorter, more frequent production cycles of IV admixtures. “This allows us to make what we need for a particular day or shorter time period, during which patients’ medication needs would likely stay stable. We

To improve standardization via 5S, Long Beach Memorial Medical Center’s pharmacy was organized clearly and consistently, for example, with blue and red bins differentiating products (left), and pink and white stickers indicating pediatric and adult doses, respectively (right).

want to make it, use it, make it, use it,” explained Dr. Hodding. “By contrast, larger batches for longer time periods

are less efficient and more wasteful because they require storage space and unused products become waste.”

RPI also led to tighter inventory controls, an 80% rise in staff satisfaction, and improved interactions between the staffs of both hospitals, said Lucille Parisho, PharmD, supervisor of CIVAS and pharmacy technology at LBMMC. The medical center employed a second lean process called 5S (sort, straighten, shine, standardize, sustain) to standardize inventory supply levels and locations for all supplies within CIVAS. In this case, two pharmacists; five technicians; a pharmacy buyer; and representatives from materials distribution, information

•

see LEAN METHODS, page 10

10 Operations & Management

Pharmacy Practice News • April 2010

Medication Safety

LEAN METHODS continued from page 9

technology and facilities support worked together to reduce the time required to find the drugs used for IV admixture preparation by creating a single location for the medications needed. “Pharmacy staff sometimes hoards in order to be sure they have what they need when they want it. To reduce waste and improve use of space, we ran utilization reports to determine not only whether we should have the particular drug or supply, but how much of it we really

‘[Lean] concepts are valid, and the outcomes are valid. I can’t speak to what went wrong at Toyota, but you don’t throw the baby out with the bath water.’ —Jane Hodding, PharmD

need,” explained Dr. Hodding. “If an item wasn’t used that often, we asked if it could reside somewhere else in the pharmacy.” For example, non-sterile gloves were no longer a necessary item, so they were returned to Central Supply

to free up valuable space. The outcome: 95 types of supplies, such as IV solutions, IV sets and tubing that were no longer used (nearly $5,000 value) were removed, and space was better organized to suit work flow. For

example, the CIVAS team designated an area to be used solely for the refilling of surgical trays with medications, and placed the necessary medications and supplies there. Throughout the CIVAS area, the team labeled every shelf for what should be there (such as drugs, reference books, and policy and procedure manuals) and the quantity, if pertinent. The team also used tape on the floor and signs on the walls to mark parking places for the four-wheeled carts they use to move supplies. “It’s about establishing efficient, logical sites for everything, including computer terminals and printers, which support efficient operations,” noted Dr. Hodding. Lean management techniques will also be applied to a large project covering the medication delivery system, from procurement to delivery to the nurse, “in the near future,” said Dr. Hodding. The idea is to build on early successes of using lean management to maximize the efficiency of every step of the medication use process, “from the time we get the drug to the time the nurse administers [it].” The hospital also plans to apply lean management techniques in other projects: to lessen drug waste and see if robotics are needed in the production of unit-dose injections in the inpatient pharmacy; to optimize work flow in the outpatient pharmacy; and to design a new pharmacy at MCH. According to Dr. Parisho, employees are driving the process of change and the application of lean techniques throughout the health system. “This has directly engaged everyone and improved teamwork, even between pharmacy areas. … We now routinely think of lean concepts as we look at our daily work.”

Johns Hopkins Hospital In Baltimore, application of lean management approaches in the Johns Hopkins pediatric pharmacy resulted in improved processes, more free time for pharmacists and technicians to do “value-added” work, less drug waste and a less stressful environment. Describing Johns Hopkins’ lean quality-improvement efforts in a recent webinar sponsored by the Institute for Safe Medication Practices, Nicole MacLaughlin, PharmD, BCPS, medication safety officer for pediatrics at the hospital, noted that projects were undertaken to add safety and efficiencies to the medication preparation processes for oral compounds, IVs and chemotherapy for the hospital’s pediatrics division. The projects were conducted within a Johns Hopkins Hospital culture that has institutionalized lean management through training done by an internal group called The Center for Innovation

Operations & Management 11

Pharmacy Practice News • April 2010

Medication Safety in Quality Patient Care, Dr. MacLaughlin told Pharmacy Practice News. Teams at Johns Hopkins have pursued several lean management concepts to improve processes at the hospital. The pediatric pharmacy used 5S to standardize its oral compounding area, which had a setup that limited visibility and access to essential liquid medications and caused a lot of extra movement. Now, one technician works A-L, another M-Z. Reorganized bins no longer block access and minimize wasted motion. A pharmacist is now positioned between the two technicians to check preparations expediently. To resolve variation in the pediatric cartfill IV production process that caused inefficiencies, errors and staff dissatisfaction, the hospital used a technique known as lean kaizen, which is a Japanese term meaning practices that focus on continuous improvement of processes. The project goal was to decrease the lead time for a product to get through the pediatric cartfill IV production process, including wait time and processing time, while improving safety. The four pharmacists and four technicians involved in this project collected observational data on the process and asked pharmacists and technicians questions about the cartfill process: Pharmacists were asked what they disliked most about checking IV doses in cartfill, what the biggest problems were in checking, and whether technicians were engaging in any “unsafe” or “best practices.” Technicians were asked for similar feedback, as well as what they would change in work flow if they could, and anything they did individually in the cartfill IV room that made their day run more smoothly. The Johns Hopkins group found a lot of variation in the pediatric cartfill process. The cartfill IV room had seven different ways to stage, 12 ways to set up, and five ways to prepare medications in the hood. “We lacked standardized work. We had cramped space and heavy traffic,” explained Dr. MacLaughlin. Also, she said, “labor wasn’t fairly balanced.” Based on these findings, they revised their processes. Now, one technician stages while another prepares medications, and this has lowered the time per dose from 0.88 minutes per dose to 0.84 minutes. A “single-piece flow process” was developed, which ensures that attention is paid to one drug at a time for one patient at a time, reducing the likelihood that errors will occur. The pediatric pharmacy uses this continuous process to prepare IV medications for a 24-hour period all at once. Instead of batch-’n’-queue—which left multiple batches of parts, supplies or orders in the hood at once and no room for staging—all items to make one product now enter the hood through a bin, and go out together for the pharmacist

to check. Colored bins show the locations of dilutions versus patient-specific doses, creating a visual process. In keeping with the concept of just-in-time production and to reduce waste, the staff now prepares dilutions the morning of each day based on need, instead of projecting the night before.

The University of Minnesota Medical Center Another hospital, the University of Minnesota Medical Center, realized substantial benefits including safety improvements and annual cost savings of

$289,256, by applying lean management approaches in its inpatient pharmacy. Reporting their results in the American Journal of Health-System Pharmacists (2009;66:2042-2047), Barbara L. Hintzen, BBA, CPhT, pharmacy operations manager, noted that among the benefits of the lean approach were a 40% reduction in patient-specific IV waste (from outdated products, discontinued medications or changed doses) and an 83% decrease in errors after more efficient operations were implemented to improve compounding accuracy. In addition, the improved work

flow resulted in reduced staffing needs. This allowed for the reallocation of two technician full-time equivalents to expand patient care services in decentralized areas. Medication inventory decreased by $50,000 and the amount of outdated products decreased by 20%. A color-coded bin system eased the identification of expensive and fastand slow-moving items, and reduced technician picking time. —Al Heller For more lean process improvement tips, see the March 2010 issue, page 42.

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Hem/Onc Pharmacy

Pharmacy Practice News • April 2010

In Focus In patients with gastric cancer ...

Trastuzumab Improves Survival, Preserves Quality of Life Orlando, Fla.—The addition of trastuzumab (Herceptin, Genentech) to standard chemotherapy in patients with human epidermal growth factor 2 (HER2)-positive gastric cancer improves overall survival (OS) without compromising quality of life (QoL), according to follow-up data from the ToGA trial presented at the 2010 Gastrointestinal Cancers Symposium (GCS; abstract 7).

At the 2009 annual meeting of the American Society of Clinical Oncology, researchers involved with the ToGA trial first reported that the addition of trastuzumab to standard chemotherapy in patients with HER2-positive gastric cancer improves OS by two months (LBA4509). In a study of 3,807 gastric cancer patients, 22.1% had high amounts of HER2 in their tumors. Of these patients, 584 patients with locally

‘Through the results of this trial, we have taken an important step forward to increase efficacy and improve quality of life during treatment of HER-2-positive gastric cancer patients.’ —Taroh Satoh, MD

dosing) until disease progression. The researchers used a standard QoL questionnaire and a disease-specific module for gastric cancer; the scoring range for both was based on a 100-point scale. Global health status scores improved over time from 51 at baseline to 72 in the trastuzumab-containing arm and 71 in the chemotherapy-only arm. “We don’t see any difference between arms. Trastuzumab … was comparable if not better than the chemotherapy-alone arm,” Dr. Satoh said. “Disease-specific and symptom-specific scores improved over time in both treatment arms.” Pain intensity scores, calculated by a visual analog scale, and use of analgesic medicine were similar between treatment arms.

Traditional chemotherapy plus trastuzumab Traditional chemotherapy

Overall survival, mo

13.8

11.1

Figure. Comparison of overall survival.

‘The New Standard’ “Through the results of this trial, we have taken an important step forward to increase efficacy and improve quality of life during treatment of HER2-positive gastric cancer patients,” said lead investigator Taroh Satoh, MD, from the Kinki University School of Medicine in Osaka, Japan. Percentage of gastric tumors that are HER2-positive

22.1%

Rituxan Approved for CLL

he FDA has approved rituximab (Rituxan, Genentech) for people with CD20-positive chronic lymphocytic leukemia (CLL). Rituxan is administered with fludarabine (Fludara, Bayer HealthCare Pharmaceuticals) and cyclophosphamide (Cytoxan, Bristol-Myers Squibb). Approval was based on two studies that measured progression-free survival (PFS). In one study of 817 patients who had not received any prior chemother-

advanced, recurrent or metastatic HER2positive gastric cancer were randomized to receive either standard chemotherapy (5-fluorouracil or capecitabine and cisplatin) plus trastuzumab or standard chemotherapy alone. Trastuzumab was given until disease progression. Median OS was 13.8 months in patients who received trastuzumab compared with 11.1 months in patients who received standard chemotherapy (P=0.0046; Figure). Safety profiles were similar with no unexpected adverse events in patients receiving trastuzumab. Asymptomatic left ventricular ejection fraction (LVEF) decreases were reported in 4.6% of patients receiving trastuzumab and 1.1% of patients in the traditional chemotherapy arm. No difference in symptomatic congestive heart failure was identified between the two arms. At the recent GCS meeting, researchers analyzed QoL data. A total of 563 of the patients (>95%) completed QoL questionnaires at baseline and every three weeks (on day 1 of each cycle prior to

apy, PFS was eight months longer for those receiving rituximab plus chemotherapy than for those who received chemotherapy alone (39.8 vs. 31.5 months). In another study of 522 individuals whose cancer had progressed following other chemotherapy drugs, PFS was five months longer for those who received rituximab plus chemotherapy (26.7 vs. 21.7 months). The drug did not benefit patients who were 70 years or older, but there also was no evidence that rituximab was harmful in the elderly. Rituximab carries a boxed warning

“For [patients with] advanced gastroesophageal cancer who are HER2positive, the combination of a fluoropyrimidine, a platinum and trastuzumab should become the new standard treatment,” said David Cunningham, MD, professor and head of the gastrointestinal and lymphoma units at the Royal Marsden Hospital in London, who was not involved with the study. Kellie L. Jones, PharmD, BCOP, clinical associate professor, Department of Pharmacy Practice, Purdue University School of Pharmacy and Pharmaceutical Sciences, in Indianapolis, agreed that the study’s findings are important. “However, the length of median follow-up in the study is not clear, which makes it difficult to assess the long-term benefit of trastuzumab in this patient population.” Thus, “I’m not sure we have enough clinical data to support the use of trastuzumab plus chemotherapy as the standard of care across the board in all HER2-positive gastric cancers.” As for the safety data in the ToGA

‘The length of median follow-up in the study is not clear, which makes it difficult to assess the longterm benefit of trastuzumab in this patient population.’ —Kellie L. Jones, PharmD, BCOP

trial, Dr. Jones said some questions remain about the cardiac effects that were documented by the investigators. “The abstract does not distinguish the severity of the decreases in LVEF that occurred in 4.6% of the trastuzumabtreated patients, so even though these were asymptomatic events, I would still want to know more about this toxicity before using trastuzumab in all of these patients.” —Kate O’Rourke

for infusion reactions, which can occur during infusion or within 24 hours afterward. Some 59% of patients treated with rituximab for CLL experienced an infusion reaction that resembled an allergic reaction (e.g., hives, low blood pressure, chills, fever and nausea). A decrease in infection-fighting, normal white blood cells also was commonly observed in patients enrolled in the rituximab clinical trials. Rituximab also can cause rashes and sores in the skin and mouth, progressive multifocal leukoencephalopathy and tumor lysis syndrome.

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Hem/Onc Pharmacy

Pharmacy Practice News • April 2010

In Focus

Q&A: William Figg, PharmD

CABAZITAXEL

continued from page 1

meeting. “This came out of nowhere,” said Philip W. Kantoff, MD, director of the Lank Center for Genitourinary Oncology at Dana- Farber Cancer Institute, in Boston, who was not involved in the study. “Very few people even knew about this drug, so there is a lot of excitement about this.” William D. Figg Sr., PharmD, head of the Molecular Pharmacology Section and senior scientist at the National Cancer Institute in Bethesda, Md., attended the ASCO-GCS meeting and discussed the findings on-site with Dr. Sartor. “I told him that the excitement over the data was certainly justified,” Dr. Figg said in an interview with Pharmacy Practice News. “Cabazitaxel showed a survival benefit in a patient population that never had a therapeutic option that went beyond mere palliative care.”

Limited Options The standard of care for first-line therapy of mCRPC is docetaxel (Taxotere, Sanofi-aventis), but there is no approved second-line therapy. Treatment options include supportive care or investigational drugs. According to Dr. Kantoff, the standard default is to treat these patients with prednisone and mitoxantrone. In the international Phase III TROPIC trial, investigators tested cabazitaxel, a novel taxane that has been shown to be active in docetaxel-resistant tumor cells. The TROPIC investigators enrolled 755 men (median age, 68 years) with mCRPC who had progressed during or after therapy with docetaxel (cumulative dose ≥225 mg/m2). Study participants were randomized in a 1-to-1 fashion to receive 10 mg per

illiam D. Figg Sr., PharmD, head of the Molecular Pharmacology Section and senior scientist at the National Cancer Institute in Bethesda, Md., has been actively involved in the development of novel new pharmacologic agents for prostate cancer. He recently spoke with Pharmacy Practice News about his research, as well as the role he feels pharmacists should be playing in the management of patients with prostate cancer and other common malignancies. Q: The TROPIC study generated a lot of excitement at the ASCO-GCS meeting. What other research initiatives hold promise for prostate cancer? A: There’s quite a few drugs in development, both in targeting the androgen receptor or androgen regulation, since this can be a very hormone-dependent malignancy. One area that we are working on is blocking the influx of androgens into the prostate cell. In addition, it has been proposed that angiogenesis inhibitors have a role in prostate cancer therapy. But recent trial data aren’t as promising as we’d hoped. For example, a Phase III trial of bevacizumab [Avastin, Genentech], used in combination with docetaxel and prednisone, failed to meet its primary objective—extending survival in men with latestage prostate cancer. So we may have to temper our initial enthusiasm over targeted therapy for these patients. Q: The TROPIC study investigator used prostate-specific antigen (PSA) values as a partial measure of response. The test has come under recent fire for not being a very sensitive marker for prostate cancer. What’s your view? A: In the context of the TROPIC study—men with hormonerefractory or castrate-resistant prostate cancer—PSA clearly has a role; nobody will argue [with] that. PSA levels in such patients will generally rise when disease worsens, and fall when the cancer improves. And in those patients whose PSA levels do fall, they generally live longer. But when it comes to screening patients for prostate cancer in the general population, I understand and appreciate the debate. Does

day of prednisone with either 12 mg/m2 mitoxantrone every three weeks (MP) for 10 cycles or prednisone in the same dose with cabazitaxel 25 mg/m2 for 10

PSA overdiagnose individuals? Clearly, we can say yes. We know that there are people who are diagnosed with prostate cancer who probably would never have any problem with their disease in their lifetimes and may not have needed to be treated. So better screening methods are needed. One approach we are taking at the NCI is to obtain genetic profiles of patients to discern who needs treatment and who doesn’t, based on several genetic variables, such as genetic “SNPs” [single nucleotide polymorphisms] that predispose patients toward producing an aggressive form of androgen that has been shown to be a driver of prostate cancer development and progression. Likewise, if there are genetic mutations or polymorphisms that affect androgen receptors, that may also create different risk levels for prostate cancer that vary from patient to patient. Thus, although you can diagnose someone with PSA, discerning who is going to have aggressive disease and who is going to have indolent disease that won’t need to be treated is an active area of research. Q: As a pharmacist and researcher, you are in a unique position to comment on whether the profession has an important role to play in cancer care. A: We can play a tremendous role, and there are so many new opportunities. Pharmacogenetics is a great example— it’s a field that many medical oncologists don’t have a good handle on. So we can help them understand the genetic polymorphisms that make some patients metabolize or react to cancer drugs differently. In such cases, we can guide our physician colleagues in the proper dosing of chemotherapy for patients, based on their genetic polymorphisms. There also is the huge issue of drug interactions. As we get more targeted agents approved, these drugs are not just cytotoxic chemotherapies that you treat to maximum toleration; they may be given for a longer period of time, thus resulting in more adverse effects. Most physicians and other caregivers would admit that pharmacists are uniquely qualified to handle those issues. So it’s an exciting time in oncology care for our profession. —David Bronstein

cycles. The median number of cycles given during the multicenter trial was four in patients receiving mitoxantrone and six in patients receiving cabazitaxel.

The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate, pain measures and safety.

Cabazitaxel + prednisone

Mitoxantrone + prednisone

P=0.0005

14.4

100 8.8 81

15.1

6 4.4

5.4

Neutropenia, %

12.7

Median TTP, mo

Response Rate, %

Median Overall Survival, mo

Figure 1. Comparison of median overall survival.

Figure 2. Tumor assessment by response rate.

Figure 3. Tumor assessment by median time to progression.

Figure 4. Comparison of grade 3/4 neutropenia.

Hem/Onc Pharmacy 15

Pharmacy Practice News • April 2010

In Focus Patients were followed for a median of 12.8 months. Dr. Sartor said the extent of disease in many of the subjects distinguished this trial from previous studies. Indeed, “more than half the patients in the trial had measurable disease [54.1% in the MP arm and 53.2% in the cabazitaxel arm],” he pointed out. “This is quite a large number compared to other trials with castrate-refractory prostate cancer” and underscores that the TROPIC trial included an advanced patient population. Additionally, “almost 25% of the patients had visceral disease,” further demonstrating the severity of their prostate cancer. Dr. Sartor also pointed out that the patients had received a fair amount of docetaxel therapy. The median total prior dose of docetaxel was 529 mg/m2 in the MP group and 576.5 mg/m2 in the cabazitaxel arm. The investigators found that patients receiving cabazitaxel demonstrated a statistically significant longer OS compared with MP—15.1 versus 12.7 months, respectively (hazard ratio, 0.70; 95% confidence interval, 0.59-0.83; P<0.0001) (Figure 1). PFS (composite of tumor, prostate-specific antigen [PSA] or pain progression; or death), response rates for tumor assessments by RECIST (Response Evaluation Criteria In Solid Tumors), PSA response and PSA progression also favored cabazitaxel (Figures 2 and 3). The most frequent grade 3/4 toxicity was neutropenia, which was observed in 81.7% of patients treated with cabazitaxel and 58.0% treated with MP. Grade 3/4 febrile neutropenia was also more common in patients receiving cabazitaxel at 7.5% and 1.3%, respectively (Figure 4), reported Dr. Sartor, who disclosed that he had been a consultant for and received honoraria and research support from Sanofi-aventis.

data warrant FDA approval, and said that having the drug as part of the armamentarium for advanced prostate cancer “will be an advance for the field.” But he added a few caveats for clinicians to consider when they are interpreting the results of the trial. “I’m not entirely convinced that all of the patients in the study were really docetaxel-refractory, because there were a relatively small number of docetaxel cycles administered prior to the study,” he said. “So although it is encouraging that cabazitaxel patients fared better than those given mitoxan-

trone–prednisone, we may need a docetaxel versus cabazitaxel trial to truly establish superiority.” Dr. Figg also pointed to the higher rates of neutropenia seen in the cabazitaxeltreated patients as a cause for concern. “I don’t think it will preclude anyone from using this drug, if approved, but it’s something that pharmacists will have to monitor more carefully, and potentially recommend other agents to reverse the side effect.” (See sidebar.) He also put the OS data in perspective. “Just over two months of increased survival may not seem like a significant

number, in terms of a person’s overall lifespan,” he said. “But it’s huge in cancer research, where advances are sometimes measured in weeks, not months.” Dr. Figg added that for some of the patients in the trial, the survival benefits were even more pronounced. “At 24 months, there were 28 patients who were still alive in the cabazitaxel arm, versus only 11 patients in the mitoxantrone–prednisone arm,” he said. Thus, for some patients, the new taxane “can really make a huge difference in survival.” —Kate O’Rourke and David Bronstein

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Results Potentially Practice-Changing Two additional experts not involved with the TROPIC study said the results may be practice-changing. “[Cabazitaxel] might well be a game-changing drug in the future,” said Scott Williams, MD, a consultant radiation oncologist with the Peter MacCallum Cancer Centre Uro-Oncology service in Melbourne, Australia. “We believe that this will be an FDAapprovable drug in the near term,” added Nicholas Vogelzang, MD, a medical oncologist at the Comprehensive Cancer Centers of Nevada, in Las Vegas, “TROPIC is a very powerful study; it’s the first positive trial of its kind, and [shows that cabazitaxel] clearly should be considered as an alternative for men who have failed docetaxel therapy.” Dr. Figg agreed that the cabazitaxel

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16 Clinical

Pharmacy Practice News â&#x20AC;˘ April 2010

Educational Review

Management of

Epidermal Growth Factor Receptor Inhibitor-Induced Dermatologic Toxicity COURTNEY KRUEGER, PHARMD, BCPS University of Illinois at Chicago College of Pharmacy Chicago, Illinois Reviewed by:

EDITH MITCHELL, MD, FACP Clinical Professor of Medicine and Medical Oncology Program Leader, Gastrointestinal Oncology Department of Medical Oncology Kimmel Cancer Center at Jefferson Philadelphia, Pennsylvania

he epidermal growth factor receptor (EGFR) is 1 of 4 types of human epidermal receptors that are found primarily on cells of epithelial origin and have a vital role in cellular growth,

proliferation, and migration.1-3 Abnormal activity at the EGFR receptor

has been implicated in many types of solid tumors, including colorectal, non-small cell lung, head and neck, and pancreatic cancers.

Two distinct drug categories have been developed to inhibit tumor growth and proliferation that results from dysregulated EGFR activity. The small molecule inhibitors, also known as tyrosine kinase inhibitors (TKIs), enter the cell and inhibit signaling pathways by binding to the adenosine triphosphate binding site. The monoclonal antibodies do not enter the cell but rather bind to the extracellular receptor, resulting in inactivation of the receptor. Table 1 lists the FDAapproved EGFR inhibitors and their indications.4-9 Other TKIs and monoclonal antibodies that affect receptors other than EGFR are available but will not be discussed in this review. One benefit of the EGFR inhibitors is that they are devoid of traditional systemic chemotherapeutic adverse effects. Their use, however, is associated with dermatologic toxicity.2,3,10,11 Skin rash is the most commonly reported dermatologic adverse effect, but other toxicities include pruritus and xerosis, as well as nail and hair changes. The mechanism

of this toxicity appears to be related to the inhibition of EGFR in the skin. EGFR is highly expressed in keratinocytes, the major cellular component of epidermal tissue, in the basal layer of the epidermis. Keratinocytes undergo a highly regulated process of differentiation as they move from the basal layer of the epidermis to the skin surface. EGFR inhibitors interfere with this regulation, thus compromising the skinâ&#x20AC;&#x2122;s integrity.2,12-14

Dermatologic Toxicities Rash The rash that occurs with EGFR inhibitors often is described as papular, pustular, or papulopustular, with a follicular distribution; it most commonly occurs on the scalp, face, and upper trunk.14,15 The rash generally appears within 1 to 2 weeks of treatment and evolves from edema and erythema to pustular eruptions.2,14,16 Rash symptoms usually dissipate within 1 month of EGFR inhibitor discontinuation and often will improve even with continued EGFR inhibitor

therapy. Some patients with rash will not require intervention, but others will be bothered by the skin dryness and itching and will need treatment. Although the terms acne-like or acneiform frequently are used to describe the rash, this is discouraged because of the differences in the pathologic processes of acne and EGFR-inhibitor rash.17 The severity of the EGFR-induced rash has been graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), initially version 3.0 and more recently version 4.0 (Table 2).18,19 However, it has been suggested that NCI-CTCAE criteria do not adequately address adverse events associated with the EGFR inhibitors, prompting a Multinational Association of Supportive Care in Cancer expert group to propose a new scale (Table 3).20 Rash has been reported to be more severe and to occur more frequently in patients treated with the monoclonal antibodies compared with those treated with TKIs.2,10,14 The

reason for this is not fully described, and multiple theories have been proposed. Li and colleagues proposed that the monoclonal antibodies suppress EGFR signaling more, resulting in greater toxicity.2 Eaby and colleagues suggested that higher peak concentrations are reached with the monoclonal antibodies due to their intermittent administration, versus the daily administration of TKIs, resulting in greater toxicity.10 The incidence of EGFR inhibitorinduced rash is difficult to determine due to differences in categorization and reporting.10 Jatoi and colleagues reviewed clinical trials of cetuximab (Erbitux, ImClone/Bristol Myers Squibb), panitumumab (Vectibix, Amgen), and erlotinib (Tarceva, Genentech) and found that, in general, rash occurred in more than 50% of patients.21 A recent metaanalysis of patients receiving cetuximab revealed that the incidence of reported rash was 88.2% (81.6% follicular-pustular).22 A small number of patients (6.5%) had rash that was grade 3 or higher. Xerosis Xerosis is dry, itchy skin that occurs in up to 35% of patients who receive EGFR inhibitors.14,23 Xerosis can occur in areas of the face and trunk but also frequently presents on the extremities after several weeks of EGFR inhibitor therapy. Patients who are older, have a history of atopic dermatitis, or have had previous cytotoxic chemotherapy are at greater risk for xerosis.24 Hyperpigmentation of the skin may occur in patients with

Clinical 17

Pharmacy Practice News • April 2010

Educational Review

Table 1. EGFR Inhibitors EGFR Inhibitor

Receptor(s)

Indications

Monoclonal Antibodies Cetuximab (Erbitux, ImClone/ Bristol-Myers Squibb)

EGFR

Colorectal cancer • As a single agent for the treatment of EGFR-expressing metastatic colorectal cancer after failure of irinotecanand oxaliplatin-based regimens or in patients who are intolerant of irinotecan regimens • In combination with irinotecan in patients with EGFR-expressing metastatic cancer who are refractory to irinotecanbased therapy Head and neck cancer • In combination with radiation therapy for locally or regionally advanced squamous cell carcinoma of the head and neck • As monotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinumbased therapy

Panitumumab (Vectibix, Amgen)

EGFR

Colorectal cancer • As a single agent for the treatment of EGFR-expressing metastatic colorectal cancer with disease progression on or following fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy regimens

Tyrosine Kinase Inhibitors Erlotinib (Tarceva, Genentech)

EGFR

Pancreatic cancer • First-line for patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine Non-small cell lung cancer • Treatment of locally advanced or metastatic disease after failure of 1 or more chemotherapy regimens

Gefitinib (Iressa, AstraZeneca)

EGFR

Non-small cell lung cancer • Monotherapy for patients with locally advanced or metastatic cancer after failure of both platinum-based and docetaxel chemotherapies

Lapatinib (Tykerb, GlaxoSmithKline)

EGFR, HER2

Breast cancer • In combination with capecitabine for patients with advanced or metastatic disease whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab • In combination with letrozole for treatment of postmenopausal women with hormone receptor-positive metastatic cancer who overexpress the HER2 receptor for whom hormonal therapy is indicated

EGFR, epidermal growth factor receptor; HER2, human epidermal receptor type 2 Based on references 4-9.

rash or xerosis and may not reverse with treatment discontinuation. Nail Changes Nail changes including cracking, discoloration, pitting, paronychia (inflammation of the lateral nail bed), and nail loss have been described.2,14,23,25 These changes are reported to occur in approximately 10% to 20% of patients. Paronychia is the most well-described nail change and is believed to result from skin thinning.14 Paronychia typically occurs on the thumbs and great toes, with a delayed onset of at least 1 month from the start of treatment and a duration that can persist months beyond discontinuation of EGFR inhibitor therapy.2,14 Patients with paronychia are predisposed to secondary infections. Hair Changes Changes in hair growth, texture, or thickness have been reported in up to 15% of patients taking EGFR inhibitors.2,23,25 Infrequently, trichomegaly (excess eyelash growth) has been reported. These alterations tend to be more delayed than other EGFR-related dermatologic adverse effects, generally occurring after 2 or more months of therapy.

Hair changes typically resolve within weeks or months after therapy discontinuation.2

Rash and Survival The presence of rash from EGFR inhibitors has been correlated with increased response to EGFR inhibitor therapy and improved survival.26-28 It has been proposed that dermatologic toxicity may be a marker for full EGFR receptor inhibition. However, results from studies that dose EGFR inhibitors until the presence of rash occurs are preliminary and have been conflicting.29,30 Further research in this area is necessary.

Management There are no well-established guidelines for the prevention or treatment of EGFR inhibitor-induced dermatologic changes. Treatment is largely based on anecdotal data from case reports, cases series, and expert opinion. Rash Prophylaxis General nonpharmacologic prophylactic recommendations are shown in Table 4. In addition to these measures, the use of oral antibiotics for prophylaxis has been studied in 2 randomized controlled trials.31,32

Tetracycline and its derivatives have been the primary antibiotics studied because of their anti-inflammatory effects. Scope and colleagues randomly assigned 48 cetuximabtreated patients to receive 100 mg of minocycline or placebo daily.31 All patients also received topical tazarotene 0.05% (Tazorac, Allergan) to be applied to one side of the face twice daily. Prophylactic therapy was initiated on the same day as cetuximab therapy and continued for 8 weeks. Patients in the minocycline group had a significantly reduced log lesion count at 4 weeks compared with placebo (P=0.005); however, by 8 weeks there was no significant difference between the groups. The proportion of patients with moderate to severe rash and itching was somewhat improved with minocycline at 4 weeks, but again, the difference between the groups was minimal by 8 weeks. Almost onethird of patients discontinued tazarotene due to skin dryness or irritation, and there appeared to be little beneficial effect with this treatment. In a second study, tetracycline (500 mg twice daily) was compared with placebo for rash prevention in patients receiving EGFR inhibitors.32 Tetracycline was initiated within 14 days of

EGFR initiation and continued for 4 weeks. Although there was little difference in overall rash incidence, the tetracycline-treated patients had a lower incidence of physician-reported grade 2 or higher skin toxicity at week 4 (17% vs 55%; P=0.04). At week 8, the incidence of moderate to severe skin toxicity remained lower in the tetracycline group (27% vs 47%), but it was not significantly different. Rash Prophylaxis Versus Treatment Recently, Lacouture et al published the first trial comparing preemptive therapy (given at the start of EGFR inhibitor therapy) with reactive therapy (treatment after the development of a rash).33 All 95 patients were being treated with panitumumab for colorectal cancer. Preemptive therapy consisted of a morning application of moisturizer, sunscreen prior to going outdoors, 1% hydrocortisone cream at bedtime, and 100 mg of doxycycline twice daily. Reactive treatment was at the discretion of the investigator and was prescribed at any point during weeks 1 to 6 of the study. Patients in the preemptive therapy group had fewer grade 2 or higher skin toxicities (29% vs 62%) during the 6-week treatment period.

•

see EGFR, page 18

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Educational Review

EGFR

continued from page 17

Based on these results, it appears that preventive therapies for rash should be further studied; however, the presence of rash has been correlated with survival, and there is concern that preventive therapy reduces the appearance of this marker of efficacy.14 Rash Treatment Table 5 summarizes several expert recommendations for the treatment of EGFR inhibitor-induced rash.10,11,17 A number of authors also have published recommendations based on their personal practice.15,34 Treatment recommendations typically include topical therapy for mild symptoms with progression to systemic antibiotics and corticosteroids for more severe rashes. Topical agents. Topical corticosteroids, antibiotics, and immunosuppressants frequently are recommended. Use of topical antiseptics, fusidic

acid, econazole, and benzoyl peroxide also have been reported without obvious benefit.35 Pimecrolimus (Elidel, Novartis), a topical immunosuppressant, was evaluated in a small trial (N=24) of patients receiving cetuximab.36 Pimecrolimus applied to one side of the face for 5 weeks reduced the lesion count on the treated side at both 2 and 5 weeks compared with the nontreated side. Additionally, patients reported decreases in burning, itching, dryness, and redness. However, the authors reported that the results did not show a clinically significant benefit, and thus they call into question the role of pimecrolimus. The use of topical corticosteroids is also controversial. Li and colleagues reported that corticosteroids may potentiate EGFR toxicity and recommend that these agents be avoided.2 Lynch and colleagues recommend topical steroids be applied for 7 days beyond resolution of symptoms but not for more than 14 consecutive days.3 One author recommends use

of topical corticosteroids for a maculopapular rash but recommends clindamycin gel if the rash has pustular characteristics.15 It is possible that topical steroids are most effective early in rash treatment.26 In addition to clindamycin, other topical antibiotics that have been used include erythromycin, fusidic acid, and metronidazole. Topical clindamycin appears most frequently in the literature and seems effective, particularly for pustular rash.15,37 Topical retinoids have been recommended by some authors, but many reports suggest they should be avoided because of their drying effects.38 In the prevention study by Scope and colleagues, tazarotene cream resulted in significant skin irritation.31 The Erlotinib Expert Panel suggests that further study of topical retinoids is necessary because one case report suggests positive results.17 Regenecare, a wound gel with lidocaine, aloe vera, collagen, and sodium alginate, is being evaluated for

its efficacy in improving itching and pain in patients receiving EGFR inhibitors.2 A pilot study revealed that a small number of patients with grade 2 rash applying the gel to affected areas had less itching and pain.39 Menadione (vitamin K3), has been shown to reverse the effects of EGFR inhibitors in the skin and is the first proposed treatment to reverse the EGFR inhibition process.40 A topical formulation is in Phase I clinical trials. Oral agents. The mechanism of oral antibiotics has been reported to be primarily anti-inflammatory rather than antibacterial; thus, tetracycline and its derivatives are the most widely recommended agents.17 Although minocycline and tetracycline were not dramatically successful when given as preventive agents, their use did improve rash severity.31,32 These data combined with success in case reports make them a reasonable option for rash treatment. Oral corticosteroids also are frequently recommended. Oishi suggests that

Table 2. NCI Grading Criteria for EGFR Inhibitor-Induced Rash Adverse Event

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

NCICTCAE v3.0

Rash (acneiform)

Intervention not indicated

Intervention indicated

Associated with pain, disfigurement, ulceration, or desquamation

Not available

Death

NCICTCAE v4.0

Rash (acneiform)

Papules and/or pustules covering <10% BSA that may or may not be associated with symptoms of pruritus or tenderness

Papules and/or pustules covering 10% to 30% BSA that may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL

Papules and/or pustules covering >30% BSA that may or may not be associated with symptoms of pruritus or tenderness; limiting self-care ADL; associated with local superinfection requiring oral antibiotics

Papules and/or pustules covering any percentage of BSA that may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection requiring IV antibiotics; lifethreatening consequences

Death

NCICTCAE v4.0

Rash (maculopapular)

Macules/papules covering <10% BSA with or without symptoms (eg, pruritus, burning, tightness)

Macules/papules covering 10% to 30% BSA with or without symptoms (eg, pruritus, burning, tightness); limiting instrumental ADL

Macules/papules covering >30% BSA, with or without associated symptoms; limiting self-care ADL

Not available

Source

ADL, activities of daily living; BSA, body surface area; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events Based on references 18 and 19.

Table 3. Suggested Grading Criteria for EGFR Inhibitor-Induced Rash Source Lacouture 2010

Adverse Event Papulopustular eruption

Based on reference 20.

Grade 1A

Grade 1B

Grade 2A

Grade 2B

Grade 3A

Grade 3B

<5 papules or pustules OR 1 area of erythema or edema <1 cm

<5 papules or pustules OR 1 area of erythema or edema <1 cm AND pain or pruritus

6-20 papules or pustules; OR 2 to 5 areas of erythema or edema <1 cm

6-20 papules or pustules OR 2 to 5 areas of erythema or edema <1 cm AND pain, pruritus, or effect on emotions or functioning

>20 papules or pustules OR >5 areas of erythema or edema <1 cm

>20 papules or pustules OR >5 areas of erythema or edema <1 cm AND pain, pruritus, or effect on emotions or functioning

Clinical 19

Pharmacy Practice News • April 2010

Educational Review corticosteroids are a good option for a rash that has progressed but is not pustular.15 Several authors recommend the use of antihistamines for itching.10,15,38 Xerosis Management Little information has been published on the management of xerosis associated with EGFR inhibitors. Emollient use is generally recommended.37 The emollient for the face and upper trunk should be an oil-inwater–based cream because greasy ointments could worsen the papulopustular rash; however, if the limbs are affected, a water-in-oil cream or ointment may be used.24 Low-dose corticosteroids can be used if eczema develops. Secondary infections should be treated appropriately. Treatment of Nail and Hair Changes Li and colleagues recommend the use of topical steroids and antiseptic soaks for paronychia.2 Segaert and colleagues suggest that a potent topical steroid applied to the nail

bed at symptom onset may prevent worsening of the paronychia.24 Suh and colleagues reported a case of paronychia that failed to respond to oral cephalexin and topical mupirocin but did respond to doxycycline 100 mg twice daily. Therapy was continued for 6 weeks, with full symptom resolution.41 The hair changes that can occur in patients treated with EGFR inhibitors often do not require intervention,2 but if trichomegaly occurs, an ophthalmologic examination may be indicated and the patient’s eyelashes may need to be cut.

Conclusion Although dermatologic reactions are common with EGFR inhibitors, treatments for these reactions have not been fully evaluated in clinical trials. Recent data suggest that preventive regimens may be valuable, but further research in this area is necessary before widespread use is recommended. Rash management will be necessary for some patients. Patients

Table 4. Basic Measures To Prevent EGFR Inhibitor-Induced Toxicities Sun exposure

• Avoid the sun when possible • Use sunscreen (preferably containing zinc oxide or titanium dioxide)

Skin care

• • • •

Nail care

• Keep nails clean and trimmed • Avoid activities that could cause nail bed trauma (eg, wearing tight-fitting shoes)

Use alcohol-free emollients to prevent dry skin Avoid dyes and perfumes Use mild body wash Take cool or lukewarm baths (rather than hot showers) • Apply hypoallergenic makeup for covering rash • Avoid over-the-counter acne products

Based on references 2, 3, 10, 15, and 38.

with mild to moderate symptoms may improve with topical therapy; however, patients with more severe rash will likely require oral therapy with antibiotics or possibly systemic corticosteroids. Typically, discontinuing

or reducing doses of EGFR inhibitors is avoided unless a severe reaction occurs. Patients undergoing treatment with EGFR inhibitors should be

•

see EGFR, page 20

Table 5. Recommendations for the Treatment of EGFR Inhibitor-Induced Rash Expert Group

Recommendations

Erlotinib Expert Panel Recommendations17

Grade 1 • Treatment with topical agents is optional (topical antibiotics, 2% sulfosalicylic creams) • No dose reduction or treatment interruption Grade 2 • Topical treatment as in Grade 1, with controversial recommendation for topical corticosteroids; patients with more severe symptoms could add oral therapy with tetracyclines and corticosteroids; antihistamines for pruritus • No dose reduction or treatment interruption; for very distressing symptoms, erlotinib may be interrupted for 3 to 5 days (restart at full dose; if rash recurs within 15 days, a dose reduction to 100 mg can be considered) Grade 3 • Topical agents, tetracycline, and oral corticosteroids can be used; tetracycline may be considered for a short duration to prevent future episodes after resolution of event • EGFR therapy should be interrupted until rash improves to Grade 2; restart at 100 mg/day; discontinue therapy if rash recurs with the reduced dose Grade 4 • Refer to burn unit for intensive care • Discontinue therapy indefinitely

Canadian Panel Recommendations for Monoclonal Antibodies in Gastrointestinal Malignancies11

Mild (Grade 1) • Topical corticosteroid (hydrocortisone 1%) and clindamycin 2% twice daily until resolution Moderate (Grade 2) • Topical treatment as above until rash improves to Grade 1 plus oral antibiotics (minocycline 100 mg twice daily or doxycycline 100 mg once or twice daily) for at least 4 weeks and as long as symptoms of rash are present • For scalp lesions, use topical clindamycin plus triamcinolone acetonide 0.1% in equal parts propylene glycol and water until resolved Severe (Grade 3) • Panitumumab: hold treatment until toxicity is Grade 2 or less • Cetuximab: hold treatment for 1 week • THEN follow Grade 2 recommendations; treatment can be continued if symptoms improve (follow dose escalation as recommended by manufacturer); treatment should be discontinued if no improvement is seen

2006 EGFR Inhibitor Dermatologic Toxicity Forum3,10

Mild • No treatment OR topical hydrocortisone (1% or 2.5%) and/or clindamycin 1% gel for 2 weeks (no alteration in EGFR inhibitor regimen); proceed to moderate treatment if no improvement or worsening reaction Moderate • Either topical hydrocortisone 2.5% cream, clindamycin 1% gel, or pimecrolimus 1% cream AND doxycycline or minocycline 100 mg twice daily for 2 weeks (no alteration in EGFR inhibitor regimen); proceed to severe treatment if no improvement or worsening reaction Severe • Add oral corticosteroid to moderate regimen and reduce EGFR inhibitor dose for 2 weeks; EGFR inhibitor may be interrupted or discontinued if symptoms worsen

20 Clinical

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Educational Review

EGFR

continued from page 19

educated about the common dermatologic toxicities, especially skin rash. Techniques for skin care, rash prevention, and potential management strategies should be thoroughly discussed. Oncologists, dermatologists, nurses, and pharmacists should remain vigilant for EGFR inhibitorinduced dermatologic toxicities, and multidisciplinary care should be instituted for patients who develop these toxicities.

References 1.

Zahorowska B, Crowe PJ, Yang JL. Combined therapies for cancer: a review of EGFR-targeted monotherapy and combination treatment with other drugs. J Cancer Res Clin Oncol. 2009;135(9): 1137-1148.

2. Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Targ Oncol. 2009;4(2):107-119. 3. Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 4. Wickersham RN, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2010. http://online. factsandcomparisons.com/searchresults. aspx?search=30946%7c24. Accessed February 10, 2010. 5. Iressa [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2005. 6. Tykerb [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010. 7. Tarceva [package insert]. Seymour, IN: Schwarz Pharma; 2009. 8. Vectibix [package insert]. Thousand Oaks, CA: Amgen; 2008. 9. Erbitux [package insert]. Branchburg, NJ: ImClone; 2009. 10. Eaby B, Culkin A, Lacouture ME. An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors. Clin J Oncol Nurs. 2008;12(2):283-290.

11. Melosky B, Burkes R, Rayson D, Alcindor T, Shear N, Lacouture M. Management of skin rash during EGFR-targeted monoclonal antibody treatment for gastrointestinal malignancies: Canadian recommendations. Curr Oncol. 2009;16(1):16-26. 12. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-812. 13. Chou LS, Garey J, Oishi K, Kim E. Managing dermatologic toxicities of epidermal growth factor receptor inhibitors. Clin Lung Cancer. 2006;8(suppl 1):S15-S22. 14. Hu JC, Sadeghi P, Pinter-Brown LC, Yashar S, Chiu MW. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol. 2007;56(2):317-326. 15. Oishi K. Clinical approaches to minimize rash associated with EGFR inhibitors. Oncol Nurs Forum. 2008;35(1):103-111. 16. Solomon BM, Jatoi A. Rash from EGFR inhibitors: opportunities and challenges for palliation. Curr Oncol Rep. 2008;10(4):304-308. 17. Gridelli C, Maione P, Amoroso D, et al. Clinical significance and treatment of skin rash from erlotinib in non-small cell lung cancer patients: results of an Experts Panel Meeting. Crit Rev Oncol Hematol. 2008;66(2):155-162. 18. National Cancer Institute. Common terminology criteria for adverse events (Version 3.0); 2003. http://ctep.cancer. gov/protocolDevelopment/electronic_ applications/docs/ctcaev3.pdf. Accessed February 9, 2010. 19. National Cancer Institute. Common terminology criteria for adverse events (Version 4.0); 2009. http://evs.nci.nih.gov/ ftp1/CTCAE/CTCAE_4.02_2009-09-15_ QuickReference_8.5x11.pdf. Accessed February 11, 2010. 20. Lacouture ME, Maitland ML, Segaert S, et al. A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group [published online ahead of print February 10, 2010]. Support Care Cancer. doi:10.1007/s00520-009-0744-x.

trial from the North Central Cancer Treatment Group (N03CB). Cancer. 2008;113(4):847-853.

systemic review and meta-analysis. Oncology. 2009;77(2):124-133. 23. Galimont-Collen AF, Vos LE, Lavrijsen AP, Ouwerkerk J, Gelderblom H. Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer. 2007;43(5):845-851. 24. Segaert S, Chiritescu G, Lemmens L, Dumon K, Van Cutsem E, Tejpar S. Skin toxicities of targeted therapies. Eur J Cancer. 2009;45(suppl 1):295-308.

33. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a Phase II, openlabel, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer [published online ahead of print February 8, 2010]. J Clin Oncol. doi: 10.1200.JCO.2008.21.7828.

25. Agero ALC, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55(4):657-670.

34. Lacouture ME, Basti S, Patel J, Benson A. The SERIES Clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol. 2006;4(5):236-238.

26. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptors. J Clin Oncol. 2004;22(7):1201-1208. 27. Mohamed MK, Ramalingam S, Lin Y, Gooding W, Belani CP. Skin rash and good performance status predict improved survival with gefitinib in patients with advanced non-small cell lung cancer. Ann Oncol. 2005;16(5):780-785. 28. Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007;13(13):3913-3921. 29. Tejpar S, Peeters M, Humblet Y, et al. Phase I/II study of cetuximab doseescalation in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic (PK), pharmacodynamic (PD) and efficacy data. J Clin Oncol. 2007;25(18 suppl):abstract 4037. 30. Sangha RS, Ho C, Beckett L, et al. Rash severity and dose in Phase I dose escalation cetuximab (c225) trial. J Clin Oncol. 2008;26:abstract 14573.

21. Jatoi A, Nguyen PL. Do patients die from rashes from epidermal growth factor receptor inhibitors? A systematic review to help counsel patients about holding therapy. Oncologist. 2008;13(11):1201-1204.

31. Scope A, Agero ALC, Dusza SW, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol. 2007;25(34):5390-5396.

22. Su X, Lacouture ME, Jia Y, Wu S. Risk of high-grade skin rash in cancer patients treated with cetuximabâ&#x20AC;&#x201D;an antibody against epidermal growth factor receptor:

32. Jatoi A, Rowland K, Sloan JA, et al. Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled

35. Jacot W, Bessis D, Jorda E, et al. Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumours. Br J Dermatol. 2004;151(1):238-241. 36. Scope A, Lieb JA, Dusza SW, et al. A prospective randomized trial of topical pimecrolimus for cetuximab-associated acne-like eruption. J Am Acad Dermatol. 2009;61(4):614-620. 37. Tan EH, Chan A. Evidence-based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors. Ann Pharmacother. 2009;43(10):1658-1666. 38. Perez-Soler R, Delord JP, Halpern A, et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/ EGFR inhibitor rash management forum. Oncologist. 2005;10(5):345-356. 39. Wong S, Osann K, Lindgren A, Byun T, Mummaneni M. Pilot cross-over study to evaluate Regenecare topical gel in patients with epidermal growth factor receptor (HER1/EGFR) inhibitors-induced skin toxicity: the final analysis. J Clin Oncol. 2008;26(15 suppl):abstract 20507. 40. Perez-Soler R, Zou Y, Li T, Tornos C, Ling T. Steroids and immunosuppressive agents potentiate the cytotoxicity of the EGFR inhibitor erlotinib (E) in human skin keratinocytes whereas Vit K3 exerts a protective effect: implications for the management of the skin rash. J Clin Oncol. 2006;24(18 suppl):abstract 3036. 41. Suh KY, Kindler HL, Medenica M, Lacouture M. Doxycycline for the treatment of paronychia induced by the epidermal growth factor receptor inhibitor cetuximab. Br J Dermatol. 2006;154(1):191-192.

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Pharmacy Practice News • April 2010

Medication Errors

Drug Safety by the Numbers Distinct labeling for adult, pediatric epidural solutions may stem errors New Orleans—If the experience of a research team in Chicago is typical of institutions across the country, hospitals may be able to improve their practice safety by revising the systems they use to categorize epidural solutions. “We perform many epidurals at the University of Chicago, and I was curious about the numbering system we use to categorize them,” said Jennifer Steiman, MD, an anesthesiology resident at the University of Chicago Medical Center. “The numbering system was implemented to increase simplicity, but it didn’t strike me as the safest way to order these solutions.” The hospital uses six epidural solutions (numbered 1-6) for adults, and four solutions (numbered 1-4) for children. Each solution contains different concentrations of local anesthetics and opioids. Dr. Steiman and her colleagues reviewed data from three years of pediatric epidural infusions. Cases in which the wrong epidural infusion was administered, if any, were reviewed for the occurrence of adverse drug events. Of the 150 procedures reviewed, two cases were identified in which the wrong solution was infused, said Dr. Steiman, who presented her findings at the 2009 annual meeting of the American Society of Anesthesiologists (abstract A605). In the first case, a child with a T6-7 epidural catheter received adult solution 1 (bupivacaine and hydromorphone) instead of the intended pediatric solution 1 (bupivacaine and fentanyl). The second child, who had a lumbar

plexus catheter, received pediatric solution 3 (bupivacaine and morphine) rather than the intended adult solution 3 (bupivacaine alone). Both patients developed respiratory depression and oxygen desaturation but responded well to naloxone. “Thank goodness both patients were rescued, without any long-term sequelae, but they definitely were at risk due to the narcotic,” Dr. Steiman told Pharmacy Practice News. “So, we’re happy we caught it.” Since the completion of the study,

ized systems, the investigators recommended that orders be written out in their entirety. “There has to be a better way to name or categorize these epidural solutions,” Dr. Steiman added. “You can’t just use numbers; it has to be written out as well.” And if an institution numbers its solutions, she added, it should make sure that adult and pediatric epidurals are recognizably distinct. “If your institution continues to use numbers, I would recommend that there be completely

‘Now there are no numbers for the epidural solutions and everything is written out on the ordered label. If I order adult solution 3, I need to enter the exact components of the solution.’ —Jennifer Steiman, MD

the institution has implemented a computerized drug ordering system that may help prevent such incidents from occurring in the future. “Now there are no numbers for the epidural solutions and everything is written out on the ordered label,” Dr. Steiman said. “If I order adult solution 3, I need to enter the exact components of the solution.” Several other safety checks also have been implemented, including medication interactions, patient age and maximum allowable dose of the daily epidural. At least two physicians now are involved in reconciling drug orders. For institutions without computer-

different numbers for adult and pediatric solutions.” Marie N. Hanna, MD, director of the acute pain service at Johns Hopkins Hospital in Baltimore, said identifying medication errors is a main target in improving clinical practice. “Systems that use information technology, such as computerized prescriber order entry [CPOE], automated dispensing, bar code medication administration and personal health records are vital components of strategies to prevent medication errors,” Dr. Hanna said. “In our institution, many clinical practice errors are avoided with the

use of computerized prescriber order entry,” Dr. Hanna added. “For pediatric patients, only a prescriber in the security group of the pediatric pain service can write orders for pediatric epidural catalog items. No other prescriber would even see them as an available order. Similarly, adult catalog items are not available in pediatric locations; therefore, an adult item could not be chosen for a pediatric patient in a pediatric location.” If the location must allow both the pediatric and adult catalog—such as the operating room holding areas—the prescriber will be able to see both adult and pediatric orders, she said. However, only the security group of the pediatric pain service can order the pediatric epidural. In addition, for every CPOE item in the system, the provider has to revise and approve the concentration, dose and administration frequency of the drug, and verify the patient’s initials before the order is submitted. —Michael Vlessides

Opioids Continue To Drive Unintentional Poisoning Deaths

new issues brief from the Centers for Disease Control and Prevention (CDC) highlights the role opioids play in unintentional overdose deaths in the United States. The brief, “Unintentional Drug Poisoning in the United States,” includes 2006 data, the latest available information, from death certificates and emergency department statistics provided by the Substance Abuse and Mental Health Services Administration’s Drug Abuse Warning Network (DAWN). In 2006, the three drugs most frequently involved in unintentional deaths in the United States were opioids, cocaine and heroin. Opioids led the way and were respon-

sible for nearly 12,000 of the 26,400 overall drug accidental overdose deaths that occurred in the country that year. The risk for an opioid-related overdose was 1.63 and 5.88 times higher in 2006 than those for cocaine and heroin, respectively. Further, opioid death rates increased dramatically in just eight years, spiking fourfold from 1999 to 2006. “The increase in drug death rates is largely because of prescription opioid painkillers,” according to the CDC brief.

Death rates related to opioid use varied significantly across the country, according to the CDC. Whereas overdose death rates related to opioids were considered low in New York and California, the rate in Washington was significantly higher than the national rate. From 2004 to 2007, there were nearly 1,700 prescription opioid-related overdoses in Washington. Nearly half of those deaths (45.4%) occurred among the state’s Medicaid population. According to the DAWN emergency

department statistics, in 2008 nearly 306,000 emergency visits to hospitals were related to opioid use. Regarding cost, the CDC brief estimated that the abuse of opioids cost the U.S. health care system approximately $8.6 billion in 2001. The CDC is conducting a study comparing prescription drug use among people who died of overdoses and a control group of prescription drug users. Results of the study are expected this year. To access the complete issues brief, go to www.cdc.gov/homeandrecreationalsafety/poisoning/activities.htm. —Donald M. Pizzi

Successful bedside scanning starts here.

Introducing PROmanager-Rx™, the first fully automated system for storing and dispensing manufacturer-packaged unit dose oral solids. With PROmanager-Rx scanning every dose in the pharmacy, you’re perfectly set up to scan at the bedside. It’s ideal for patient-centric filling. By using pre-packaged meds and scanning every dose dispensed, PROmanager-Rx frees pharmacists from packaging verification and dispensing checks. They can spend more time on the floor, focused on bedside scanning processes and other patient care programs. Bar-code scanning also simplifies tasks such as managing returns, expired meds, and overall inventory. And PROmanager-Rx doesn’t even take up much room – it’s only 9 ’x 3 ’, yet capable of holding an impressive 12,000 unit doses. See for yourself what PROmanager-Rx can do. Visit www.PROmanager-Rx.com or call 1-800-594-9145. © 2010 McKesson Corp.

“Between improved staff satisfaction, automation of the picking process, and improved safety, PROmanager-Rx is a big win. On the front end, we can order a pre-packaged product direct from a wholesaler, receive it, and immediately put it into our medication-use process. And because we have a check waiver in place from the Ohio Board of Pharmacy, we can improve patient safety at the same time we’re minimizing pharmacist involvement in cart ﬁll.” — Charles McCluskey, Pharm.D., Director of Pharmacy Services, Riverside Methodist Hospital, Columbus, Ohio

Important Safety Information WARNING: FOR SHORT-TERM HOSPITAL USE ONLY ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have registered in and met all of the requirements for the ENTEREG Access Support & Education (E.A.S.E.â&#x201E;˘) Program may use ENTEREG. taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG

treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic pain. In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of alvimopan, including studies of patients undergoing bowel resection surgery who received alvimopan 12 mg twice daily for up to 7 days. A causal relationship with alvimopan has not been established

For more information on the E.A.S.E. Program, contact Adolor Corporation at 1.866.4ADOLOR (1.866.423.6567) or visit www.entereg.com.

The first and only FDA-approved agent indicated to accelerate the time to upper and lower gastrointestinal (GI) recovery following partial large or small bowel resection surgery with primary anastomosis

Make ENTEREG Part of Your Preop and Postop Routine Clinical studies showed ENTEREG reduced mean time to GI recovery by up to 1 day (11 to 26 hours) vs placebo1 —Improved time to GI recovery was beyond a standardized, accelerated postoperative care pathway1

receiving more than 3 doses of an opioid within the week prior to surgery. These patients may be more sensitive to ENTEREG and may experience GI side effects (eg, abdominal pain, nausea and vomiting, diarrhea) ENTEREG is not recommended for use in patients with severe hepatic impairment, end-stage renal disease, or in patients undergoing surgery for correction of complete bowel obstruction E.A.S.E. Program Please see Brief Summary of Prescribing Information following this ad.

To enroll in the E.A.S.E. Program, the hospital must acknowledge that: —Hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use —Patients will not receive more than 15 doses of ENTEREG —ENTEREG will not be dispensed to patients after they have been discharged from the hospital

28 Clinical

Pharmacy Practice News • April 2010

Cardiology

INVEST

continued from page 1

emerged from a post hoc analysis of the International Verapamil SR-Trandolapril (INVEST) study. The trial followed 6,400 patients with diabetes and documented CAD for a mean of 2.7 years (maximum, five years) after allocating them to receive either a calcium channel blocker or a β-blocker, plus an angiotensin-converting enzyme (ACE) inhibitor and a thiazide diuretic. No differences were found in the prevention of nonfatal stroke, nonfatal myocardial

infarction (MI) and all-cause mortality between treatment strategies. In the post hoc analysis, the investigators examined the effect of level of systolic blood pressure (SBP) on outcomes according to three categories: tight control (<130 mm Hg), usual control (130 to <140 mm Hg) and not controlled (>140 mm Hg). During a follow-up period equivalent to more than 16,893 patient-years, Dr. Cooper-DeHoff and her colleagues found that the uncontrolled BP patients had nearly a 50% higher combined risk for death, MI or stroke compared with

the usual-control and the tight-control groups, but there was no difference in these outcomes between the usual- and tight-control patients. “This highlights the importance of keeping systolic blood pressure under 140 mm Hg, because this significantly cuts cardiovascular risk,” Dr. Cooper-DeHoff commented. However, further analysis showed that lowering SBP below 130 mm Hg significantly increased the risk for all-cause mortality compared with usual control (11% vs. 10.2%, respectively). The researchers extended the followup in 4,370 patients in the United States

in vitro

In vitro

[see Warnings and Precautions (5.1 and 5.2)]

in vitro In vitro in vitro

[see Clinical Pharmacology (12.3) of full prescribing information]

[see Clinical Pharmacology (12.3) of full prescribing information].

see Clinical Pharmacology (12.3)]

[See Warnings and Precautions (5.4) and Dosage and Administration (2.2) and Clinical Pharmacology (12.3) of full prescribing information]

[see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) of full prescribing information]

Reference: 1. ENTEREG Prescribing Information. Exton, PA: Adolor Corporation; 2009. ENTEREG is a registered trademark and E.A.S.E. is a trademark of Adolor Corporation. © 2009 Adolor Corporation. All rights reserved. Printed in USA. ETG249R0 December 2009

for an additional five years by searching the National Death Index and saw a trend for increased mortality in patients with tight control (P=0.058). After adjusting for differences in baseline conditions, they found a significant 15% excess risk for death in the tight-control versus the usual-control group (P=0.038). Focusing on the tight-control group only, the team discovered that an SBP below 115 mm Hg was linked to increased mortality. “One of our most important takehome messages is that in diabetic patients with coronary artery disease, lowering blood pressure to less than 140 mm Hg systolic was extremely beneficial,” Dr. Cooper-DeHoff told Pharmacy Practice News. “But in the same population, lowering systolic blood pressure to less than 130 [mm Hg] did not confer additional benefit.” The latter finding is important, Dr. Cooper-DeHoff noted, because “our current hypertension treatment guidelines [Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC 7)] recommend that blood pressure should be lowered to less than 130 in all patients with diabetes.” Lowering blood pressure too much risks decreasing perfusion to important organs such as the brain, kidneys and heart, and this may be where some of the excess mortality risk is coming from, she added. “We also believe that this may be a surrogate for other comorbid conditions in this high-risk population, and that it is a marker for very severe vascular dysfunction.” The focus now should be on lifestyle changes such as increasing exercise and improving diet, rather than on reducing blood pressure in this group of patients, Dr. Cooper-DeHoff said. “Certainly, lower is not always better.” Asked to comment on the study, which was funded by Abbott Laboratories, C. Michael White, PharmD, professor of pharmacy, University of Connecticut, in Storrs, said, “INVEST was a well-run trial. It is my understanding that the lower blood pressure goals for patients with diabetes was based, in part, on results from the UKPDS [UK Prospective Diabetes Study], which showed a linear relationship between blood pressure and negative renal outcomes. However, subsequent studies have found that the use of ACE inhibitors and ARBs [angiotensin II receptor blockers] provides much greater renal protection than other antihypertensives even with the same level of blood pressure reduction.” Thus, “at the end of the day, the data suggesting that clinicians should push for a blood pressure goal of <130/80 versus 140/90 mm Hg was not based on strong evidence.” —Fran Lowry

Clinical 29

Pharmacy Practice News • April 2010

Collaborative Care

BARIATRICS continued from page 1

Working with a team that included pharmacists as well as physicians, nurses and a dietitian, Dr. Jacob and her colleagues demonstrated how a pharmacist-designed supplementation protocol could restore bariatric patients’ depleted vitamin D levels (Table 1) and lower the long-term risk for bone loss, osteoporotic fractures and other adverse events that have been shown to occur when vitamin D levels fall below normal levels of 30 to 100 ng/mL. The study included 64 patients who underwent bariatric surgery (Roux-enY gastric bypass, lap band, sleeve gastrectomy or duodenal switch) between Aug. 23, 2006, and Nov. 11, 2009. Of these, 23 (36%) were found to be vitamin D-deficient following the procedure, with blood levels averaging 21.72 ng/mL,

Table 1. VA Vitamin D Repletion Protocol Prior to Bariatric Surgerya Vitamin D (25[OH]D) Level

Dose

<20 ng/mL

Ergocalciferol 50,000 units once weekly for 6 to 8 wk, then cholecalciferol 800-1,000 IU thereafter

20-30 ng/mL

Cholecalciferol 800-1,000 IU daily for 3 mo

Note: For every 40 IU/d (1 mcg/d) increment of vitamin D, serum 25(OH)D concentration increases by approximately 0.3 to 0.4 ng/mL (0.7 -1 mmol/L) Duration of therapy: 3 mo Labs to monitor: Alkaline phosphate Chem 13 Magnesium a

Follow-up: 3 mo

Patients with normal absorptive capacity

‘My advice to pharmacists is, do the baseline lab work and treat the [vitamin] deficiencies prior to surgery, because treating them after surgery is a lot harder.’

—Susan Jacob, PharmD

noted Dr. Jacob, who sees patients at the VA but is employed by Western University of Health Sciences, in Pomona, Calif., where she is an assistant professor of pharmacy practice. The researchers were able to track outcomes in 13 of the vitamin D-deficient patients, each of whom received 10,000 units of ergocalciferol daily to correct the deficiency. After six weeks of treatment, 11 had achieved vitamin D blood levels averaging 36.12 ng/mL; the remaining two were being re-treated at the time the study was written. Since the study, according to Dr. Jacob, VA Loma Linda has implemented a protocol requiring prospective bariatric patients to undergo a multidisciplinary evaluation a year in advance of surgery. “We developed a team approach with a dietitian, primary care doctor, bariatric surgeon, nursing and case manager,” she said. “We draw all of their labs, look at their baselines, and if there is anything that needs to be corrected— vitamin D, calcium, glucose—we do it before surgery.” The pharmacy team is looking at possible thiamine deficiencies (Table 2) and has uncovered one case of copper deficiency, noted Dr. Jacob. Thiamine deficiency, which is more prevalent in people with alcoholic disease, can lead to severe cardiovascular, nervous system and gastrointestinal disorders (http:// lpi.oregonstate.edu/infocenter/vitamins/thiamin), while severely depleted copper levels are associated with a host

Phosphorus Vitamin D (25[OH]) Intact parathyroid hormone Calcium (24h urine)

of conditions, including osteoporosis and cardiovascular disease (http://www.copperinfo.com/health/ deficiencies.html). One reason for the large percentage of vitamin D deficiencies, Dr. Jacob added, is that the patient population at Loma Linda tends to be made up of older veterans, who may not be getting enough exposure to sunlight, even in southern California. As part of the total workup, patients also are assessed for compliance, Dr. Jacob said, “because if they are not compliant before surgery, they’re not going to be compliant at all.” A psychiatrist also is involved, “because we started seeing a lot of depression and binge eating, and you have to worry about dumping syndrome,” where a large quantity of ingested food enters the small intestine of bariatric surgery patients largely undigested. The bottom line, she said, is that “the process takes one year and then we say yea or nay. We won’t do the surgery otherwise now. My advice to pharmacists is, do the baseline lab work and treat the deficiencies prior to surgery, because treating them after surgery is a lot harder.”

Pharmacy Consultation Service At Brigham and Women’s The second study described how clinical pharmacists at Brigham and Wom-

en’s Hospital (BWH) in Boston developed a pharmacy consultation service to help bariatric patients optimize their medication therapy based on the type of procedure they were having. Referred to the service up to one month before surgery, patients had their regimens evaluated by a pharmacist and changed if necessary to ensure therapeutic continuity through the procedure and after discharge. Prior to implementing the service, bariatric surgeons had been solely responsible for medication management, according to the poster study. However, “an increased number of complicated cases prompted the surgeons and the Department of Pharmacy to initiate a collaborative effort to more effectively manage these patients.” Pharmacists retrospectively reviewed 149 patient charts and “identified numerous opportunities for medication changes to safer therapeutic alternatives and dosage forms.” During a four-month pilot study period, five consulting pharmacists documented 181 interventions for 20 patients (average age, 55; body mass index, 46 kg/m2). The mean number of medications per patient was 13 before surgery and 12 after surgery. According to the researchers, all patients required at least one therapeutic adjustment, and as a group they received recommendations to adjust approximately 50% of their regimens. The most common recommendations were: change from pill to liquid formulations, don’t crush, change from pill to chewable formulations, discontinue medication and switch from

‘We did a survey of many of the patients and found they absolutely loved the service.’ —Deborah A. Cios, PharmD, BCPS

extended- to immediate-release formulations. Surgeons accepted 99% of the pharmacist recommendations. Although the researchers did not measure whether patient outcomes improved as a result of the pharmacist interventions, “we did a survey of many of the patients and found they absolutely loved the service,” said Deborah A. Cios, PharmD, BCPS, senior clinical pharmacist at BWH. “They felt they knew what was going on and how to transition their medications. They felt more comfortable taking them” as a result of pharmacist assistance. Jennifer Catella, PharmD, BCPS, the clinical pharmacist who led the BWH study, said the pharmacy consultation service had grown to include as many as nine pharmacists drawn from all areas of the hospital, including general medicine, intensive care units, the emergency department and the investigational drug service. The group meets weekly to review new patients and assign them to individual pharmacists for consultations that can take 45 minutes or more, she said, and other pharmacists cover for them during the sessions. “To ensure a safe and efficacious transition for this patient population, we try to adjust their medication regimen to prevent complications,” Dr. Catella said. “By scheduling separate appointments, we are able to perform a complete medication reconciliation with the patient, answer any questions they have about their medications, identify any problems with their current regimen, and transition their medications safely

•

see BARIATRICS, page 30

Table 2. VA Bariatric Surgery Thiamine Deficiency Protocol Thiamine supplementation: 200 mg bid × 30 d, then 100 mg/d for maintenance Duration of therapy: Initial: 30 d Maintenance: Indefinite Labs to monitor: Thiamine Follow-up: Baseline, 1, 3, 6 and 12 mo

30 Clinical

Pharmacy Practice News • April 2010

Collaborative Care

BARIATRICS continued from page 29

through [the bariatric] procedure.” Dr. Catella noted that changes in anatomy resulting from Roux-en-Y or laparoscopic banding procedures significantly alter the passage and absorption of certain medication forms, and medication may need to be changed to ensure optimal pharmacokinetic and pharmacodynamic effectiveness. Roux-en-Y, she noted, results in a complete bypass of the stomach, which affects medications requiring an acidic pH for absorption. Calcium carbonate, for example, needs to be changed to calcium citrate. Dr. Catella offered other examples of pharmacist-recommended medication changes: • Extended-release medications are changed to immediate-release, crushable formulations. • Solid dose medications that have liquid formulation equivalents are changed to the latter form. • Patients are instructed to crush solid oral medications that are bigger than a pencil eraser, and are instructed on how to open capsules and mix them in liquid or applesauce. • In a few instances, pharmacists have located a pharmacy that will compound a medication for easier passage and absorption. After each session, the pharmacist sends recommended therapy changes to the referring surgeon. If they are approved, the pharmacist faxes any new prescriptions to the patient’s pharmacy to make sure the patient has begun the new regimen prior to admission for surgery. “We then post a note in the patient’s electronic medical records and copy all of their doctors,” Dr. Catella said. Patients also are sent charts by e-mail that detail the new regimens and are encouraged to get back with any questions they might have. Additionally, the pharmacist who conducted the consult arranges a visit to the patient after admission. The pilot study program has now become a permanent service at BWH, and pharmacists have conducted close to 90 consults to date. Dr. Catella said the service was “also going to be used as a model to add other collaborative drug therapy management pharmacy services at our institution.”

‘A multidisciplinary approach to care for the bariatric patient is important for achieving an optimal outcome, not only from the surgery but also for good long-term patient success.’ —Stewart Rendon, MD Dr. Rendon said the team should consist of the bariatric surgeon, a bariatrician, a pharmacist, a psychologist, a nutritionist and a care coordinator. “A pharmacist plays a particular role in adjusting all medications preoperatively

and postoperatively. Dosage, compatibility to prior medications and routes of administration all need to be considered.” Such efforts “are very important, considering that absorption of medications may change. Vitamin and min-

—Bruce and Joan Buckley

EGFR-Expressing Metastatic Colorectal Cancer In In EGFR-Expressing Metastatic Colorectal Cancer . . .. . .

Consider ERBITUX Appropriate Patient Population Consider ERBITUX in in anan Appropriate Patient Population ERBITUX the Only MAb With: ERBITUX Is Is the Only MAb With: EFFICACY COMBINATION EFFICACY IN IN COMBINATION With Irinotecan After Irinotecan Failure With Irinotecan After Irinotecan Failure

SINGLE AGENT OVERALL SURVIVAL SINGLE AGENT OVERALL SURVIVAL After Irinotecan and Oxaliplatin Failure After Irinotecan and Oxaliplatin Failure

® (cetuximab), in combination with irinotecan, ® (cetuximab), ERBITUX ERBITUX in combination with irinotecan, is indicated for the treatment of EGFR-expressing is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients metastatic colorectal carcinoma in patients whowho are are refractory to irinotecan-based chemotherapy. refractory to irinotecan-based chemotherapy. TheThe effectiveness of ERBITUX in combination irinotecan effectiveness of ERBITUX in combination withwith irinotecan is based on objective response rates. Currently, is based on objective response rates. Currently, no no available demonstrate an improvement datadata are are available thatthat demonstrate an improvement in in disease-related symptoms or increased survival disease-related symptoms or increased survival ERBITUX in combination irinotecan for the withwith ERBITUX in combination withwith irinotecan for the treatment of EGFR-expressing metastatic treatment of EGFR-expressing metastatic 1 1 colorectal carcinoma. colorectal carcinoma.

ERBITUX, a single agent, is indicated for the treatment ERBITUX, as aassingle agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer of EGFR-expressing metastatic colorectal cancer after failure of both irinotecanoxaliplatin-based after failure of both irinotecanandand oxaliplatin-based regimens. ERBITUX, a single agent, is also indicated regimens. ERBITUX, as aassingle agent, is also indicated for the treatment of EGFR-expressing metastatic for the treatment of EGFR-expressing metastatic colorectal cancer in patients intolerant colorectal cancer in patients whowho are are intolerant to to 1 1 irinotecan-based regimens. irinotecan-based regimens.

K-ras STATUS K-ras STATUS Retrospective subset analyses of metastatic or advanced colorectal cancer trials have shown Retrospective subset analyses of metastatic or advanced colorectal cancer trials have notnot shown a treatment benefit ERBITUX in patients whose tumors K-ras mutations in codon 12 13. or 13. a treatment benefit forfor ERBITUX in patients whose tumors hadhad K-ras mutations in codon 12 or 1 1 of ERBITUX is not recommended treatment of colorectal cancer with these mutations. UseUse of ERBITUX is not recommended forfor thethe treatment of colorectal cancer with these mutations.

ERBITUX + BSC Signiﬁ cantly Increased Overall Survival 34%vs BSC Alone (P=0.0046) ERBITUX + BSC Signiﬁ cantly Increased Overall Survival by by 34%vs BSC Alone (P=0.0046) 1 1 Overall Survival, Patients (N=572)* Overall Survival, All All Patients (N=572)*

Safety Limitation Based on K-ras Safety Limitation Based on K-ras Mutational Status Mutational Status

Incidence of K-ras Mutations Among Incidence of K-ras Mutations Among K-ras K-ras Evaluable Patients in CTG NCICCO.17 CTG CO.17 Evaluable Patients in NCIC Trial1 Trial1

MutantMutant 41.6%41.6%

Bariatric Surgeon Also Sees Value in Service Stewart Rendon, MD, bariatric surgeon at the new Bariatric Center of Excellence at the Loma Linda VA Healthcare system and Loma Linda University, said, “a multidisciplinary approach to care for the bariatric patient is important for achieving an optimal outcome, not only from the surgery but also for good longterm patient success.”

eral supplements, as well as psychiatric, diabetic, hypertensive and many other medications need to be monitored and adjusted frequently. “In working with Dr. Jacob, we have been able to provide successful management of nutrient deficiency and medication management in a much more efficient manner for our patients. We have been able to prevent and catch any clinically significant problems. I am a strong believer of a multidisciplinary approach to patient care.”

OS=overall CI=confidence OS=overall survival;survival; CI=confidence interval.interval.

Wild Type Wild Type 58.4%58.4%

■ of Use of ERBITUX not recommended for the ■ Use ERBITUX is notisrecommended for the treatment of colorectal cancer treatment of colorectal cancer withwith K-rasK-ras mutations in codon 13 because retrospective mutations in codon 12 or12 13or because retrospective subset analyses not shown a treatment subset analyses havehave not shown a treatment 1 1 benefit for ERBITUX in these patients benefit for ERBITUX in these patients ■ overall The overall survival presented include ■ The survival datadata presented herehere include patients mutations because patients withwith K-rasK-ras mutations because K-rasK-ras mutational status not assessed attime the time mutational status was was not assessed at the the study conducted the study was was conducted ■a retrospective In a retrospective analysis ofNCIC the NCIC CO.17 ■ In analysis of the CTG CTG CO.17 shown atERBITUX left, ERBITUX not effective datadata shown at left, was was not effective in in 1 1 patients mutated tumors patients withwith K-rasK-ras mutated tumors Inanalysis, this analysis, investigational — In— this investigational teststests werewere usedused to detect mutations in codon to detect K-rasK-ras mutations in codon 12 or12 13or 13 — 68.9% (394/572) ofpatients the patients — 68.9% (394/572) of the in thein the original trial were evaluable for K-ras status original trial were evaluable for K-ras status Of those patients, 41.6% (164/394) — Of—those patients, 41.6% (164/394) had had tumors containing mutations tumors containing K-rasK-ras mutations

*NCIC CO.17 a multicenter, open-label, randomized, clinical conducted in 572 patients EGFR-expressing, previously treated, recurrent *NCIC CTG CTG CO.17 was was a multicenter, open-label, randomized, clinical trial trial conducted in 572 patients withwith EGFR-expressing, previously treated, recurrent 2 2 metastatic colorectal cancer. Patients randomized to receive either ERBITUX or BSC alone. ERBITUX administered a 400-mg/m metastatic colorectal cancer. Patients werewere randomized (1:1)(1:1) to receive either ERBITUX plusplus BSCBSC or BSC alone. ERBITUX waswas administered as aas 400-mg/m 2 2 initial dose, followed by 250 mg/m weekly disease progression or unacceptable toxicity. Of 572 the 572 randomized patients, the median initial dose, followed by 250 mg/m weekly untiluntil disease progression or unacceptable toxicity. Of the randomized patients, the median age age was was 63 years, male, Caucasian, baseline ECOG performance status of All 0-1.patients All patients to have received progressed 63 years, 64%64% werewere male, 89%89% werewere Caucasian, and and 77%77% had had baseline ECOG performance status of 0-1. werewere to have received and and progressed on on therapy, including an irinotecan-containing regimen an oxaliplatin-containing regimen. The main outcome measure ofstudy the study all survival. priorprior therapy, including an irinotecan-containing regimen and and an oxaliplatin-containing regimen. The main outcome measure of the was was overover all survival. 1 1 shown arepatients for patients in whom K-ras status a predetermined eligibility criterion. The The datadata shown herehere are for in whom K-ras status waswas not anot predetermined eligibility criterion. EGFR=epidermal growth receptor; MAb=monoclonal antibody; BSC=best supportive EGFR=epidermal growth factorfactor receptor; MAb=monoclonal antibody; BSC=best supportive care.care.

Please see Important Safety Information including Boxed WARNINGS on adjacent Please see Important Safety Information including Boxed WARNINGS on adjacent page.page.

Clinical 31

Pharmacy Practice News • April 2010

Brief

Nestlé Launches Safety Campaign on Enteral Medication Delivery N

estlé HealthCare Nutrition has launched a new campaign to promote safer medication delivery through enteral feeding tubes in hospitals, based on the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Enteral Nutrition Practice Recommendations. The “Be A.W.A.R.E.” campaign is designed to raise awareness and knowledge of the simple steps needed to increase patient safety among health care professionals who deliver medications through enteral feeding tubes to hospital patients. The program will be implemented in hospitals nationwide to help reduce the risk for medication errors and improve patient outcomes.

In releasing recommendations for improving enteral feeding safety last year, A.S.P.E.N. noted that practice differs considerably from guidelines for medication delivery through the enteral route. Surveys found that practitioners failed to complete certain simple practices and that such failures may contribute to measurable adverse outcomes. Practices that have been noted to be of concern include: • failure to flush enteral feeding tubes before or between medications; • administration of multiple drugs together; • improper dilution of liquid medication; and • crushing modified-release dosage forms

Building on Nestlé’s ongoing patient safety initiatives, the “Be A.W.A.R.E.” campaign accompanies the 2009 “Be A.L.E.R.T.” campaign to promote safer enteral practices. Nestlé also developed SpikeRight, an enteralspecific port with a screw-top design that reduces compatibility with IV sets, thereby reducing the risk for tubing misconnections. A poster outlining the recommendations for safe medication delivery through feeding tubes is available for download free of charge at www.nutritioncare.org/safety. —Based on a press release from Nestlé HealthCare Nutrition

Important Safety Information Including Boxed WARNINGS Important Safety Information Including Boxed WARNINGS Infusion Reactions Infusion Reactions Grade infusion reactions occurred in approximately of patients receiving ERBITUX (cetuximab) in clinical trials, outcome ■ ■ Grade 3/43/4 infusion reactions occurred in approximately 3% 3% of patients receiving ERBITUX (cetuximab) in clinical trials, withwith fatalfatal outcome reported in less in 1000 reported in less thanthan 1 in11000 Serious infusion reactions, requiring medical intervention immediate, permanent discontinuation of ERBITUX, included rapid — — Serious infusion reactions, requiring medical intervention andand immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, of consciousness, myocardial infarction, onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, lossloss of consciousness, myocardial infarction, and/or cardiac arrest and/or cardiac arrest Immediately interrupt permanently discontinue ERBITUX infusions for serious infusion reactions — — Immediately interrupt andand permanently discontinue ERBITUX infusions for serious infusion reactions Most (90%) of the severe infusion reactions were associated infusion of ERBITUX despite premedication antihistamines ■ ■ Most (90%) of the severe infusion reactions were associated withwith the the firstfirst infusion of ERBITUX despite premedication withwith antihistamines Caution must be exercised every ERBITUX infusion, as there were patients experienced their severe infusion reaction — — Caution must be exercised withwith every ERBITUX infusion, as there were patients whowho experienced their firstfirst severe infusion reaction during later infusions during later infusions Monitor patients 1 hour following ERBITUX infusions a setting resuscitation equipment other agents necessary to treat — — Monitor patients for 1for hour following ERBITUX infusions in ain setting withwith resuscitation equipment andand other agents necessary to treat anaphylaxis epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, oxygen). Longer observation periods anaphylaxis (eg,(eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, andand oxygen). Longer observation periods be required in patients require treatment for infusion reactions maymay be required in patients whowho require treatment for infusion reactions Pulmonary Toxicity Pulmonary Toxicity Interstitial disease (ILD), which in one case, occurred of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. ■ ■ Interstitial lunglung disease (ILD), which waswas fatalfatal in one case, occurred in 4inof41570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where is confirmed Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD ILD is confirmed Dermatologic Toxicities Dermatologic Toxicities In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, drying fissuring, paronychial inflammation, ■ ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skinskin drying andand fissuring, paronychial inflammation, infectious sequelae S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), hypertrichosis, infectious sequelae (eg,(eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), andand hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. occurred in patients receiving ERBITUX therapy. Acneform rashrash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform occurred in 1-17% of patients Severe acneform rashrash occurred in 1-17% of patients Acneform usually developed within weeks of therapy resolved a majority of the patients cessation — — Acneform rashrash usually developed within the the firstfirst twotwo weeks of therapy andand resolved in ain majority of the patients afterafter cessation of of treatment, although in nearly event continued beyond 28 days treatment, although in nearly half,half, the the event continued beyond 28 days Monitor patients receiving ERBITUX for dermatologic toxicities infectious sequelae — — Monitor patients receiving ERBITUX for dermatologic toxicities andand infectious sequelae exposure exacerbate these effects — — SunSun exposure maymay exacerbate these effects Electrolyte Depletion Electrolyte Depletion Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX severe grades in 6-17%. onset ■ ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX andand waswas severe (NCI(NCI CTCCTC grades 3 & 34)&in4)6-17%. TheThe onset of of hypomagnesemia accompanying electrolyte abnormalities occurred to months initiation of ERBITUX therapy hypomagnesemia andand accompanying electrolyte abnormalities occurred daysdays to months afterafter initiation of ERBITUX therapy Monitor patients periodically for hypomagnesemia, hypocalcemia hypokalemia, during, forleast at least 8 weeks following — — Monitor patients periodically for hypomagnesemia, hypocalcemia andand hypokalemia, during, andand for at 8 weeks following the the completion of, ERBITUX therapy completion of, ERBITUX therapy Replete electrolytes as necessary — — Replete electrolytes as necessary Pregnancy Pregnancy In women of childbearing potential, appropriate contraceptive measures must be used during treatment ERBITUX 6 months ■ ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment withwith ERBITUX andand for 6for months following dose of ERBITUX. ERBITUX be transmitted mother to the developing fetus, potential to cause following the the lastlast dose of ERBITUX. ERBITUX maymay be transmitted fromfrom the the mother to the developing fetus, andand hashas the the potential to cause fetalfetal harm when administered to pregnant women. ERBITUX should be used during pregnancy if the potential benefit justifies potential harm when administered to pregnant women. ERBITUX should onlyonly be used during pregnancy if the potential benefit justifies the the potential riskrisk to the fetus to the fetus Adverse Events Adverse Events most serious adverse reactions associated ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic ■ ■ TheThe most serious adverse reactions associated withwith ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial disease, pulmonary embolus toxicity, sepsis, renal failure, interstitial lunglung disease, andand pulmonary embolus most common adverse reactions associated ERBITUX (incidence ≥25%) cutaneous adverse reactions (including rash, pruritus, ■ ■ TheThe most common adverse reactions associated withwith ERBITUX (incidence ≥25%) are are cutaneous adverse reactions (including rash, pruritus, andand changes), headache, diarrhea, infection nailnail changes), headache, diarrhea, andand infection most frequent adverse events in patients metastatic colorectal cancer (n=288) in the ERBITUX + best supportive ■ ■ TheThe most frequent adverse events seenseen in patients withwith metastatic colorectal cancer (n=288) in the ERBITUX + best supportive carecare armarm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal (59%), pain-other (51%). most common grade (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal painpain (59%), andand pain-other (51%). TheThe most common grade 3/43/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal (14%), infection without neutropenia (13%), adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal painpain (14%), infection without neutropenia (13%), rash/desquamation (12%), other-gastrointestinal (10%) rash/desquamation (12%), andand other-gastrointestinal (10%) most frequent adverse events in patients metastatic colorectal cancer (n=354) treated ERBITUX irinotecan in clinical ■ ■ TheThe most frequent adverse events seenseen in patients withwith metastatic colorectal cancer (n=354) treated withwith ERBITUX plusplus irinotecan in clinical trials (incidence ≥50%) were acneform (88%), asthenia/malaise (73%), diarrhea (72%), nausea (55%). most common grade trials (incidence ≥50%) were acneform rashrash (88%), asthenia/malaise (73%), diarrhea (72%), andand nausea (55%). TheThe most common grade 3/43/4 adverse events (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), acneform (14%) adverse events (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), andand acneform rashrash (14%) ® ® Reference: 1. ERBITUX (cetuximab) [package insert]. NY and Princeton, NJ: ImClone Systems Incorporated Bristol-Myers Squibb Company; Reference: 1. ERBITUX (cetuximab) [package insert]. NewNew York,York, NY and Princeton, NJ: ImClone Systems Incorporated andand Bristol-Myers Squibb Company; 2009. July July 2009.

Please summary of Full Prescribing Information including Boxed WARNINGS on adjacent pages. Please seesee briefbrief summary of Full Prescribing Information including Boxed WARNINGS on adjacent pages.

Weigh Evidence That Supports Weigh thethe Evidence That Supports

© 2009, ImClone LLC, New 10014, U.S.A. © 2009, ImClone LLC, New York,York, New New York York 10014, U.S.A. and and Bristol-Myers Squibb Company, Princeton, Jersey 08543, Bristol-Myers Squibb Company, Princeton, New New Jersey 08543, U.S.A. All rights reserved. U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone ERBITUX is a registered trademark of ImClone LLC. LLC.

693US09AB17908 693US09AB17908

1/101/10

Please www.ERBITUX.com Please visitvisit www.ERBITUX.com or call 1-888-ERBITUX (372-4889). or call 1-888-ERBITUX (372-4889).

32 Policy

Pharmacy Practice News • April 2010

Research Ethics

Fospropofol Studies Pulled Over Problems With PK/PD Data S

ix studies published in three journals that assessed properties of fospropofol disodium (Aquavan, MGI Pharma; Lusedra, Eisai) have been retracted because of unresolved assay problems that produced flawed pharmacokinetic (PK) and pharmacodynamic (PD) data in company-sponsored, early-stage clinical trials. However, the resulting data were not used in PK studies submitted to the FDA for drug approval, and there is no

evidence that patients were affected in any way. The corresponding and senior study authors of the studies requested the retractions in a letter published Feb. 19, 2010, in Anesthesiology, writing that the sponsoring drug company had failed to reanalyze a revised assay of the drug within a 12-month deadline imposed by the three journals in November 2008. “As such, we, the undersigned corresponding and senior authors from the

six original articles, in the name of all coauthors, request that the articles in question that provide flawed pharmacokinetic-pharmacodynamic data be retracted.” The letter was signed by Michel M.R.F. Struys, MD, PhD, anesthesiology chair at the University of Groningen, The Netherlands, and colleagues from the Department of Anesthesiology at the University of Erlangen-Nuremberg, in Germany.

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

Fospropofol is a water-soluble prodrug of propofol that was approved by the FDA in December 2008 for monitored anesthesia care in adult patients undergoing diagnostic or therapeutic procedures. After injection, fospropofol is converted by alkaline phosphatase enzymes into propofol. It creates clinically useful sedation and suppression of brain activity with less respiratory depression than propofol. Pain at the injection site, a common effect with

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

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 Infusion Reaction2 15 3 2 0 Infection 13 1 9 1 1 Chills 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 Alanine Transaminase, high3 43 2 21 1 3 Aspartate Transaminase, high 38 1 24 1 3 Alkaline Phosphatase, high 33 <1 24 0 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages Acneform Rash4 87 17 10 1 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

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

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

Policy 33

Pharmacy Practice News • April 2010

Research Ethics a new study in the coming months. The drug has changed hands through a series of company acquisitions. Guilford Pharmaceuticals, which was acquired by MGI Pharma in 2005, developed and validated the drug and assay and sponsored the Phase I and II studies that were conducted in Europe. The assays for all six studies were performed at MDS Pharma Services, an external lab in Montreal. Both the academic and sponsor-based investigators co-authored the study results, which were published in three anesthesiology journals. In November 2008, the MGI Pharma

propofol, was not reported with fospropofol. Side effects included paresthesias, pruritus, hypotension, hypoxemia and nausea. “Eisai supports the retraction of the fospropofol disodium PK/PD manuscripts in peer-reviewed journals,” said Judee Shuler, Eisai’s senior director of corporate communications. “The prescribing information does not include the flawed data.” Eisai “will continue to communicate with [clinicians] about fospropofol in accordance with our approved prescribing information,” she said, adding the company plans to begin

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2: Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation Dry Skin Pruritus Other-Dermatology Nail Changes Body as a Whole Fatigue Fever Infusion Reactions3 Rigors, Chills Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis Other-Gastrointestinal Mouth Dryness Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression

89 49 40 27 21

12 0 2 1 0

16 11 8 6 4

<1 0 0 1 0

89 30 20 13

33 1 5 <1

76 18

26 <1

59 51 33 15

14 16 4 3

52 34 11 7

16 7 0 2

48 29

16 2

43 19

12 1

46 39 37 25 23 11

4 2 6 1 10 0

38 20 29 10 18 4

5 2 6 <1 8 0

30 15 14 13

1 6 2 1

15 9 8 6

1 2 1 <1

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

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. Aseptic meningitis

co-authors published a letter to the editor in the three journals disclosing the existence of a faulty assay that “may have” affected the measurement of propofol plasma concentrations. “The originally reported propofol pharmacokinetic and pharmacodynamic results and the derived conclusions could be inaccurate,” the researchers wrote (Anesthesiology 2008;109:937; Anesth Analg 2009;108:32; Eur J Anaesthesiol 2009;26:81). The assay problems affected the quantification of propofol, not fospropofol, concentrations, they added. In a published consensus reply, the

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

editors-in-chief of the three journals issued an ultimatum: They gave the researchers 12 months to submit a manuscript validating the new assay, analyzing the likely error and bias in each of the six articles, and determining how the error influences the conclusions. Otherwise, they would retract all six articles. At the time, the MGI Pharma researchers claimed they had already fixed and validated the assay and had conducted additional studies to assess the pharmacokinetics and pharmacodynamics of fospropofol in healthy volunteers and patients. “We plan to publish these results shortly,” they wrote in November 2008. But that did not happen. According to the academic researchers, this was largely because the ownership of the drug had changed hands once again, this time with MGI Pharma having been acquired by Eisai in early 2008. In a recent interview, Dr. Struys said the sponsoring drug company was responsible for the assay and all decisions concerning its use. “We are an independent scientific center and this was a sponsor-initiated research trial,” Dr. Struys said. “We drew the blood samples and sent it to the lab per the sponsor’s request.” Dr. Struys said a 12-month deadline imposed by the journal editors was reasonable, and probably would have been met had not the company once again changed ownership. Ms. Shuler said Eisai had informed the FDA about issues with the assay in early Phase I studies when it submitted the New Drug Application. “It is important to note that the fospropofol FDA-approved prescribing information contains accurate PK/PD data,” she said. “Our goal is to begin a new fospropofol PK/PD study in Q1 FY2010 [year ending March 31, 2011].” The FDA confirmed it “was aware of the issues with the assays, and evaluated their potential implications as we did our review,” said Crystal Rice, a spokeswoman for the agency. In its clinical pharmacology review of the drug, the FDA noted that Eisai did not use unreliable PK data. —Ted Agres

Erbitux® is a registered trademark of ImClone Systems Incorporated. Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876 Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543

Educational & Commercial Reprints Rev March 2010

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34 Opinion

Pharmacy Practice News • April 2010

Causes and Remedies for the ‘Miserable’ Workplace Todd K. Connor, PharmD, MS* Associate Director of Pharmacy Parkland Health and Hospital System Dallas, Texas

Lorrie L. Burns, PharmD Residency Co-Coordinator Neuroscience Clinical Pharmacist Riverside Methodist Hospital Columbus, Ohio

o pharmacy employees in your department feel they have a miserable job? In his 2007 book, “The Three Signs of a Miserable Job,”1 Patrick Lencioni explores the causes of job misery and offers management strategies to improve workplace culture and develop more satisfied employees. Lencioni creates the tale of a business executive who is thrust from a cushy life in the “C-suite” to serving pizza and busing tables at a rundown restaurant. Along this journey he discovers three universal causes of employee misery at work: anonymity, irrelevance and “immeasurement.” The author explains that the most important person in preventing these three signs from being present in the work environment is the direct supervisor. Like managers in any profession, pharmacy leaders sometimes forget to focus on the simple aspects of personnel management, which can contribute to pharmacy staff feeling unappreciated and unfulfilled. It may appear to managers that patient care-related work should automatically lead to job fulfillment, but many health-system pharmacy employees may find it difficult to relate their tasks to directly helping patients. For example, a technician who is making a narcotic drip in a clean room is logistically distanced from the end point of pain relief for a postoperative patient. Additionally, managers simply may not realize what effect the supervisor–employee relationship has on employee satisfaction. Likewise, it is understandable if night-shift pharmacists feel undervalued or even unknown if there is little interaction with their supervisor. Job misery can be a common experience. It does not have to do with whether the job is boring or menial; even interesting and high-paying jobs in posh surroundings can lead to the anguish of dreading to go to work, anticipation of the end of the workday, and the “Sunday blues.” Besides the personal consequences of job misery, organizations may be beset by reduced productivity, excessive turnover and low morale. Below is a description of the three signs of job misery and how they apply to pharmacy managers and employees.

Anonymity In life, all people want to feel known

and understood. The workplace is no exception. Without basic personal relationships, employees conclude that they are working in obscurity and no one is taking a personal interest in them. This invisibility fosters a hollowness that leads to job misery. One of the most important workplace relationships is between the employee and the direct supervisor. Being able to demonstrate a genuine interest in employees is necessary for true leaders to establish these relationships.

Lencioni suggests “simply getting to know them” as a means of reducing employees’ feelings of anonymity. This may require a shift of focus for some managers who have been accustomed to avoiding such discussions during interviewing. Simply having a five-minute conversation with a pharmacist about what kind of music he or she listens to or asking a technician how his or her children are builds the framework for a more rewarding work environment. Even the

smallest act, such as a manager greeting each employee while walking through the department, is a sign of respect for them as human beings. However, it is essential to show a genuine interest in employees, as staff will detect insincere attempts at bonding. Sometimes the organizational structure of health-system pharmacies can be a barrier to interpersonal relationships. Managers may have anywhere from one to more than 75 employees reporting to

A trusted source brings Tacrolimus Capsules to your shelf.

WARNING Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Tacrolimus Capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see brief summary of full prescribing information including boxed warning on following pages. Prograf® is a registered trademark of Astellas Pharma Inc.

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Opinion 35

Pharmacy Practice News • April 2010

them, many of whom work during different shifts and perform a variety of tasks. Also, having too many managers to report to can severely limit a manager’s abilities to spend sufficient time in relationship building. Given the current economic climate, correcting this limitation may be outside of the control of the manager and pharmacy administration. However, it is imperative that managers make every effort to become familiar with each person who reports to them.

Irrelevance Lencioni says the second sign of a mis-

Tacrolimus Capsules WARNING WARNING Increased Increased susceptibility susceptibility to to infection infection and and the the possible possible development development of of lymphoma lymphoma may may result result from from immunosuppression. immunosuppression. Only Only physicians physicians experienced experienced in in immunosuppressive immunosuppressive therapy therapy and and management management of of organ organ transplant transplant patients patients should should prescribe prescribe tacrolimus tacrolimus capsules. capsules. Patients Patients receiving receiving the the drug drug should should be be managed managed in in facilities facilities equipped equipped and and staffed staffed with with adequate adequate laboratory laboratory and and supportive supportive medical medical resources. resources. The The physician physician responsible responsible for for maintenance maintenance therapy therapy should should have have complete complete information information requisite requisite for for the the follow-up follow-up of of the the patient. patient. INDICATIONS INDICATIONS AND AND USAGE USAGE Tacrolimus Tacrolimus capsules capsules isis indicated indicated for for the the prophylaxis prophylaxis of of organ organ rejection rejection inin patients patients receiving receiving allogeneic allogeneic liver liver or or kidney kidney transplants. transplants. ItIt isis recommended recommended that that tacrolimus tacrolimus capsules capsules be be used used concomitantly concomitantly with with adrenal adrenal corticosteroids. corticosteroids. In In kidney kidney transplant transplant recipients, recipients, itit isis recommended recommended that that tacrolimus tacrolimus capsules capsules be be used used inin conjunction conjunction with with azathioprine azathioprine or or mycophenolate mycophenolate mofetil mofetil (MMF). (MMF). The The safety safety and and efficacy efficacy of of the the use use of of tacrolimus tacrolimus capsules capsules with with sirolimus sirolimus has has not not been been established. established. CONTRAINDICATIONS CONTRAINDICATIONS Tacrolimus Tacrolimus capsules capsules are are contraindicated contraindicated inin patients patients with with aa hypersensitivity hypersensitivity to to tacrolimus. tacrolimus. WARNINGS WARNINGS (See (See boxed boxed WARNING) WARNING) Post-Transplant Post-Transplant Diabetes Diabetes Mellitus Mellitus Insulin-dependent Insulin-dependent post-transplant post-transplant diabetes diabetes mellitus mellitus (PTDM) (PTDM) was was reported reported in in 20% 20% of of tacrolimus-treated tacrolimus-treated kidney kidney transplant transplant patients patients withwithout pretransplant history of diabetes mellitus in the Phase III study. out pretransplant history of diabetes mellitus in the Phase III study. The The median median time time to to onset onset of of PTDM PTDM was was 68 68 days. days. Insulin Insulin dependence dependence was was reversible reversible in in 15% 15% of of these these PTDM PTDM patients patients at at one one year year and and in in 50% 50% at at 22 years years post post transplant. transplant. Black Black and and Hispanic Hispanic kidney kidney transplant transplant patients patients were at an increased risk of development of PTDM. were at an increased risk of development of PTDM. Insulin-dependent Insulin-dependent post-transplant post-transplant diabetes diabetes mellitus mellitus was was reported reported in in 18% 18% and and 11% 11% of of tacrolimus-treated tacrolimus-treated liver liver transplant transplant patients patients and and was was reversible reversible in in 45% 45% and and 31% 31% of of these these patients patients at at 11 year year post post transplant, transplant, in in the the U.S. U.S. and and European European randomized randomized studies, studies, respectively. respectively. HyperHyperglycemia glycemia was was associated associated with with the the use use of of tacrolimus tacrolimus inin 47% 47% and and 33% 33% of of liver liver transplant transplant recipients recipients inin the the U.S. U.S. and and European European randomized randomized studies, studies, respectively, respectively, and and may may require require treatment treatment (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Nephrotoxicity Nephrotoxicity Tacrolimus Tacrolimus capsules capsules can can cause cause nephrotoxicity, nephrotoxicity, particularly particularly when when used used inin high high doses. doses. Nephrotoxicity Nephrotoxicity was was reported reported inin approximately approximately 52% 52% of of kidney kidney transplantation transplantation patients patients and and inin 40% 40% and and 36% 36% of of liver liver transplantransplantation patients receiving tacrolimus capsules in the U.S. and European tation patients receiving tacrolimus capsules in the U.S. and European randomized randomized trials, trials, respectively respectively (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). More More overt overt nephrotoxicity nephrotoxicity isis seen seen early early after after transplantation, transplantation, characterized characterized by by increasing increasing serum serum creatinine creatinine and and aa decrease decrease inin urine urine output. output. Patients Patients with with impaired renal function should be monitored closely as the dosage impaired renal function should be monitored closely as the dosage of of tacrolimus tacrolimus capsules capsules may may need need to to be be reduced. reduced. In In patients patients with with persistent persistent elevations elevations of of serum serum creatinine creatinine who who are are unresponsive unresponsive to to dosage dosage adjustadjustments, ments, consideration consideration should should be be given given to to changing changing to to another another immunoimmunosuppressive suppressive therapy. therapy. Care Care should should be be taken taken inin using using tacrolimus tacrolimus with with other other nephrotoxic nephrotoxic drugs. drugs. In In particular, particular, to to avoid avoid excess excess nephrotoxicity, nephrotoxicity, tacrolimus tacrolimus capsules capsules should should not not be be used used simultaneously simultaneously with with cyclo cyclo-sporine. sporine. Tacrolimus Tacrolimus capsules capsules or or cyclosporine cyclosporine should should be be discontinued discontinued at at least least 24 24 hours hours prior prior to to initiating initiating the the other. other. In In the the presence presence of of elevated elevated tacrolimus capsules or cyclosporine concentrations, dosing with the tacrolimus capsules or cyclosporine concentrations, dosing with the other other drug drug usually usually should should be be further further delayed. delayed. Hyperkalemia Hyperkalemia Mild Mild to to severe severe hyperkalemia hyperkalemia was was reported reported inin 31% 31% of of kidney kidney transplant transplant recipients recipients and and inin 45% 45% and and 13% 13% of of liver liver transplant transplant recipients recipients treated treated with with tacrolimus tacrolimus capsules capsules inin the the U.S. U.S. and and European European randomized randomized trials, trials, respectively, respectively, and and may may require require treatment treatment (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Serum Serum potassium potassium levels levels should should be be monitored monitored and and potassium-sparing potassium-sparing diuretics diuretics should should not not be be used used during during tacrolimus tacrolimus capsules capsules therapy therapy (see (see PRECAUTIONS). PRECAUTIONS). Neurotoxicity Neurotoxicity Tacrolimus Tacrolimus capsules capsules can can cause cause neurotoxicity, neurotoxicity, particularly particularly when when used used inin high high doses. doses. Neurotoxicity, Neurotoxicity, including including tremor, tremor, headache, headache, and and other other changes changes inin motor motor function, function, mental mental status, status, and and sensory sensory function function were were reported reported inin approximately approximately 55% 55% of of liver liver transplant transplant recipients recipients inin the the two two randomized randomized studies. studies. Tremor Tremor occurred occurred more more often often inin tacrolimus tacrolimus capsulescapsulestreated kidney transplant patients (54%) compared to cyclosporinetreated kidney transplant patients (54%) compared to cyclosporinetreated treated patients. patients. The The incidence incidence of of other other neurological neurological events events inin kidney kidney transplant transplant patients patients was was similar similar inin the the two two treatment treatment groups groups (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Tremor Tremor and and headache headache have have been been associated associated with with high high whole-blood whole-blood concentrations concentrations of of tacrolimus tacrolimus and and may may respond respond to to dosage dosage adjustment. adjustment. Seizures Seizures have have occurred occurred inin adult adult and and pediatric pediatric patients patients receiving receiving tacrolimus tacrolimus capsules capsules (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Coma Coma and and delirium delirium also also have have been been associated associated with with high high plasma plasma concentrations concentrations of of tacrolimus. tacrolimus.

erable job is irrelevance. It is critical that employees know that their work has an impact on the lives of others and that what they do matters. It is important for direct supervisors to ensure that all pharmacy employees can answer two questions: Who am I helping and how am I helping? For pharmacy personnel who are involved in direct patient care, it is easy to identify to whom their work matters. Interviewing a patient to obtain a home medication list and counseling a patient new to warfarin therapy have a direct impact on patients’ lives, thus providing immediate positive feedback to the prac-

Patients Patients treated treated with with tacrolimus tacrolimus have have been been reported reported to to develop develop posterior posterior reversible reversible encephalopathy encephalopathy syndrome syndrome (PRES). (PRES). Symptoms Symptoms indicating indicating PRES PRES include include headache, headache, altered altered mental mental status, status, seizures, seizures, visual visual disturbances disturbances and and hypertension. hypertension. Diagnosis Diagnosis may may be be confirmed confirmed by by radiradiological ological procedure. procedure. IfIf PRES PRES isis suspected suspected or or diagnosed, diagnosed, blood blood pressure pressure control control should should be be maintained maintained and and immediate immediate reduction reduction of of immunoimmunosuppression suppression isis advised. advised. This This syndrome syndrome isis characterized characterized by by reversal reversal of of symptoms symptoms upon upon reduction reduction or or discontinuation discontinuation of of immunosuppression. immunosuppression. Malignacy Malignacy and and Lymphoproliferative Lymphoproliferative Disorders Disorders As As inin patients patients receiving receiving other other immunosuppressants, immunosuppressants, patients patients receiving receiving tacrolimus tacrolimus capsules capsules are are at at increased increased risk risk of of developing developing lymphomas lymphomas and and other other malignancies, malignancies, particularly particularly of of the the skin. skin. The The risk risk appears appears to to be be related related to to the the intensity intensity and and duration duration of of immunosuppression immunosuppression rather rather than than to to the the use use of of any any specific specific agent. agent. AA lymphoproliferative lymphoproliferative disorder disorder (LPD) (LPD) related related to to Epstein-Barr Virus (EBV) infection has been reported in immunosupEpstein-Barr Virus (EBV) infection has been reported in immunosuppressed pressed organ organ transplant transplant recipients. recipients. The The risk risk of of LPD LPD appears appears greatest greatest inin young young children children who who are are at at risk risk for for primary primary EBV EBV infection infection while while immunoimmunosuppressed suppressed or or who who are are switched switched to to tacrolimus tacrolimus capsules capsules following following long-term immunosuppression therapy. Because of the danger long-term immunosuppression therapy. Because of the danger of of overoversuppression suppression of of the the immune immune system system which which can can increase increase susceptibility susceptibility to to infection, infection, combination combination immunosuppressant immunosuppressant therapy therapy should should be be used used with with caution. caution. Latent Latent Viral Viral Infections Infections Immunosuppressed Immunosuppressed patients patients are are at at increased increased risk risk for for opportunistic opportunistic infections, infections. These These include include BK BK virus virus infections, including including latent latent viral viral infections. associated associated nephropathy nephropathy and and JC JC virus virus associated associated progressive progressive multifocal multifocal leukoencephalopathy (PML) which have been observed in patients leukoencephalopathy (PML) which have been observed in patients receiving receiving tacrolimus. tacrolimus. These These infections infections may may lead lead to to serious, serious, including including fatal, fatal, outcomes. outcomes. PRECAUTIONS PRECAUTIONS General General Hypertension Hypertension isis aa common common adverse adverse effect effect of of tacrolimus tacrolimus therapy therapy (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Mild Mild or or moderate moderate hypertension hypertension isis more more frequently frequently reported reported than than severe severe hypertension. hypertension. Antihypertensive Antihypertensive therapy therapy may may be be required; required; the the control control of of blood blood pressure pressure can can be be accomplished accomplished with with any any of of the the common common antihypertensive antihypertensive agents. agents. Since Since tacrolimus tacrolimus may may cause cause hyperkalemia, hyperkalemia, potassium-sparing potassium-sparing diuretics diuretics should should be be avoided. avoided. While While calcium-channel calcium-channel blocking blocking agents agents can can be be effective effective inin treating treating tacrolimus-associated tacrolimus-associated hypertension, hypertension, care care should should be be taken taken since since interferinterference with tacrolimus metabolism may require a dosage reduction ence with tacrolimus metabolism may require a dosage reduction (see (see Drug Drug Interactions). Interactions). Renally Renally and and Hepatically Hepatically Impaired Impaired Patients Patients For For patients patients with with renal renal insufficiency insufficiency some some evidence evidence suggests suggests that that lower lower doses should be used. The use of tacrolimus doses should be used. The use of tacrolimus capsules capsules inin liver liver transplant transplant recipients recipients experiencing experiencing post-transplant post-transplant hepatic hepatic impairment impairment may may be be associated associated with with increased increased risk risk of of developing developing renal renal insufficiency insufficiency related related to to high high whole-blood whole-blood levels levels of of tacrolimus. tacrolimus. These These patients patients should should be be monitored monitored closely closely and and dosage dosage adjustments adjustments should should be be considered. considered. Some Some evidence evidence suggests suggests that that lower lower doses doses should should be be used used inin these these patients. patients. Myocardial Myocardial Hypertrophy Hypertrophy Myocardial Myocardial hypertrophy hypertrophy has has been been reported reported inin association association with with the the administration administration of of tacrolimus tacrolimus capsules, capsules, and and isis generally generally manifested manifested by by echocardiographically echocardiographically demonstrated demonstrated concentric concentric increases increases inin left left venventricular tricular posterior posterior wall wall and and interventricular interventricular septum septum thickness. thickness. Hypertrophy Hypertrophy has has been been observed observed inin infants, infants, children children and and adults. adults. This This condition condition appears appears reversible reversible inin most most cases cases following following dose dose reduction reduction or or discontinuance discontinuance of of therapy. In a group of 20 patients with preand post-treatment echocartherapy. In a group of 20 patients with pre- and post-treatment echocardiograms diograms who who showed showed evidence evidence of of myocardial myocardial hypertrophy, hypertrophy, mean mean tacrolimus tacrolimus whole whole blood blood concentrations concentrations during during the the period period prior prior to to diagnosis diagnosis of of myocardial myocardial hypertrophy hypertrophy ranged ranged from from 11 11 to to 53 53 ng/mL ng/mL inin infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age 22 to to 15 15 years) years) and and 11 11 to to 24 24 ng/mL ng/mL inin adults adults (N=3, (N=3, age age 37 37 to to 53 53 years). years). In In patients patients who who develop develop renal renal failure failure or or clinical clinical manifestations manifestations of of ventricuventricular lar dysfunction dysfunction while while receiving receiving tacrolimus tacrolimus therapy, therapy, echocardiographic echocardiographic evalevaluation should be considered. If myocardial hypertrophy is diagnosed, uation should be considered. If myocardial hypertrophy is diagnosed, dosage dosage reduction reduction or or discontinuation discontinuation of of tacrolimus tacrolimus should should be be considered. considered. Information Information for for Patients Patients Patients Patients should should be be informed informed of of the the need need for for repeated repeated appropriate appropriate labolaboratory ratory tests tests while while they they are are receiving receiving tacrolimus tacrolimus capsules. capsules. They They should should be be given given complete complete dosage dosage instructions, instructions, advised advised of of the the potential potential risks risks during during pregnancy, pregnancy, and and informed informed of of the the increased increased risk risk of of neoplasia. neoplasia. Patients Patients should should be be informed informed that that changes changes inin dosage dosage should should not not be be undertaken undertaken without without first first consulting their physician. consulting their physician. Patients Patients should should be be informed informed that that tacrolimus tacrolimus capsules capsules can can cause cause diabetes diabetes mellitus mellitus and and should should be be advised advised of of the the need need to to see see their their physician physician ifif they they develop develop frequent frequent urination, urination, increased increased thirst thirst or or hunger. hunger. As As with with other other immunosuppressive immunosuppressive agents, agents, owing owing to to the the potential potential risk risk of of malignant malignant skin skin changes, changes, exposure exposure to to sunlight sunlight and and ultraviolet ultraviolet (UV) (UV) light light should should be be limited limited by by wearing wearing protective protective clothing clothing and and using using aa sunscreen sunscreen with with aa high high protection protection factor. factor.

titioner. However, some pharmacists and technicians may only interact with those in their own department. If a leader can constantly remind employees of the people who are affected by their work and provide specific examples of how their customers are impacted, employees may find their work more fulfilling. For example, instead of telling a pharmacist that she really helped out by staying late, the manager might say, “Jane, it meant a lot to Denise and Bob last night that you checked code trays yesterday after your shift. The second shift was very busy and it let them concentrate on deliver-

Laboratory Laboratory Tests Tests Serum Serum creatinine, creatinine, potassium, potassium, and and fasting fasting glucose glucose should should be be assessed assessed regularly. regularly. Routine Routine monitoring monitoring of of metbolic metbolic and and hematologic hematologic systems systems should should be be performed performed as as clinically clinically warranted. warranted. Drug Drug Interactions Interactions Due Due to to the the potential potential for for additive additive or or synergistic synergistic impairment impairment of of renal renal function, function, care care should should be be taken taken when when administering administering tacrolimus tacrolimus capsules capsules with with drugs drugs that that may may be be associated associated with with renal renal dysfunction. dysfunction. These These include, include, but but are are not not limited limited to, to, aminoglycosides, aminoglycosides, amphotericin amphotericin B, B, and cisplatin. Initial clinical experience with the co-administration and cisplatin. Initial clinical experience with the co-administration of of tacrolimus tacrolimus and and cyclosporine cyclosporine resulted resulted inin additive/synergistic additive/synergistic nephronephrotoxicity. toxicity. Patients Patients switched switched from from cyclosporine cyclosporine to to tacrolimus tacrolimus should should receive receive the the first first tacrolimus tacrolimus capsules capsules dose dose no no sooner sooner than than 24 24 hours hours after after the the last last cyclosporine cyclosporine dose. dose. Dosing Dosing may may be be further further delayed delayed inin the the presence presence of of elevated cyclosporine levels. elevated cyclosporine levels. Drugs Drugs that that May May Alter Alter Tacrolimus Tacrolimus Concentrations Concentrations Since Since tacrolimus tacrolimus isis metabolized metabolized mainly mainly by by the the CYP3A CYP3A enzyme enzyme systems, substances known to inhibit systems, substances known to inhibit these these enzymes enzymes may may decrease decrease the the metabolism metabolism or or increase increase bioavailability bioavailability of of tacrolimus tacrolimus as as indicated indicated by by increased increased whole whole blood blood or or plasma plasma concentrations. concentrations. Drugs Drugs known known to to induce induce these these enzyme enzyme systems systems may may result result inin an an increased increased metabolism metabolism of of tacrolimus tacrolimus or or decreased decreased bioavailability bioavailability as as indicated indicated by by decreased decreased whole blood or plasma concentrations. Monitoring of blood concenwhole blood or plasma concentrations. Monitoring of blood concentrations trations and and appropriate appropriate dosage dosage adjustments adjustments are are essential essential when when such such drugs drugs are are used used concomitantly. concomitantly. Drugs Drugs that that may may increase increase tacrolimus tacrolimus blood blood concentrations: concentrations: Calcium Calcium Channel Channel Blockers: Blockers: diltiazem, diltiazem, nicardipine, nicardipine, nifedipine, nifedipine, verapamil; verapamil; AntiAntifungal fungal Agents: Agents: clotrimazole, clotrimazole, fluconazole, fluconazole, itraconazole, itraconazole, ketoconazole, ketoconazole, voriconazole; voriconazole; Macrolide Macrolide Antibiotics: Antibiotics: clarithromycin, clarithromycin, erythromycin, erythromycin, troleandomycin; troleandomycin; Gastrointestinal Gastrointestinal Prokinetic Prokinetic Agents: Agents: cisapride, cisapride, metometoclopramide; Other Drugs: bromocriptine, chloramphenicol, clopramide; Other Drugs: bromocriptine, chloramphenicol, cimetidine, cimetidine, cyclosporine, cyclosporine, danazol, danazol, ethinyl ethinyl estradiol, estradiol, methylprednisolone, methylprednisolone, omeprazole, omeprazole, pretease pretease inhibitors, inhibitors, nefazodone, nefazodone, magnesium-aluminum-hydroxide. magnesium-aluminum-hydroxide. Drugs Drugs that that may may decrease decrease tacrolimus tacrolimus blood blood concentrations: concentrations: AnticonvulAnticonvulsants: Antimicrobials: sants: carbamazepine, carbamazepine, Phenobarbital, Phenobarbital, penytoin; penytoin; Antimicrobials: rifabutin, rifabutin, caspofungin, caspofungin, rifampin; rifampin; Herbal Herbal Preparations: Preparations: St. St. John’s John’s Wort; Wort; Other Other Drugs: Drugs: sirolimus sirolimus This This list list isis not not all-inclusive. all-inclusive. St. St. John’s John’s Wort Wort (Hypericum (Hypericum perforatum) perforatum) induces induces CYP3A4 CYP3A4 and and P-glycoprotein. P-glycoprotein. Since Since tacrolimus tacrolimus isis aa substrate substrate for for CYP3A4, CYP3A4, there there isis the the potential potential that that the the use use of of St. St. John’s John’s Wort Wort inin patients patients receiving receiving tacrolimus tacrolimus capsules could result in reduced tacrolimus levels. capsules could result in reduced tacrolimus levels. Interaction Interaction studies studies with with drugs drugs used used inin HIV HIV therapy therapy have have not not been been conducted. conducted. However, However, care care should should be be exercised exercised when when drugs drugs that that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., (e.g., nelfinavir, nelfinavir, ritonavir) ritonavir) are are administered administered concomitantly concomitantly with with tacrolimus. tacrolimus. Tacrolimus Tacrolimus may may affect affect the the pharmacokinetics pharmacokinetics of of other other drugs drugs (e.g., (e.g., phenytoin) phenytoin) and and increase increase their their concentration. concentration. Grapefruit Grapefruit juice juice affects affects CYP3A-mediated CYP3A-mediated metabolism metabolism and and should should be be avoided. avoided. Following Following co-administration co-administration of of tacrolimus tacrolimus and and sirolimus sirolimus (2 (2 or or 55 mg/ mg/ day) day) inin stable and CCmin stable renal renal transplant transplant patients, patients, mean mean tacrolimus tacrolimus AUC AUC0-12 0-12 and min decreased decreased approximately approximately by by 30% 30% relative relative to to tacrolimus tacrolimus alone. alone. Mean Mean tacrolimus and CCmin following co-administration co-administration of of 11 mg/day mg/day tacrolimus AUC AUC0-12 0-12 and min following of of sirolimus sirolimus decreased decreased approximately approximately 3% 3% and and 11%, 11%, respectively. respectively. The The safety safety and and efficacy efficacy of of tacrolimus tacrolimus used used inin combination combination with with sirolimus sirolimus for for the the prevention prevention of of graft graft rejection rejection has has not not been been established established and and isis not not recommended. recommended. Other Other Drug Drug Interactions Interactions Immunosuppressants Immunosuppressants may may affect affect vaccination. vaccination. Therefore, Therefore, during during treatment treatment with with tacrolimus tacrolimus capsules, capsules, vaccination vaccination may may be be less less effective. effective. The The use use of of live live vaccines vaccines should should be be avoided; avoided; live live vaccines vaccines may may include, but are not limited to measles, mumps, rubella, oral polio, BCG, include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow yellow fever, fever, and and TY TY 21a 21a typhoid. typhoid.11 At At aa given given MMF MMF dose, dose, mycophenolic mycophenolic acid acid (MPA) (MPA) exposure exposure isis higher higher with with tacrolimus tacrolimus capsules capsules co-administration co-administration than than with with cyclosporine cyclosporine co-administration co-administration due due to to the the differences differences inin the the interruption interruption of of the the entero entero-hepatic hepatic recirculation recirculation of of MPA. MPA. Clinicians Clinicians should should be be aware aware that that there there isis also also aa potential potential for for increased increased MPA MPA exposure exposure after after crossover crossover from from cyclosporine cyclosporineto totacrolimus tacrolimusininpatients patientsconcomitantly concomitantlyreceiving receivingMMF MMFor orMPA. MPA. Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, Impairment Impairment of of Fertility Fertility An An increased increased incidence incidence of of malignancy malignancy isis aa recognized recognized complication complication of of immunosuppression immunosuppression inin recipients recipients of of organ organ transplants. transplants. The The most most common common forms forms of of neoplasms neoplasms are are non-Hodgkin’s non-Hodgkin’s lymphomas lymphomas and and carcinomas carcinomas of of the the skin. skin. As As with with other other immunosuppressive immunosuppressive therapies, therapies, the the risk risk of of malignancies malignancies inin tacrolimus tacrolimus recipients recipients may may be be higher higher than than inin the the normal, normal, healthy healthy population. population. Lymphoproliferative Lymphoproliferative disorders disorders associated associated with with Epstein-Barr Epstein-Barr Virus Virus infection infection have have been been seen. seen. ItIt has has been been reported reported that that reduction reduction or or discontinuation of immunosuppression may cause the lesions discontinuation of immunosuppression may cause the lesions to to regress. regress.

ing the TPNs. It meant a lot to me that you would help out your co-workers like that. Thanks.” It often is overlooked that employees’ work also matters to their direct supervisor.

‘Immeasurement’ “Immeasurement” is a word created by Lencioni to describe the lack of tangible means to assess one’s own success at work. Job misery can be associated with an absence of objective feedback that a task is being done correctly, resulting in employees not having a sense of progress

•

see JOB MISERY, page 36

36 Opinion

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 - 2.5 times (mice) and 3.5 - 7.1 times (rats) the recommended clinical dose range of 0.1 - 0.2 mg/kg/day when corrected for body surface area. No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1 mg/kg (0.7 - 1.4X the recommended clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of preimplantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations. Pregnancy: Category C In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 - 1X and 1.6 - 3.3X the recommended clinical dose range (0.1 - 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1 and 3.2 mg/kg (equivalent to 0.7 - 1.4X and 2.3 - 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights. No reduction in male or female fertility was evident. There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus capsules should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus. Nursing Mothers Since tacrolimus is excreted in human milk, nursing should be avoided. Pediatric Patients Experience with tacrolimus in pediatric kidney patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using tacrolimus capsules. Two randomized trials of tacrolimus capsules in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimusbased and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus capsules to maintain blood trough concentrations of tacrolimus similar to adult patients. ADVERSE REACTION Liver Transplantation The principal adverse reactions of tacrolimus are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of tacrolimus and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Hyperkalemia and hypomagnesemia have occurred in patients receiving tacrolimus therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS). Kidney Transplantation The most common adverse reactions reported were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain and insomnia. Less Frequently Reported Adverse Reactions The following adverse events were reported in either liver and/or kidney transplant recipients who were treated with tacrolimus in clinical trials.

VA NC E

Nervous System (see WARNINGS) Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, headache, hypertonia, incoordination, insomnia, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paresthesia, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired Special Senses Abnormal vision, amblyopia, ear pain, otitis media, tinnitus Gastrointestinal Anorexia, cholangitis, cholestatic jaundice, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, nausea, nausea and vomiting, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting Cardiovascular Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, chest pain, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital (see WARNINGS) Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis Metabolic/Nutritional Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, edema, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, peripheral edema, weight gain Endocrine (see PRECAUTIONS) Cushing’s syndrome, diabetes mellitus Hemic/Lymphatic Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia Miscellaneous Abdomen enlarged, abdominal pain, abscess, accidental injury, allergic reaction, asthenia, back pain, cellulitis, chills, fall, feeling abnormal, fever, flu syndrome, generalized edema, hernia, mobility decreased, pain, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis Respiratory Asthma, bronchitis, cough increased, dyspnea, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration

T EN EM UR AS ME IM

in their work experience. Employees want to feel like they have had a successful day, but if there is no way to measure what was achieved they can lose interest or become frustrated. Pharmacy leaders must establish metrics, quantitative or behavioral in nature, that are relevant to their employees’ work. These metrics may be individual, position-specific, or designed for department-level reporting. However, if high-level metrics solely are used

continued from page 35

cult for members of a pharmacy to measure performance, team to use these data to assess employees may feel that how they, as individuals, are pertheir work cannot directly forming. Lencioni emphasizes influence the metrics. that metrics must directly An example of a highinfluence employees or level metric could be they will be confusing using results from JOB and irrelevant. An a survey that example of a meandescribed nursMISERY ingful metric may ing satisfaction be what perlevels with centage of pharmacy phone calls services. a technician It would ANONYMITY answered be diffi-

JOB MISERY

Pharmacy Practice News • April 2010

Gastrointestinal Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis,hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease Hemic/Lymphatic Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura Metabolic/Nutritional Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Nervous System Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope Respiratory Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure Skin Stevens-Johnson syndrome, toxic epidermal necrolysis Special Senses Blindness, blindness cortical, hearing loss including deafness, photophobia Urogenital Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder. There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving tacrolimus therapy (see PRECAUTIONS-Myocardial Hypertrophy). Please see current package insert for complete adverse events information. OVERDOSAGE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in the ADVERSE REACTIONS section except in one case where transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage. REFERENCE: 1 CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993;42(RR-4):1-18.

Skin Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating

Cardiovascular Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation

Overcoming Obstacles And Realizing Benefits Obstacles to creating a more satisfactory environment include both employee and organizational issues. Employees may think that if they maximize their pay or choose the perfect job, their employment will provide satisfaction and engagement. However, a dream job or large compensation package is not fulfilling if the three signs of job misery are present. Organizations may not recognize deteriorations in employee satisfaction, or may assume the issue to be related only to compensation. Rather than finding out at exit interviews, Lencioni suggests that companies with high turnover rates should ask far earlier, “What is making you even consider leaving in the first place?” If a manager can begin to eliminate the three signs of job misery, many benefits may be realized. Staff will start to enjoy coming to work and will begin treating others with more kindness and respect. Department productivity and safety can improve because individuals who are more passionate and enthusiastic about work pay more attention to quality and safety. The pharmacy department culture can change, leading to better employee retention and improved recruiting. Also, a culture of accountability can develop in which individuals hold peers to higher standards because of workplace pride. A competitive advantage will eventually develop due to the sustainability of cultural change, making the pharmacy the “employer of choice” for pharmacists and technicians.

Conclusion One of the most important aspects of being in a supervisory role is personnel management, which includes meeting the basic needs of employees. Pharmacy managers must learn to identify and eliminate anonymity, irrelevance and “immeasurement” from the workplace experiences of employees to prevent the symptoms and consequences of job misery.

Reference

POST MARKETING Post Marketing Adverse Events The following adverse events have been reported from worldwide marketing experience with tacrolimus.

within 10 seconds of the phone ringing. Even if the direct supervisor cannot easily measure the metric, assigning the employee to self-evaluate can lead to a greater sense of personal success and accountability. However, the manager must follow up with the employee periodically to discuss the results. Otherwise, the activity will lose importance and is likely to be dismissed.

Manufactured in India by Sandoz Private Limited for Sandoz Inc; Princeton NJ 08540 Issued: August 2009

1. Lencioni P. The Three Signs of a Miserable Job: A Fable for Managers (and their employees). San Francisco, CA: Jossey-Bass; 2007. * At the time of writing, Dr. Connor was HealthSystem Pharmacy Administration Resident, Riverside Methodist Hospital, Columbus, Ohio.

Expanded broad-spectrum coverage1* is on your side

*TYGACIL does not cover Pseudomonas aeruginosa.

TYGACIL is indicated for the treatment of adults with: • Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis • Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros • Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus inﬂuenzae (beta-lactamase negative isolates), and Legionella pneumophila

Important Safety Information • TYGACIL is contraindicated in patients with known hypersensitivity to tigecycline • Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening. TYGACIL should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics • Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function. Adverse events may occur after the drug has been discontinued • The safety and efficacy of TYGACIL in patients with hospital-acquired pneumonia have not been established • TYGACIL may cause fetal harm when administered to a pregnant woman • The use of TYGACIL during tooth development may cause permanent discoloration of the teeth. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated • Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis • Monotherapy should be used with caution in patients with clinically apparent intestinal perforation • TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL • To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat infections proven or strongly suspected to be caused by susceptible bacteria. As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi • The most common adverse reactions (incidence >5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased SGPT • In a pooled analysis of all Phase 3 and 4 studies that included a comparator, the risk difference of all-cause mortality was 1.0% (95% CI 0.2, 1.8) between TYGACIL (3.9%) and comparator-treated patients (2.9%). No significant differences were observed between treatments by infection type and, in general, deaths were the result of worsening or complications of infection or underlying comorbidities. The cause of the imbalance has not been established • Prothrombin time or other suitable anticoagulant test should be monitored if TYGACIL is administered with warfarin • Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective • The safety and effectiveness of TYGACIL in patients below age 18 and lactating women have not been established Please see brief summary of Prescribing Information on adjacent page. Reference: 1. TYGACIL® (tigecycline) Prescribing Information, Wyeth Pharmaceuticals Inc.

Expanded broad-spectrum coverage

38 Opinion

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

TYGACIL (N=2514)

Comparatorsa (N=2307)

6 3 3 6 8

4 3 2 7 5

12 2 26 18

11 2 13 9

4 3 2 3 4 5 4 5

3 2 1 1 3 3 5 5

Vancomycin/Aztreonam, Imipenem/Cilastatin, Levoﬂoxacin, Linezolid. LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy. In all Phase 3 and 4 studies that included a comparator, death occurred in 3.9% (147/3788) of patients receiving TYGACIL and 2.9% (105/3646) of patients receiving comparator drugs. In a pooled analysis of these studies, the risk difference of all-cause mortality was 1.0% (95% CI 0.2, 1.8) between TYGACIL and comparator treated patients. No signiﬁcant differences were observed between treatments by infection type (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening or complications of infection or underlying co-morbidities. Table 2. Patients with Adverse Events with Outcome of Death by Infection Type b

TYGACIL Infection Type cSSSI cIAI CAP HAP Non-VAPa VAPa RP DFI

n/N

Comparator %

Risk Difference* % (95% CI)

12/834 40/1382 12/424 65/467 40/336 25/131 11/128 7/553

1.4 2.9 2.8 13.9 11.9 19.1 8.6 1.3

6/813 27/1393 11/422 56/467 42/345 14/122 2/43 3/508

0.7 1.9 2.6 12.0 12.2 11.5 4.7 0.6

0.7 (-0.5, 1.9) 1.0 (-0.3, 2.2) 0.2 (-2.3, 2.7) 1.9 (-2.6, 6.4) -0.3 (-5.4, 4.9) 7.6 (-2.0, 16.9) 3.9 (-9.1, 11.6) 0.7 (-0.8, 2.2)

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

Don’t Forget Organ Transplant Drug Coverage Kwaku Marfo, PharmD, BCPS Organ Transplant Pharmacist Montefiore Medical Center Bronx, New York

atients who receive a solid organ transplant (heart, kidney, liver, pancreas or small bowel) require anti-rejection medications for the life of their transplanted organ. Without the medications, organs can be rejected within days or weeks, not only threatening the patients’ lives but also creating a huge increase in overall health care spending. Why then, is coverage for anti-rejection medications so spotty?

In a study of 1,000 kidney transplant recipients, graft loss more than doubled when Medicare coverage for antirejection drugs ended. Consider, as an example, federal health coverage. If Medicare covered an individual’s transplant, then Medicare Part B pays 80% of the cost of these anti-rejection medications for 36 months posttransplant. The remaining 20% is a financial hardship for most patients, but one that only gets worse when the 36 months are over, at which point Medicare coverage cuts off and the patients are expected to pay $1,000 to $3,000 per month for their anti-rejection medications. Currently the 36-month limitation only applies to end-stage renal disease (ESRD) beneficiaries, but not Medicare beneficiaries who are aged or disabled. Still, that is a large group of patients facing an extended period without coverage for these life-saving anti-rejection medications. Patients with private insurance also face financial hardship, in the form of co-pays. These patients also contend with paying full price for their medications if and when they reach the lifetime maximum coverage amount stipulated by their policies. Then there are the 16% of American adults who do not have any form of health coverage at all. All told, the cost of anti-rejection medications places a heavy burden on transplant recipients. In a survey by the United Network for Organ Sharing and the American Society of Transplantation,

Opinion 39

Pharmacy Practice News • April 2010

70% of transplant centers report that patients have “extreme” or “very serious” problems paying for their medications, and 68% of kidney transplant deaths or graft failures are thought to result from lack of access to anti-rejection medications. Need more proof? Consider the plight of kidney patients who lose access to anti-rejection medications. In a study of 1,000 kidney transplant recipients, graft loss more than doubled when Medicare coverage for anti-rejection drugs ended. This is associated with a significant cost to society because patients who lose transplanted kidneys must return to dialysis. Often, they end up undergoing organ re-transplantation. Furthermore, once a transplanted kidney no longer works, the patient’s risk for death increases ninefold.

According to the most recent report from the United States Renal Data System, Medicare spends an average of $77,000 per year indefinitely dialyzing patients with kidney failure. However, it spends $106,000 the first year after transplant and an average of $17,000 per year thereafter, including the cost of anti-rejection medications. It thus makes financial sense for Medicare to remove the 36-month coverage limitation for anti-rejection medications. Sen. Richard J. Durbin (D-Ill.), along

with other members of the U.S. Senate, supports extending coverage for anti-rejection medications for kidney transplant recipients. The Durbin Kidney Immuno Drug Amendment in the Senate’s health care reform bill (S.Amdt. 3102 to H.R. 3590, The Patient Protection and Affordable Care Act) mirrors a provision in the health care reform bill in the U.S. House of Representatives (H.R. 3962, The Affordable Health Care of America Act). This amendment would lift the current 36-month rule for Medi-

care anti-rejection drug coverage. Not only will it save money by preventing unnecessary re-dialyzing and retransplantation in patients with kidney failure, it will save lives. Whether these amendments survive reconciliation of the health care reform bill signed into law on March 22 remains to be seen. Regardless of the fate of S.Amdt. 3102, it should serve as a model for continued efforts to make drug coverage for organ transplant recipients more affordable. As for private insurance, drug coverage varies widely. In some cases, anti-

•

see TRANSPLANT, page 40

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40 Opinion

TRANSPLANT

Pharmacy Practice News • April 2010

Table 1. Brand and Generic Anti-rejection Medication Prices

Table 2. Mycophenolate Mofetil Products And Their Manufacturers

continued from page 39

rejection drugs are covered adequately. Other plans require very high co-pays or may not offer coverage at all. For these patients, the Medicare program— without the onerous 36-month cap on drug coverage—can help them afford their lifesaving medications and maintain their transplanted organ.

Reform Efforts Are Not the Only Answer Because no immediate relief may be in sight from health care reform, other strategies are needed to help lower the cost of anti-rejection medications. One option is to reduce reliance on costly brand-name drugs and instead to use less expensive bioequivalent generics as substitutes. Laws governing substitution vary by state, but in general, patients can expect a 30% to 50% reduction in anti-rejection medication costs when a generic bioequivalent is substituted for a brand-name drug (Table 1). However, in the field of solid organ transplantation, generic substitution has been an emotional issue. Much of the tension occurs as a result of two opposing forces that are brought to bear on the organ transplant team: insurance companies that promote the use of lower-cost generics, and innovator companies that want to protect their branded products’ market share, sometimes by calling into question the bioequivalence of those medications. Transplant clinicians must walk a fine line. Although they recognize the financial hardship that using brand-name anti-rejection medications can impose on their patients, many feel that the proposed guidelines for demonstrating bioequivalence for transplant indications are too loose and could be potentially dangerous. Also, the availability of several generic bioequivalents for each anti-rejection drug creates a potential for medication errors. For instance, there are eight FDA-approved generic mycophenolate mofetil bioequivalents available as substitutes for Genentech’s CellCept (Table 2). Depending on manufacturers’ supply and shifting purchasing costs as competitors jockey for sales to pharmacies, patients may receive a different mycophenolate mofetil product each time they refill a prescription. That raises the possibility of patients unknowingly doubling up on their prescriptions, which can lead to potentially serious adverse reactions. These are just a few of the clinical and policy challenges facing the organ transplant team. By pressing for workable solutions to these challenges, hopefully we can bring about safer and more affordable health care for our organ transplant patients.

Price/ Quantity

Brand CellCept, Genentech 500 mg tablet

$865.62/ 100 tablets

Neoral, Novartis 100 mg capsule

$319.87/ 60 capsules

Prograf, Astellas 1 mg capsule

$409.93/ 100 capsules

Generic

Price/ Quantity

Mycophenolate mofetil 500 mg tablet

$129.99/ 100 tablets

Cyclosporine modified 100 mg capsule

$160.99/ 60 capsules

Tacrolimus 1 mg capsule

$350.01/ 100 capsules

Savings From Generics, % 85

Pharmaceutical Product

Manufacturer

CellCept 500 mg tablet

Genentech

Mycophenolate mofetil 500 mg tablet

Accord Healthcare, Inc.

Mycophenolate mofetil 500 mg tablet

Apotex Corp

Mycophenolate mofetil 500 mg tablet

Mylan Pharmaceuticals Inc

Mycophenolate mofetil 500 mg tablet

Roxane Laboratories Inc

Mycophenolate mofetil 500 mg tablet

Sandoz Inc

Mycophenolate mofetil 500 mg tablet

Teva Pharmaceuticals USA Inc

15 Mycophenolate mofetil 500 mg tablet

UDL Laboratories Inc

Mycophenolate mofetil 500 mg tablet

Zydus Pharmaceuticals (USA) Inc

Same Name. New Size. Introducing 3 mL of Humalog® and Humulin® R U-100 in a Smaller Vial* The New Smaller Vial, Another Insulin Delivery Option Intended To: Give hospitals more ﬂexibility when evaluating insulin storage and distribution (ﬂoor stock vs individual patient supply), in addition to the 10 mL vial and Humalog® KwikPen™.

Indication Humalog is for use in patients with diabetes mellitus for the control of hyperglycemia. Humalog should be used with longer-acting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.

• Same Bar-Coding Technique, New Size • Same Color-Differentiating System, New Size • National Drug Code (NDC) Humalog - NDC Number - 0002-7510-17 Humulin R U-100 - NDC Number - 0002-8215-17

Select Safety Information Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal.

*3 mL of Humalog and Humulin R U-100 are in a 5 mL vial. Pens are for single-patient use only and should not be shared among patients. Please see Important Safety Information on adjacent page and accompanying Brief Summary of full Prescribing Information.

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

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

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

Important Safety Information Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients. 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. Starting or changing insulin therapy should be done cautiously and only under medical supervision. Hypoglycemia Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia can happen suddenly, and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening. Other Side Effects Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and hypersensitivity. Systemic allergy is less common, but may be life-threatening. Because of the difference in action of Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those who are fasting, have autonomic neuropathy or renal impairment, are using potassium-lowering drugs, or taking drugs sensitive to serum potassium level). For additional safety proﬁle and other important prescribing considerations, see accompanying Brief Summary of full Prescribing Information. Please see full user manual that accompanies the pen. Humalog® is a registered trademark of Eli Lilly and Company and is available by prescription only. Humalog® KwikPen™ is a trademark of Eli Lilly and Company and is available by prescription only. Humulin® is a registered trademark of Eli Lilly and Company.

HI59950-1

1109 PRINTED IN USA

42 Opinion

Pharmacy Practice News • April 2010

REMS for Opioids: A Review and Critique John J. Coleman, PhD Kenneth L. Kirsh, PhD John F. Peppin, DO

rescription drug abuse has become a major concern in the United States and has attracted increased attention from media, community leaders, law enforcement and public health officials.1,2 The most prevalent and consequential form of prescription drug

abuse involves opioids legitimately prescribed to treat patients with chronic and acute pain. Chronic pain, in particular, remains a major public health concern whose treatment with opioids often must be weighed against the risks for abuse and increased regulatory scrutiny.3-6 Until recently, the control of prescription drug abuse was primarily the responsibility of state and federal law enforcement agencies. This has changed as a result of a series of congressio-

nal hearings, government inquiries, increased regulatory actions and remedial legislation.7-12 Since the widespread abuse of oxycodone became a significant public health problem in the late 1990s, the FDA has been under pressure from the public and Congress to be more active in preventing the abuse of approved drugs. The Food and Drug Administration Amendments Act of 2007 (FDAAA) contained provisions authorizing the FDA to require,

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

animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted. Nursing Mothers—It is unknown whether Humalog is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both. Pediatric Use—In a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf life may be reduced (see DOSAGE AND ADMINISTRATION). Geriatric Use—Of the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were 65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed. ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a difference in frequency of adverse events between the 2 treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Whole—allergic reactions (see PRECAUTIONS). Skin and Appendages—injection site reaction, lipodystrophy, pruritus, rash. Other—hypoglycemia (see WARNINGS and PRECAUTIONS). OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent premeal hyperglycemia. When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longer-acting insulin being given may need to be adjusted when using Humalog. The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin preparations, the time course of action of Humalog may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques. Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30, and Humulin® R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted Humalog may remain in patient use for 28 days when stored at 5°C (41°F) and for 14 days when stored at 30°C (86°F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump. Parenteral drug products should be inspected visually before use whenever the solution and the container permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be refilled with insulin. External Insulin Pumps—Humalog was tested in MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. HOW SUPPLIED: Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each presentation containing 100 units insulin lispro per mL [U-100]): 10 mL vials NDC 0002-7510-01 (VL-7510) 3 mL vials NDC 0002-7510-17 (VL-7533) NDC 0002-7516-59 (VL-7516) 5 x 3 mL cartridges 3 5 x 3 mL prefilled insulin delivery devices (Pen) NDC 0002-8725-59 (HP-8725) 5 x 3 mL prefilled insulin delivery devices (Humalog® KwikPen™ ) NDC 0002-8799-59 (HP-8799)

1 2 3

MiniMed® and Polyﬁn® are registered trademarks of MiniMed, Inc. Disetronic®, H-TRONplus®, D-TRON®, and Rapid® are registered trademarks of Roche Diagnostics GMBH. 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.

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

under certain conditions, drug sponsors to implement specific measures to evaluate and mitigate safety risks in the use of their products. For perhaps the first time in the history of U.S. food and drug laws, the definition of an adverse drug experience was broadened to include drug abuse and drug overdose.13 In accordance with the new law, the FDA established a program called Risk Evaluation and Mitigation Strategies (REMS). In 2009, the FDA called on sponsors of long-acting opioids to develop a “class-wide” REMS for their products, an approach that represented a unique historical event for the FDA. Consisting of representatives from 22 pharmaceutical companies, the group was called the Industry Working Group (IWG). The IWG was exempted from anti-trust statutes and asked to fashion a policy that would accomplish the goals of the opioid REMS and have industry-wide acceptance. Beginning in March, and continuing throughout July 2009, the IWG convened several times to discuss the project and to review additional guidance from the FDA. In December 2009, the IWG invited all stakeholders to a public meeting in Washington, D.C., to critique a draft of its proposed class-wide opioid REMS.14

Critique of REMS The goal of the REMS project was to decrease “abuse, misuse, addiction and overdose deaths.”15 Although this is a laudable goal, the REMS program has been beset with serious problems from the beginning. There are no universally accepted parameters in the law or the relevant literature that can be used to measure drug abuse or misuse, and drug addiction and drug-related overdose deaths are indistinct phenomena that more often than not involve multiple drugs.a If, for example, a person dies after taking an FDA-approved opioid coadministered with heroin, cocaine, alcohol or some other psychoactive substance or a combination thereof, to what degree, if any, can the FDA-approved drug be considered responsible for that death? Because most drug-related overdose deaths result from intentional polypharmacy, how can we conclude that the action of just one chemical or pharmaceutical may have caused the death, and therefore may require additional REMS attention? Will we need medical examiners to certify that deaths resulted directly from the toxic effects of a REMS-specific drug, or will the mere presence of the drug in the victim’s bodily fluids be sufficient to confirm an unmitigated adverse event (AE)? In the absence of clear standards, outcomes cannot be

Pharmacy Practice News • April 2010

measured, and without such measures, an accurate evaluation of specific REMS is impossible. Therefore, the first step in developing a successful class-wide opioid REMS is to establish, if possible, measurable performance standards. Quantifying the incidence of drug abuse or misuse for REMS purposes raises a long-standing deficiency in drug abuse epidemiology. Drug abuse behavior is a clandestine activity and one that does not lend itself to direct observation. Prevalence is estimated by using proxy measures of drug-related morbidity and mortality. These measures, however, have severe limitations. For example, the Drug Abuse Warning Network (DAWN) is a governmentmanaged public health surveillance system that tracks drug-related emergency admissions reported by a nationwide sample of hospitals. Redesigned several times since its introduction in 1972, DAWN-trained technicians conduct retrospective surveys of medical charts at participating hospitals. The group studies all drugrelated emergency admissions and compiles lists of drugs by the frequency of their mentions in a matrix of case types, several of which can be used inferentially to measure drug abuse. DAWN data in the form of national estimates are published usually three or more years after they are collected. Most DAWN hospital visits involve more than one psychoactive substance and many involve several substances, including alcohol. For this reason, DAWN researchers caution readers not to conclude that the mere mention of a drug in a DAWN hospital visit caused the emergency. Since 2003, the DAWN system has used an online restricted database, DAWN Live! to collect and store data reported by participating hospitals. Drug companies conducting product surveillance, including REMS, may request access to the online system. Companies will be provided data for their own branded drugs, by product name, as well as chemical or generic versions of comparator drugs within the same class. Although the online system can be used to track the abuse of brand-name drugs within the sample, its findings cannot be generalized. Additionally, because some opioids are available in numerous proprietary and generic forms, tracking a single branded product by name may reflect fewer mentions for it than for all other drugs in the same class or with the same active pharmaceutical ingredient when, in fact, this may not be the case. Consider, for example, Embeda (King Pharmaceuticals), a morphine sulfate drug approved in 2009 and required by

Opinion 43

FDA to have a REMS consisting of a medication guide and a communications plan. If this drug’s sponsor requests access to DAWN online data, the sponsor will be able to obtain all mentions of Embeda entered into the DAWN online system, plus all mentions of morphine and morphine sulfate. There are more than two dozen branded and generic morphine products available in the U.S. market.16 A large percentage of DAWN drug mentions are entered into the system as “not tabulated above (NTA),” meaning that the medical chart from which the DAWN data were collected did not indicate a product name for the form of morphine involved in the case. About half of all DAWNreviewed medical charts include confirmatory toxicology data from urine or serum screens. Unless otherwise noted in the patient’s medical chart, a routine toxicology screen will show the chemical name only for detected drugs of abuse. In the above example, unless noted by its brand name in a patient’s medical chart, a patient admitted for a drug-related emergency occasioned by an overdose of Embeda may simply be charted (and subsequently listed in the DAWN case report) as having been treated for an overdose of “morphine.” Similarly, toxicology results do not typically distinguish between an immediate and a sustained form of the intoxicating drug substances present in a patient’s urine or serum. Such a distinction, although important for tracking product abuse, is inconsequential in a drug-related emergency treatment setting. Continuing with the above example, an immunoassay toxicology screen occasionally may produce a false-positive finding for morphine because of metabolic transformation. Codeine, for example, available as a single entity or combination drug, is metabolized to morphine. According to Dart, “Three days after codeine use, the urine shows only morphine and is identical to [the urine result] after heroin or morphine use.”17 Despite these serious limitations, the DAWN system remains the only national public health surveillance system specifically intended to detect drug abuse signals. The MedWatch and Adverse Events Reporting System (AERS) is a postmarketing surveillance system managed by the FDA and intended to identify serious AEs, product quality problems, product use errors and therapeutic inequivalence/failures associated with the use of an FDA-regulated product. This system has limited sensitivity for detecting drug abuse signals. Reporting

•

see REMs, page 44

No test dose or 30-minute observation period required In pre-dialysis CKD anemia

safe

play it go proven

IMPORTANT SAFETY INFORMATION: Venofer® (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Hypersensitivity reactions have been reported with IV iron products. Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving IV iron. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered. In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer ® administration, were taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension.

™

Millions prescribed. Millions treated.

Please see brief summary of full prescribing information on following pages.. Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2009 American Regent, Inc. Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com

Leading anemia management.™

VENFA3 Iss.8/2009

44 Opinion

Pharmacy Practice News • April 2010

REMS

continued from page 43

drug-related AEs is voluntary for patients and health care professionals but mandatory for drug manufacturers, distributors and packers.18 A reportable AE is defined, in part, as: “occurring from drug overdose whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal.”19 Although drug-related AEs are detected via its DAWN system, the Substance Abuse and Mental Health

Services Administration (SAMHSA) does not report them as such to the MedWatch/AERS program. In 2006, the most recent year for which data are available, the DAWN sample of hospitals (N=544) reported 131,146 actual (unweighted) drug-related emergency department visits resulting from drug misuse and abuse. This accounted for 80% of all unweighted drug-related visits reported in 2006 by DAWN.b,c;20 In addition to DAWN and MedWatch/ AERS, the U.S. government sponsors

several other drug abuse data collection programs that, for the most part, are designed to track drug abuse by categories and trends over time, not to identify specific signals of product misuse or abuse. There is no reliable system for drug sponsors to evaluate, much less mitigate, drug abuse safety risks required by the REMS program. Before continuing, we should note that the REMS program was not established specifically for opioids. Rather, the FDA can use the program for any medication

Reference: 1. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S, for the United States Iron Sucrose (Venofer®) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005;68:2846-2856. 2. Data on file. American Regent, Inc., Shirley, NY.

(Table 2 continued)

Brief Summary (See Package Insert For Full Prescribing Information) Therapeutic Class: Hematinic CLINICAL INDICATIONS AND USAGE Venofer® (iron sucrose injection, USP) is indicated in the treatment of iron deficiency anemia in the following patients: • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin CONTRAINDICATIONS The use of Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. WARNINGS Hypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS and ADVERSE REACTIONS. PRECAUTIONS General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload. Patients receiving Venofer® require periodic monitoring of hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum iron values may be reliably obtained 48 hours after IV dosing. See DOSAGE AND ADMINISTRATION and OVERDOSAGE. Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving Venofer®. No life-threatening hypersensitivity reactions were observed in the clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening hypersensitivity reactions in patients receiving Venofer. See ADVERSE REACTIONS. Hypotension: Hypotension has been reported frequently in hemodialysis dependent chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose administered. Caution should be taken to administer Venofer® according to recommended guidelines. See DOSAGE AND ADMINISTRATION. Carcinogenesis, Mutagenesis, and Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer®. Venofer® was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Venofer® at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Venofer®. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Venofer® is excreted in milk of rats. 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 Venofer® is administered to a nursing woman. Pediatric Use: Safety and effectiveness of Venofer® in pediatric patients have not been established. In a country where Venofer® is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer®, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugs could be established. Geriatric Use: The five pivotal clinical trials did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Adverse Events observed in all treated populations The frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis dependent and 75 peritoneal dialysis dependent-CKD patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent-CKD patients for a total of 1,496 patients. In addition, over 2,000 patients treated with Venofer® have been reported in the medical literature. Treatment-emergent adverse events reported by 2% of treated patients with NDD-CKD in the randomized clinical trials, whether or not related to Venofer® administration, are listed by indication in Table 2. Table 2. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Clinical Indication (Multidose Safety Population) NDD-CKD Oral Iron Adverse Events Venofer® (Preferred Term) (N=139) (N=139) % % Subjects with any adverse event 76.3 73.4 Ear and Labyrinth Disorders Ear Pain 2.2 0.7 Eye Disorders Conjunctivitis 0 0 Gastrointestinal Disorders Abdominal pain NOS* 1.4 2.9 Constipation 4.3 12.9 Diarrhea NOS 7.2 10.1 Dysgeusia 7.9 0 Nausea 8.6 12.2 Vomiting NOS 5.0 8.6 General Disorders and Administration Site Conditions Asthenia 0.7 2.2 Chest pain 1.4 0 Edema NOS 6.5 6.5 Fatigue 3.6 5.8 Feeling abnormal 0 0 Infusion site burning 3.6 0 Injection site extravasation 2.2 0 Injection site pain 2.2 0 Peripheral edema 7.2 5.0 Pyrexia 0.7 0.7 Infections and Infestations Catheter site infection 0 0 Nasopharyngitis 0.7 2.2 Peritoneal infection 0 0 Sinusitis NOS 0.7 0.7 Upper respiratory tract infection NOS 0.7 1.4 Urinary tract infection NOS 0.7 5.0 Injury, Poisoning and Procedural Complications Graft complication 1.4 0 Investigations Cardiac murmur NOS 2.2 2.2 Fecal occult blood positive 1.4 3.6 Metabolism and Nutrition Disorders Fluid overload 1.4 0.7 Gout 2.9 1.4 Hyperglycemia NOS 2.9 0 Hypoglycemia NOS 0.7 0.7 Musculoskeletal and Connective Tissue Disorders Arthralgia 1.4 2.2 Arthritis NOS 0 0

Treatment-emergent adverse events reported in 2% of patients by dose group are shown in Table 3. Table 3. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)

Adverse Events (Preferred Term) Subjects with any adverse event Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain NOS* Constipation Diarrhea NOS Dysgeusia Nausea Vomiting NOS General Disorders and Administration Site Conditions Asthenia Chest pain Edema NOS Fatigue Feeling abnormal Infusion site burning Injection site pain Peripheral edema Pyrexia Infections and Infestations Catheter site infection Nasopharyngitis Peritoneal infection Sinusitis NOS Upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications Graft complication Investigations Cardiac murmur NOS Fecal occult blood positive Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia NOS Hypoglycemia NOS Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp Myalgia

NDD-CKD 200 mg 500 mg (N=109) (N=30) % % 75.2 80.0 0.9

6.7

1.8 3.7 6.4 9.2 9.2 5.5

0 6.7 10.0 3.3 6.7 3.3

0.9 0.9 7.3 4.6 0 3.7 2.8 5.5 0.9

0 3.3 3.3 0 0 3.3 0 13.3 0

0 0.9 0 0 0.9

0 0 0 3.3 0

1.8

2.8 1.8

0 0

1.8 1.8 3.7 0.9

0 6.7 0 0

0.9 1.8 0 2.8

3.3 3.3 3.3 6.7

(Table 3 continued)

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

Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Back pain Muscle cramp Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Hypoesthesia Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Dyspnea exacerbated Nasal congestion Pharyngitis Rhinitis allergic NOS Skin and Subcutaneous Tissue Disorders Pruritus Rash NOS Vascular Disorders Hypertension NOS Hypotension NOS *NOS=Not otherwise specified

2.2 0.7 3.6 4.3

3.6 0.7 0 0

6.5 2.9 0.7

1.4 0.7 0.7

2.2 3.6 2.2 1.4 0 0.7

0.7 0.7 0.7 2.2 0 2.2

2.2 1.4

4.3 2.2

6.5 2.2

4.3 0.7

NDD-CKD 200 mg 500 mg (N=109) (N=30) % %

Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Pharyngitis Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension NOS Hypotension NOS

4.6

3.3

5.5 3.7

10.0 0

0.9 1.8 0

6.7 10.0 0

0.9

6.7

6.4 0.9

6.7 6.7

*NOS=Not otherwise specified

Drug related adverse events reported by 2% of Venofer® (iron sucrose injection, USP) treated patients are shown by dose group in Table 4. Table 4. Most Common Adverse Events Related to Study Drug Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)

NDD-CKD Adverse Events (Preferred Term) Subjects with any adverse event Gastrointestinal Disorders Diarrhea NOS* Dysgeusia Nausea General Disorders and Administration Site Conditions Infusion site burning Injection site pain Peripheral edema Nervous System Disorders Dizziness Headache Vascular Disorders Hypotension NOS

200 mg (N=109) % 23.9

500 mg (N=30) % 20.0

0 7.3 2.8

0 3.3 0

3.7 2.8 1.8

0 0 6.7

2.8 2.8

6.7 0

6.7

*NOS=Not otherwise specified Adverse Events Observed in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD) Patients In the pivotal study of 182 NDD-CKD patients, 91 were exposed to Venofer®. Adverse events, whether or not related to Venofer®, reported by 5% of the Venofer® exposed patients were as follows: dysgeusia (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related adverse reaction was reported (hypotension and shortness of breath not requiring hospitalization in a Venofer® patient). Two patients experienced possible hypersensitivity/allergic reactions (local edema/hypotension) during the study. Of the 5 patients who prematurely discontinued the treatment phase of the study due to adverse events (2 oral iron group and 3 Venofer® group), three Venofer® patients had events that were considered drug-related (hypotension, dyspnea and nausea). Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. Serious episodes of hypotension occurred in 2 patients treated with Venofer® at a dose of 500 mg. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration. OVERDOSAGE Dosages of Venofer® (iron sucrose injection, USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis. Periodic monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation. Venofer® should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines [1]. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia. Symptoms associated with overdosage or infusing Venofer® too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution as recommended or at a slower rate may also alleviate symptoms. Preclinical Data: Single IV doses of Venofer® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation, hypoactivity, pale eyes, and bleeding in the gastrointestinal tract and lungs. DOSAGE AND ADMINISTRATION The dosage of Venofer® is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron. Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over sequential sessions, to achieve a favorable hemoglobin response and to replenish iron stores (ferritin, TSAT). Administration: Venofer® must only be administered intravenously either by slow injection or by infusion. Recommended Adult Dosage: Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer®, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated. (See CLINICAL TRIALS, Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients sections.) HOW SUPPLIED Venofer® is supplied in 5 mL and 10 mL single dose vials. Each 5 mL vial contains 100 mg elemental iron (20 mg/mL) and each 10 mL vial contains 200 mg elemental iron (20 mg/mL). Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F). [See the USP controlled room temperature]. Do not freeze. Sterile NDC-0517-2340-01 100 mg/5 mL Single Dose Vial Individually Boxed NDC-0517-2310-01 200 mg/10 mL Single Dose Vial Individually Boxed NDC-0517-2340-10 100 mg/5 mL Single Dose Vial Packages of 10 NDC-0517-2310-05 200 mg/10 mL Single Dose Vial Packages of 5 NDC-0517-2340-25 100 mg/5 mL Single Dose Vial Packages of 25 NDC-0517-2310-10 200 mg/10 mL Single Dose Vial Packages of 10 Rx Only REFERENCE: [1] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis. 37: S182-S238, (suppl 1) 2001. BS2340 Rev. 10/08 Venofer® is manufactured under license from Vifor (International) Inc., Switzerland.

it identifies, “to ensure that the benefits of the drug outweigh the risks of the drug.”21 Prior to the passage of the FDAAA, the FDA regulated the use and distribution of certain high-risk drugs to protect certain patients from severe AEs. Continued approval depended on a risk– benefit ratio in which risks, although elevated, could be managed successfully through proper patient selection and restricted distribution. Some of these high-risk drugs have been subsumed into the REMS program, a good portion of which appears to have been modeled after these previously successful risk management strategies. Since 2004 and the FDA’s adoption of drug abuse as a defined safety risk for the purpose of its Risk Minimization Action Plan (RiskMAP) program—a forerunner to REMS—the agency has used its authority to regulate drugs to propose and, more recently, to require, actions by drug sponsors to address drug abuse. Although some efforts have been impressive and worthy of public acclaim, they are not likely to accomplish their goals in reducing drug abuse. The reasons for this are surprisingly simple and will be described later in this article. Of the 97 approved REMS, five pertain to controlled substances, including four opioids. Nearly 95% of approved REMS pertain to drugs with no psychoactivity, and therefore no abuse potential. The REMS for these drugs address potentially serious safety risks posed by their use in medical treatments. These risks are managed or mitigated by requiring medication guides and communications plans, and in a few specific cases by restricting distribution to prescribers and patients. The FDA approaches its REMS program as if the safety risks of all drugs are the same. However, the safety risks are not the same, and they cannot be addressed successfully by a one-sizefits-all solution. The overwhelming majority of approved REMS are for drugs whose safety risks are not even remotely related to abuse. Two of three REMS components—a medication guide and communications plan—are basic educational materials intended to inform patients and prescribers of potential safety risks. The use of medication guides was characterized as ineffective by the IWG in its 2009 study of a class-wide opioid REMS. Whether effective or not, they are simple and inexpensive to provide in cases where they are not already provided under state pharmacy regulations. Similarly, a REMS communication plan, consisting of a “Dear Healthcare Provider” letter or some other form of direct communication to prescribers, seems easy and inexpensive for drug sponsors to provide. As with the REMS-imposed medication

•

see REMS, page 46

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niques in regional anesthesia and pain medicine. Dr. Rathmell demonstrates how to perform all commonly used injection techniques and familiarizes pain practitioners with the radiographic anatomy encountered during these procedures.

Atlas of Pain Management Injection Techniques: Second Edition

Steven D. Waldman, MD, JD This resource conveniently places at your fingertips every essential pain management injection technique used today — in a straightforward, beautifully illustrated manner that lends itself to ready implementation in any clinical setting. Leading expert Steven D. Waldman, MD, JD gives you the benefit of his extensive experience, both as a clinician and as the author of numerous best-selling pain management references.

Decision Making in Pain Management: Second Edition Somayaji Ramamurthy, MD; Euleche Alanmanou, MD; James N. Rogers, MD

Clear algorithms and concise accompanying explanations facilitate the evaluation and management of nearly 140 common pain management problems. The new edition of this best-selling resource features a completely new section on cancer pain plus brandnew chapters on patient evaluation, chronic pain, upper and lower extremity pain, nerve blocks and more. It also incorporates comprehensive updates throughout to reflect the latest evaluation techniques, treatment approaches and pain syndromes.

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Interventional Pain Management: Image-Guided Procedures with DVD

P. Prithvi Raj; Leland Lou; Serdar Erdine; Peter S. Staats; Steven D. Waldman; Gabor Racz; Michael Hammer; David Niv; Ricardo Ruiz-Lopez; James E. Heavner Thoroughly revised and reorganized, this second edition offers you meticulous how-to guidance on performing today’s top radiographically guided regional anesthesia and pain management techniques. Renowned experts explain how to make optimal use of fluoroscopy, MRI and CT to pinpoint the exact anatomic site for each procedure.

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Marjorie A. Satinsky, MBA; Randall T. Curnow Jr., MD, MBA This book will help physicians understand the breadth of practice management, learn the essentials about start-up, organization and management, managing finances, recruiting and managing staff and outside resources, improving health care delivery and clinical outcomes and ensuring compliance.

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Pete Egoscue

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Honorio T. Benzon; James P. Rathmell; Christopher L. Wu; Dennis C. Turk; Charles E. Argoff

The fourth edition guides you through every aspect of pain medicine with concise descriptions of evaluation, diagnosis of pain syndromes, rationales for management, treatment modalities and much more. From commonly seen pain syndromes to specific pain management challenges, this popular text will equip you with the know-how you need to effectively manage even your most challenging cases. PPN0410

46 Opinion

REMS

continued from page 44

guide, their usefulness in mitigating abuse risks is doubtful. However, a third REMS component, called Elements to Assure Safe Use (ETASU), may present serious obstacles to patients and prescribers required to meet product-related educational criteria before being granted access to opioids with this REMS component. If a REMS with ETASU is required, drug sponsors also must establish and maintain restrictive distribution systems. At its December 2009 public meeting, the IWG issued the following statement regarding ETASU as a component of a class-wide opioid REMS: “At this time, IWG does not sup-

Pharmacy Practice News • April 2010

an opportunity for all interested parties to provide information and share views on the matter.”24

Discussion Does the REMS program have a role in reducing the incidence of prescription drug abuse, particularly the abuse of opioids? As it stands now, the answer to this question is no, except, perhaps, for the ETASU component, which, in the opinion of the IWG, is out of the question and considered tantamount to removing a drug from the market. A fundamental flaw in the FDA’s analysis is its assumption that all safety risks can be managed in the same way and by

The overwhelming majority of currently approved REMS are for drugs whose safety risks are not even remotely related to abuse. port inclusion of any Elements to Assure Safe Use including mandatory prescriber training or certification.”14 One opioid, Onsolis (Meda Pharmaceuticals)—a fentanyl buccal soluble film approved for breakthrough cancer pain— is required to have a three-part REMS, including ETASU provisions calling for a patient and prescriber registry, training certification of patients and prescribers and centralized dispensing.22,23 Given the severity of the distribution restrictions imposed by the Onsolis REMS, there is little doubt that the safety risk for abuse will be reduced, if not eliminated entirely, for this product. In its 2009 study of a class-wide opioid REMS program, the IWG sought and received guidance from scores of independent nongovernmental organizations representing stakeholders in the pain treatment field. In its presentation of findings at its December 2009 public meeting, the IWG clearly struggled to apply REMS concepts to opioids without limiting their access for patients. Having rejected out of hand the only REMS component (the ETASU) that could prevent abuse, the IWG settled on recommending additional education for patients and prescribers, as well as a class-wide medication guide to provide prescribers with information about common opioid risks. The IWG also suggested legislation that would permit the Drug Enforcement Administration (DEA) to require training and testing as a precondition for DEA registration.14 Perhaps recognizing that a class-wide opioid REMS program may be more difficult than envisioned, on Oct. 19, 2009, the FDA issued a Notice reopening the comment period for the REMS program until Oct. 19, 2010, “in light of continued public interest in this topic and to provide

the same program. This is wrong. Preventing medication errors—the goal of most REMS—is qualitatively different from preventing drug abuse. Opioids are scheduled controlled substances because they have known risks, including the risk for abuse and addiction. Abuse does not result from prescribers being unaware of these risks or from patients not being furnished a medication guide. The evidence for this was cited in the findings of the IWG study. According to a national drug abuse survey sponsored by the SAMHSA: “Among persons aged 12 or older in 2007-2008 who used pain relievers nonmedically in the past 12 months, 55.9 percent got the drug they most recently used from a friend or relative for free. Another 18.0 percent reported they got the drug from one doctor. Only 4.3 percent got pain relievers from a drug dealer or other stranger, and 0.4 percent bought them on the Internet. Among those who reported getting the pain reliever from a friend or relative for free, 81.7 percent reported in a follow-up question that the friend or relative had obtained the drugs from just one doctor.”25 The FDA, in promulgating the need for a class-wide opioid REMS, ignored the above information about the etiology of opioid abuse. Medication guides and communications plans approved for opioid REMS in force likewise ignore these findings. Instead, they provide technical information redundantly synopsized from the product’s label. Finally, as the above discussion of drug abuse data systems suggests, sufficient reliable data to evaluate prescription drug abuse on a timely basis does not exist. Given our inability to assess with any degree of accuracy the magnitude and scope of drug abuse, it stands to

reason that any evaluation of an opioid REMS that is based on these weak and faulty data, by necessity, must fail. As drug sponsors attempt to meet imposed REMS requirements, the added costs will be passed along to consumers and third-party payers in the form of higher drug costs. These costs might be justifiable if the REMS program could be shown to reduce or mitigate opioid abuse. For the above reasons and more, however, this seems unlikely.

12. Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, Stat. 121-823 (Sept. 27, 2007).

John J. Coleman, PhD, is president of the Prescription Drug Research Center, Fairfax, Va.

16. Wolters Kluwer Health Inc. Drug Facts and Comparisons: 2009. St. Louis, MO: Wolters Kluwer Health; 2008.

Kenneth L. Kirsh, PhD, is assistant professor in the Department of Pharmacy Practice and Science at the University of Kentucky, chairs the Hospice of the Bluegrass Research Committee and The Pain Treatment Center of the Bluegrass Pain Committee, and is a member of the Kentucky Prescription Drug Diversion and Abuse Council, Lexington. John F. Peppin, DO, is director of the Clinical Research Division at The Pain Treatment Center of the Bluegrass, clinical associate professor, University of Kentucky, and associate medical director, Hospice of the Bluegrass, Lexington.

References 1.

Manchikanti L. Prescription drug abuse: what is being done to address this new drug epidemic? Testimony before the Subcommittee on Criminal Justice, Drug Policy and Human Resources. Pain Physician. 2006;9:287-321.

2. National Center on Addiction and Substance Abuse. Controlled prescription drug abuse at epidemic level. J Pain Palliat Care Pharmacother. 2006;20:61-64. 3.

Hertz JA, Knight JR. Prescription drug misuse: a growing national problem. Adolesc Med Clin. 2006;17:751-769.

4. Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc. 2009;84:593-601. 5. Passik SD, Heit H, Kirsh KL. Reality and responsibility: a commentary on the treatment of pain and suffering in a drug-using society. J Opioid Manage. 2006;2:123-127. 6. Wunsch MJ, Cropsey KL, Campbell ED, Knisely JS. OxyContin use and misuse in three populations: substance abuse patients, pain patients, and criminal justice participants. J Opioid Manage. 2008;4:73-79. 7.

US General Accounting Office. Prescription drugs: OxyContin abuse and diversion and efforts to address the problem (GAO-04-110). USGPO; 2003 [Dec 2009]. http://www.gao.gov/new.items/ d04110.pdf. Accessed January 10, 2010.

Hearing Before the Subcommittee on Crime of the Committee on the Judiciary, House of Representatives, 106th Cong (1999).

Office of National Drug Control Policy [press release]. White House Department of Justice releases first-ever comprehensive national action plan to reduce synthetic drug production, trafficking, and abuse: Plan focuses on methamphetamine, prescription drugs, and club drugs; 2004.

10. Hearing Before the House Committee on Government Reform, Subcommittee on Criminal Justice, Drug Policy and Human Resources, 110th Cong, 2nd Sess (2006) (testimony of J. T. Rannazzisi, deputy assistant administrator, Office of Diversion Control, Drug Enforcement Administration, on the National Synthetic Drug Control Strategy). http://www.dea.gov/pubs/cngrtest/ct061606. html. Accessed January 10, 2010. 11. Hearing Before the House Subcommittee on Regulatory Affairs, Committee on Government Reform, 109th Cong, 2nd Sess (2005) (testimony of Robert J. Meyer, MD, director, Office of Drug Evaluation II, Center for Drug Evaluation and Research, FDA: FDA’s role in preventing prescription drug abuse).

13. Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, Stat. 121-823 (Sept. 27, 2007). 14. Food and Drug Administration. December 4, 2009 FDA/Industry Working Group (IWG) Public Meeting on Risk Evaluation and Mitigation Strategies (REMS) for Certain Opioids. 2009. http://www.fda. gov/Drugs/DrugSafety/InformationbyDrugClass/ ucm193499.htm. Accessed January 16, 2010. 15. Rappaport R. REMS for opioid analgesics. Industry meeting with FDA to discuss opioid REMS (2009), prepared by Pinney Associates.

17. Dart RC, ed. Medical Toxicology. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2004. 18. Food and Drug Administration. Reporting serious problems to the FDA. 2010. http://www.fda.gov/ Safety/MedWatch/HowToReport/default.htm. Accessed February 18, 2010. 19. Code of Federal Regulations. § 314.80 Postmarketing reporting of adverse drug experiences. 2009. http://frwebgate6.access.gpo.gov/cgi-bin/PDFgate.cgi?WAISdocID=584592105130+7+2+0& WAISaction=retrieve. Accessed February 19, 2010. 20. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits. DAWN Series D-30, DHHS Publication No. (SMA) 08-4339, Rockville, MD; 2008. https://dawninfo.samhsa.gov/files/ED2006/ DAWN2k6ED.pdf. Accessed February 19, 2010. 21. Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, Stat. 121-927 (Sept. 27, 2007). 22. Onsolis [prescribing information]. Somerset, NJ: Meda Pharmaceuticals; 2009. http://www.onsolis. com/pdf/onsolis_pi.pdf. Accessed February 19, 2010. 23. Risk Evaluation and Mitigation Strategy (REMS): FOCUS™ Program for Onsolis™. BioDelivery Sciences International, Inc.; 2009. http://www.fda. gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ UCM187537.pdf. Accessed February 19, 2010. 24. Federal Register, Vol. 74, No. 200; p53509. DHHS: FDA: Risk Evaluation and Mitigation Strategies for Centail-Opioid Drugs; Notice of Public Meeting; Reopening of Comment Period. 2009. http:// www.regulations.gov/search/Regs/contentStreame r?objectId=0900006480a44cce&disposition= attachment&contentType=pdf. Accessed February 19, 2010. 25. Substance Abuse and Mental Health Services Administration. Results from the 2008 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-36, HHS Publication No. SMA 09-4434). Rockville, MD; 2009.

Footnotes a

In January 2010, the FDA published “Guidance

for Industry: Assessment of Abuse Potential of Drugs.” This document provides definitions of several terms, including “potential for abuse,” “addiction-sustaining liability” and “dependence,” as these terms are used in the Controlled Substances Act and used to evaluate drugs for scheduling purposes (http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf ). This FDA document, however, does not mention the REMS program nor does it show how its guidance is relevant to the program. b These are unweighted sample data, and as such represent actual cases. c

Although published DAWN data generally do not provide product-specific information, presumably, if DAWN reported AEs to MedWatch/AERS, productspecific data, when available in DAWN case reports, would be furnished and available for use by sponsors and others in evaluating required REMS.

Midazolam Hydrochloride Injection CIV Brief Summary See package insert for full prescribing information Adult and Pediatric Intravenous midazolam HCl has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam HCl should be used only in hospital or ambulatory care settings, including physicians’ and dental offices, that provide for continuous monitoring of respiratory and cardiac function, i.e., pulse oximetry. Immediate availability of resuscitative drugs and age- and sizeappropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. (See WARNINGS.) For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure and route dependent (see DOSAGE AND ADMINISTRATION in full prescribing information). Neonates Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl (see DOSAGE AND ADMINISTRATION in full prescribing information). INDICATIONS AND USAGE Midazolam HCl Injection is indicated: intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia; intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants; intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia); continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting. Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours (see CLINICAL PHARMACOLOGY in full prescribing information). CONTRAINDICATIONS Injectable midazolam is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with openangle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied. Midazolam HCl Injection is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form. WARNINGS Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression. Prior to the intravenous administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Patients should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry. Hypoventilation, airway obstruction and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because intravenous midazolam depresses respiration (see CLINICAL PHARMACOLOGY in full prescribing information) and because opioid agonists and other sedatives can add to this depression, midazolam should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway and supporting ventilation. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. See DOSAGE AND ADMINISTRATION in full prescribing information. Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic. Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients. Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly (see CLINICAL PHARMACOLOGY in full prescribing information). Because elderly patients frequently have inefficient function of one or more organ systems, and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered. Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances. There have been limited reports of intra-arterial injection of midazolam hydrochloride. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided. The safety and efficacy of midazolam following nonintravenous and nonintramuscular routes of administration have not been established. Midazolam should only be administered intramuscularly or intravenously. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam (see CLINICAL PHARMACOLOGY in full prescribing information) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation. Usage in Pregnancy An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section).

Usage in Preterm Infants and Neonates Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration. The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including midazolam hydrochloride) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of midazolam for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources. PRECAUTIONS General Intravenous doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS above and DOSAGE AND ADMINISTRATION in full prescribing information). These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia. Use with Other CNS Depressants The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient and the use of concomitant medications capable of depressing the CNS. Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Care must be taken to individualize and carefully titrate the dose of midazolam to the patient’s underlying medical/surgical conditions, administer to the desired effect being certain to wait an adequate time for peak CNS effects of both midazolam and concomitant medications, and have the personnel and size-appropriate equipment and facilities available for monitoring and intervention (see BOX WARNING, WARNINGS above and DOSAGE AND ADMINISTRATION section in full prescribing information.) Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management. For information regarding withdrawal, see DRUG ABUSE AND DEPENDENCE section. Drug Interactions The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION in full prescribing information). Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam. For additional drug interaction information, refer to full prescribing information. Pregnancy Teratogenic Effects – Pregnancy Category D (see WARNINGS) Labor and Delivery In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug. Following intramuscular administration of 0.05 mg/kg of midazolam, both the venous and the umbilical arterial serum concentrations were lower than maternal concentrations. The use of injectable midazolam in obstetrics has not been evaluated in clinical studies. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, midazolam is not recommended for obstetrical use. Nursing Mothers Midazolam is excreted in human milk. Caution should be exercised when midazolam is administered to a nursing woman. ADVERSE REACTIONS See WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, e.g., upper endoscopy and dental procedures. Adults: The following additional adverse reactions were reported after intramuscular administration: headache (1.3%); Local effects at IM injection site included: pain (3.7%), induration (0.5%), redness (0.5%), muscle stiffness (0.3%). Administration of IM midazolam hydrochloride to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION in full prescribing information). The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: hiccoughs (3.9%), nausea (2.8%), vomiting (2.6%), coughing (1.3%), “oversedation” (1.6%), headache (1.5%), drowsiness (1.2%); Local effects at the IV site included: tenderness (5.6%), pain during injection (5.0%), redness (2.6%), induration (1.7%), phlebitis (0.4%). Pediatric Patients The following adverse events related to the use of IV midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent. Neonates For information concerning hypotensive episodes and seizures following the administration of midazolam to neonates, see BOX WARNING, CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections. DRUG ABUSE AND DEPENDENCE Midazolam is subject to Schedule IV control under the Controlled Substances Act of 1970. Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs. Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam. Withdrawal symptoms similar in character to those noted with barbiturates and alcohol (convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuation of benzodiazepines, including midazolam. Abdominal distention, nausea, vomiting and tachycardia are prominent symptoms of withdrawal in infants. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. There is no consensus in the medical literature regarding tapering schedules; therefore, practitioners are advised to individualize therapy to meet patient’s needs. In some case reports, patients who have had severe withdrawal reactions due to abrupt discontinuation of high-dose long-term midazolam, have been successfully weaned off of midazolam over a period of several days. Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) BAXTER is a trademark of Baxter International Inc. 462-051-06 4/2009

Midazolam HCI Injection

Now available with Distinctive Labels. To learn more, contact your Baxter representative at 1-888-229-0001. Please see preceding page for brief summary of full Prescribing Information including boxed warning.

Baxter, Committed to a Safer Healthcare Environment, and the distinct product label design are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111198B 09/09