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Volume 36 • Number 11 • November 2009 ❃
The Pharmacist’s News Source
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Q&A: Judi Jacobi, PharmD
First Pharmacist To Lead SCCM Says Team Approach Is Crucial T
he run-up to the Society of Critical Care Medicine’s annual meeting in January 2010 is gathering steam, and Judi Jacobi, PharmD, is feeling the heat. During a morning in which she was putting the final touches on new guidelines for insulin infusion management in the ICU, juggling phone calls as a critical care pharmacy specialist at Methodist Hospital/Clarian Health and eyeing her growing list of duties as the first pharmacist/president-elect of SCCM, Dr. Jacobi spoke with Pharmacy Practice News editor David Bronstein about her accomplishments and the current and future direction of the specialty.
in this issue Change in Heparin Potency Up Front Events
Catches Profession by Surprise
Using TV spots, other outreach efforts to sing praises of the profession.
Operations & Mgmt
Assistance Programs Making medications more affordable for low-income patients.
Critical Care Documenting the value of ED pharmacy services: part 2 in a series.
: Critical care pharmacy has come a long way since 1989, when you helped form the Clinical Pharmacy and Pharmacology [CPP] section of SCCM. Have the ensuing 20 years given pharmacists a strong enough presence on the ICU team? A: The fact that SCCM has gone so far as to recognize me as a key member of the critical care team and supports me as its next president speaks volumes.
The basics of federal 340B discount program.
People in Pharmacy
Addiction Medicine A pharmacist’s tale of substance abuse and recovery.
see FIRST PHARMACIST, page 56
New Study Shines Light On Vancomycin Toxicity More vigilance on trough levels by specialty urged
Health IT funding and BPOC: Are we there yet?
see VANCOMYCIN, page 34
s of early last month, all heparin products shipped in the United States were about 10% less potent than earlier formulations, the result of efforts by the FDA and the U.S. Pharmacopeia (USP) to harmonize dosage measurement units with international standards established by the World Health Organization (WHO). Although the change, which took effect Oct. 8, had been in the works for months, the official announcement by the FDA on Oct. 1 caught many clinicians and patient safety experts off guard. They worry that hospitals and other facilities that administer the widely used anticlotting drug may not be prepared to adjust dosing protocols, manage inventory procedures and monitor patients for anticoagulation efficacy. “One week is a pretty short time for most institutions to think through all the logistical and therapeutic issues that this seemingly small change might require,” said Stuart T. Haines, PharmD, professor and pharmacotherapy specialist at the University of Maryland School of Pharmacy in Baltimore. “For those institutions that decide to change their heparin dosing protocols, educating the physicians, nurses and pharmacists about the change will require considerably more time to plan and implement,” he told Pharmacy Practice News.
Educational Review Contemporary Management of Hyponatremia See page
Anaheim, Calif.—Vancomycin trough levels greater than 15 mg/L may cause nephrotoxicity and should be closely monitored, especially in patients at risk for renal problems, according to new research from the University of California, Davis. Pharmacists at UC Davis Medical Center casually observed over the years that patients treated with higher trough levels seemed to develop more nephrotoxicity than patients treated with lower levels. In a retrospective study, they reviewed the charts of 105 patients admitted to the center between December 2005 and January 2006. They separated patients into
Improving the Safety of IV Drug Delivery Clinical Use of Desirudin, a New Subcutaneously Administered Direct Thrombin Inhibitor
see HEPARIN POTENCY, page 48
Pharmacists Help Minimize Delays to Proper Sepsis Care Anaheim, Calif.—Failure to recognize severe sepsis or septic shock and delays in antibiotic administration after pharmacy processing present significant obstacles to treating patients promptly, according to new research from Mayo Clinic. An internal review of Mayo Clinic patients found that in some cases, it took more than three hours for patients to be treated for sepsis, including more than two hours to
New Product EPS, Inc. releases two new SHRINKSAFE ID Bands for chemotherapy and other “highalert” drugs. See page
properly diagnose sepsis, and close to one hour to administer antibiotics. These results, presented at the American College of Clinical Pharmacy’s annual meeting, have led to a number of changes in the evaluation and treatment of sepsis patients at Mayo Clinic that are improving outcomes. The review was part of a quality improvement program to boost compliance with the medical center’s
see SEPSIS DELAYS, page 32
Research Awards Rural pharmacy, medication safety among topics garnering gold stars. See page
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Up Front 3
Pharmacy Practice News • November 2009
Capsules In heart failure patients …
Warfarin Bleeding Risk May Be Overstated
The six most-viewed articles last month on pharmacypracticenews.com:
1. Raising the Quality Bar: A Primer on Safe Practices From Nat’l Quality Forum 2. September 2009—Digital Edition 3. Compatibility of Commonly Used Intravenous Drugs 4. Pharmacists Excel at Managing Antibiotic Rx for Cystic Fibrosis 5. Antimicrobial Efficacy (Educational Review) 6. FDA Issues Warning on Glucose Test Strips Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.
heard here first
‘[Don’t assume that] just because you have a CPOE system in place, safe medication use is assured. You need to periodically analyze your work flow and how well it meshes with the technology to ensure optimal outcomes.’ —Kwaku Marfo, PharmD
See article, page 72
The Book Page
MCMAHONMEDICALBOOKS.COM Clarke’s Analysis of Drugs & Poisons Anthony C. Moffat; M. David Osselton; Brian Widdop See page
everal studies have suggested that heart failure (HF) patients are prone to excessive anticoagulation, and that warfarin therapy thus places them at risk for potentially dangerous ous bleeds. But the first study in nearly 50 years to prospectively analyze such an interaction has found little evidence for concern. That’s not to say the potential for excessive anticoagulation in these patients should be ignored. Bleeding complications from warfarin “can be catastrophic,” said lead author Toni Ripley, PharmD, a clinical pharmacist at The University of Oklahoma Health Sciences Center (OUHSC), in Oklahoma City. “The problem is that causation [in HF patients] has not been looked at prospectively for nearly five decades, at least that we could determine.” In their study, Dr. Ripley and her colleagues recorded international normalized ratio (INR) values in 40 patients who were enrolled in the HF Treatment Program at OUHSC. Patients were prospectively observed for 14.5±9 months; all suffered from hypervolemia, a fluid overload syndrome that commonly occurs in HF patients due to poor perfusion. Patient visits were excluded from the analysis if complete data regarding HF or the degree of anticoagulation could not be obtained; INR values were excluded if the results were associated with a known cause for INR fluctuation. Increases in INR values Toni L. Ripley, of 50% or more were considered clinically significant. HypervPharmD, BCPS olemia was classified as mild, moderate or severe if diuretics were increased by less than 50%, 50% or more, or if the patient required intravenous diuretics, respectively. A total of 41 episodes of HF-associated hypervolemia with corresponding INR data were evaluable, accounting for 53% of all hypervolemic episodes; most were mild or moderate, Dr. Ripley and her research team reported at the annual meeting of the American College of Clinical Pharmacy. INR elevations of 50% or more occurred only two times during hypervolemia (P=0.29). There were no differences in average INR change between patients with hypervolemia classified as mild, moderate or severe or between patients classified as NYHA II, III or IV (P=NS for all). Patients classified as NYHA III had lower weekly warfarin doses than those classified as NYHA II (P<0.01). Based on the results, “mild, and possibly moderate, HF exacerbations appear to not cause an exaggerated response to warfarin,” the investigators concluded. “Thus, the results challenge hypotheses from prior research suggesting HF exacerbations cause an exaggerated response to [the anticoagulant].” —David Bronstein
James O’Neill, Senior Systems Manager
Dan Radebaugh, Director of Production and Technical Operations
Robert Adamson, PharmD, Livingston, NJ Ernest R. Anderson Jr., MS, RPh, Boston, MA
Volume 36 • Number 11 • November 2009 • pharmacypracticenews.com
ANESTHESIOLOGY/PAIN Robert Barkin, PharmD, Chicago, IL Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY
ONCOLOGY Robert T. Dorr, PhD, RPh, Tucson, AZ
Robert Ignoffo, PharmD, San Francisco, CA
Indu Lew, PharmD, Livingston, NJ
Philip E. Johnson, MS, RPh, FASHP, Tampa, FL
Cindy O’Bryant, PharmD, Aurora, Colo.
C. Michael White, PharmD, Storrs, CT
Jim M. Koeller, MS, San Antonio, TX
Susan Goodin, PharmD, BCOP, New Brunswick, NJ
Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA Larry Ereshefsky, PharmD, San Antonio, TX
PEDIATRICS Gretchen Brummel, PharmD, BCPS, Hudson, Ohio
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4 Up Front
Pharmacy Practice News • November 2009
‘Active Learning’ in Las Vegas Interactive approach featured at ASHP Midyear Meeting
he American Society of HealthSystem Pharmacists’ 44th Midyear Clinical Meeting and Exhibition returns to the glitter of Las Vegas, Dec. 6-10, with a dynamic array of interactive educational programs, networking sessions and entertainment events designed to fit the diversified interests of the 20,000 or more people who are expected to attend. Highlighting this year’s educational programming will be the new “active learning” approach required by the Accreditation Council for Pharmacy Education as well as a schedule that packs in more CE-accredited sessions than ever before, according to JoAnn S. Harris, BSPharm, MBA, director of educational programs. Also in the spotlight is a Monday morning keynote speech by actor Dennis Quaid, who will discuss how he and his wife, Kimberly, established a family foundation to focus on medical error prevention in the aftermath of a 1,000-fold heparin overdose that nearly took the lives of their newborn twin daughters in November 2007.
Getting Paid for Ambulatory Services On Tuesday, a six-hour Learning Community program will concentrate on how pharmacists can build, sustain and negotiate reimbursement for ambulatory services such as pain management, anticoagulation therapy and diabetes management. Leading the morning and afternoon sessions will be Seena Haines, PharmD, BC-ADM, CDE, associate professor of pharmacy practice at Palm Beach Atlantic University’s Lloyd L. Gregory School of Pharmacy. “In the morning, we will be talking about how to design and develop clinical services and how to begin negotiating with payers and setting up outcomes collection,” said Dr. Haines, who is also chair of the Advisory Group on Reimbursement for Cognitive Services
in the ASHP Section of Home, Ambulatory and Chronic Care Practitioners. The afternoon session, she said, will feature vignettes by speakers representing various niche areas of pharmacy practice. “There are aspects of the program that will speak to clinicians at various levels of experience,” said Dr. Haines, so the audience might include administrators and new practitioners who need advice on establishing revenue streams or developing systems to capture metrics for new services or seasoned practitioners who want to explore new niches or expand existing services. The increasing attention being paid to the impact of emergency department (ED) pharmacists on medication safety is reflected in several Midyear Clinical Meeting programs. On Wednesday morning, for example, Daniel P. Hays, PharmD, BCPS, clinical pharmacist in the Departments of Pharmacy/Emergency Medicine at University Medical Center, University of Arizona, in Tucson, will moderate a clinical pearls session devoted to ED medicine. Twenty clinical pharmacists will take part in the 8 to 9:45 a.m. session, discussing topics ranging from “The Treatment of Eclampsia in the ED” to “Approach to the Toxic Patient.” “It’s a first for the Midyear,” Dr. Hays said. “I thought it would be interesting to see if we could put together a session just for people who are currently practicing in emergency medicine or interested in the idea.” He said he sent an e-mail query to ASHP members on several listservs “and had an overwhelming response. I’m hoping to see both seasoned and new practitioners at the session, and I hope it continues to spur the interest of pharmacists in practicing in the emergency world.” [For a related article on ED pharmacy, see page 31.] At midday on Wednesday, the Section of Clinical Specialists and Scientists will host an emergency medicine networking session, with discussions of hypothermia
protocols, the droperidol controversy (the drug has a black-box warning about side effects, the clinical significance of which has been debated vigorously for several years), and conscious and ventilator sedation, among other topics. On Wednesday afternoon from 2 to 3 p.m., investigators will present the findings of a major multicenter study on the impact of pharmacists on preventing medication errors in the ED. That presentation will be followed by a 30-minute session detailing the results of another ED safety study carried out at the University of Arizona Medical Center in Tucson. The research for both studies was supported by grants from the ASHP Foundation. (See Pharmacy Practice News, October, page 1.)
Antibiotic Stewardship With the threat of antibiotic resistance growing worldwide, a three-hour session Thursday morning will focus on “Unique Approaches to Implementing Successful Antimicrobial Stewardship Programs.” Leading the session will be Curtis D. Collins, PharmD, MS, BCPS AQ-ID, clinical pharmacist, Infectious Diseases, at the University of Michigan Health System. “Our program starts with a general overview of the consensus antimicrobial stewardship guidelines,” Dr. Collins said. “We will discuss some challenges facing successful management of an antimicrobial stewardship program with a focus on antimicrobial resistance trends and maintaining tangible financial value.” He added that “Dr. James Viera is going to discuss the challenges of implementing stewardship programs in nonacademic and smaller hospital settings. Finally, Dr. Elizabeth Hermsen is covering the challenges associated with choosing a clinical decision support system to augment stewardship efforts.” “We hope audience participation is dynamic,” Dr. Collins said, “with attendees willing to share problems they’re
Come See us at Booth #1818 Be sure to pick up one of our Special Projects and Publications At the ASHP meeting, we’re giving away free copies of a wide variety of medical education, covering such topics as idiopathic thrombocytopenia purpura, and updates on key cancer therapeutic regimens, chemotherapy-related medication errors, and more.
facing or voice unique approaches to some of the challenges we introduce for discussion.” Among other meeting highlights mentioned by Ms. Harris were the following: • Sunday’s all-day “Great eXpectations” workshop program for new practitioners. It will offer three different tracks: “Fine-Tuning Your Clinical Skills,” “Mentoring and Leadership” and “Advancing Your Career.” • Six hours of oncology specialty programming Tuesday aimed at BoardCertified Oncology Pharmacists (BCOP) seeking recertification. • An expansion of the popular “CE Power Hour” programs, which offer a variety of one-hour sessions from 4 to 5 p.m. on Monday, Tuesday and Wednesday, a total of 11 hours in all. Ms. Harris also noted that a “fair number of physicians” would be taking part in various sessions. For example, David W. Bates, MD, MSc, a renowned expert in the use of information technology to improve patient safety, will discuss the role of the pharmacist in the medical home as part of a session on Monday from 4 to 5 p.m. (The medical home is an evolving model of comprehensive treatment that relies, at least in part, on primary care physicians.) On Tuesday from 8 to 9 a.m., Peter Angood, MD, FACS, will lead a session titled “Pharmacists, Leadership, and Safe Practices—What They Mean For You.” Dr. Angood is a senior adviser to the National Quality Forum and former vice president and chief safety officer for the Joint Commission. “We like it when physicians come to speak,” Ms. Harris said, “because we really think it fosters interdisciplinary [collaboration].” A team approach to patient care will also be the theme of a Spotlight on Science presentation by Larry Wellikson, MD, CEO of the Society of Hospital Medicine. —Bruce Buckley
THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES
Improving the Safety of IV Drug Delivery: Interpreting Current Standards To Improve Practices Thomas Van Hassel, RPh, MPA
Table 1. Common Issues Associated With IV Drug Delivery Systems
Director of Pharmacy Yuma Regional Medical Center Yuma, Arizona
Various recommendations are available to help health systems improve their intravenous (IV) drug delivery processes. One of the more significant guidelines came out of the Second Consensus Development Conference on the Safety of Intravenous Drug Delivery Systems, held in August 2008,1 which reflects the standards put forth in the United States Pharmacopoeia (USP) Chapter <797> guidelines and the Joint Commission’s medication management standards. These recommendations, which were highlighted in the previous articles in this series, establish a framework to assist institutions in improving the safety of IV drug delivery. However, many health systems continue to struggle over how to implement some of these recommendations. This article discusses some factors to consider during the implementation of, and compliance with, the consensus recommendations and current standards.
Streamlined Systems Pharmacy IV admixture programs can involve a variety of product types, including manufacturer-prepared, premixed (ready-to-use) products; outsourced ready-to-use products, point-of-care– activated products, pharmacy-compounded products, and products compounded at the point-of-care (Table).1 Specific delivery vehicles can include syringes, mini-bags, frozen premix products, and other premixes. Many health systems have 6 or 7 different IV drug delivery systems using an assortment of the aforementioned products. Although a single system would be ideal, there is no single system that can meet all the possible needs related
Non–pharmacycompounded at point of care
Can customize dose for each patient, immediate availability
High potential for error, low compliance with regulatory requirements, labeling typically handwritten or absent, risk for contamination
Can customize dose for each patient, significant Risk for contamination, significant operational quality control, labeled in accordance with hospital requirements related to USP Chapter <797> standards
Works well with automated cabinets, longest expiration date
Products not available for special patient populations, cost analysis recommended, risk for inactivation errors
Can customize dose for each patient, low risk for contamination
Cost analysis recommended, requires advance planning and storage
Low risk for contamination, ease of use and dispensing, longest expiration date
Products not available for special patient populations, lack of pharmacoeconomic data, frozen products require thawing
IV, intravenous; USP, United States Pharmacopeia Adapted from the Second Consensus Development Conference on the Safety of Intravenous Drug Delivery Systems.
to different patient and disease-state parameters. Minimizing the disparity of systems used may improve efficiency by reducing waste and allowing reuse of a greater number of products. With that in mind, the best approach may be for facilities to set up 1 major system, with 1 or 2 minor systems in place to cover unusual circumstances.
Making the Choice Facilities should determine which 2 or 3 drug delivery system options are best suited for them. These systems can differ with respect to cost, safety, ease of use, regulatory compliance, and applicability to various patient populations. Although the Joint Commission has not recommended a specific drug delivery system, it has established specific goals with regard to standardized concentrations of solutions.2 These recommendations, identified as medication management standards, support the
PHARMACY PRACTICE NEWS • NOVEMBER 2009
use of premixed or manufacturer-pre- example, although premix drug delivpared products. Such products ensure ery systems may have a higher acquisienhanced quality and system integrity tion cost, they also can allow pharmacy for a defined period of time. Outsourced resources to be used more efficiently (ie, products offer many of the same attri- having a decentralized clinical pharmabutes but may require shorter dating and cists or pharmacy technicians admixing increased pharmacy oversight in con- only necessary compounds).3 Individual health systems must detertracting, etc.3 The combination of these 2 methods along with some pharmacy mine the best way to balance all of these compounding may fit into many work- factors in order to meet their particular flow plans. Facilities may choose to use needs, which can vary widely based on vial-attached systems such as Vial-Mate, patient demographics, institution type, ADD-Vantage, or Mini-Bag Plus to avoid size of pharmacy staff, available storage compounding directly when possible. space, budgets, group purchasing conDetermining which IV drug deliv- tracts, and other financial considerations. ery system is best requires a thorough Still, prevention of medication errors evaluation of the net cost of each prod- whenever possible should be a primauct type before settling on a particular ry goal of any major system. IV comapproach. Pure product acquisition costs pounding has a large potential for errors are not the only costs to consider when to occur. The MEDMARX Data Report, choosing IV drug delivery systems. There which focused on a database of more are time, safety, and risk costs, as well than 400 hospital systems nationwide, as additional expenses related to han- cited 11,239 perioperative errors reportdling, waste, and medication errors that ed voluntarily to the system between should be factored into the analysis. For 1998 and 2005. Of the errors reported to
MEDMARX, dosing errors accounted for 17%; drug preparation errors accounted for 5%.4 The Joint Commission and state boards of pharmacy empower directors of pharmacy to implement the systems that fulfill the needs of their institutions (Table 2).5 However, a pharmacy director cannot make these decisions in a vacuum. They must be made with input from all relevant departments throughout the institution, including nursing, financial, shipping and receiving, etc. Although pharmacy is involved in coordinating all aspects of the system, the other departments need to weigh in regarding their individual roles. The entire system should be evaluated from top to bottom.
Gearing Up for Implementation Once the drug delivery systems are chosen, they must be implemented the way they are intended to provide their full benefits. Efficient use of these systems will result in optimal cost savings and patient safety improvements. Clearly delineating how the systems will be used and the specific roles of the various staff in the process will greatly assist in the program’s implementation. The components of implementation include purchasing all required products and addressing storage needs. Training staff is a mandatory step in this process that is often overlooked. Errors may occur when the staff uses a new drug delivery system without fully understanding the features of the system. Certain aspects of implementing a new drug delivery system may discourage staff as unfamiliar steps may be required. These areas need to be discussed and resolved before the system is implemented.
Staff Training and Documentation Additional regulations and technical requirements are involved when
make specific suggestions. Another option is to use Lean Six Sigma principles and statistics to analyze current processes and compare with desired future state.7 Defining the process, collecting and analyzing the data, and identifying opportunities will assist in developing and presenting the justification for the drug delivery system chosen by identifying variables and results to support the decision.
Table 2. Summary of the ASHP Statement on the Role of the Pharmacist in the Selection of IV Drug Delivery Systems Evaluate and research the direct and comparative efficacy, safety, and cost-effectiveness of specific drug delivery systems and administration devices. Work with all appropriate medical and administrative staff on the selection or exclusion of particular drug delivery systems and administration devices for use in specific organizational settings. Assist in the development of organization-specific policies and procedures regarding the acquisition, storage, distribution, use, maintenance, and ongoing product quality control of drug delivery systems and administration devices.
Conclusion IV delivery systems are a major consideration with regard to patient safety. Institutions must ensure policies and procedures match the actual use of product and that all involved staff are properly trained on the use of the system being implemented. This reevaluation process should take into account changes in technology as well as new products that may offer increased efficiency and/or safety.
Assist in the selection of a particular drug delivery system or administration device for use in a specific patient’s drug therapy. Instruct patients on the use of such systems and devices and to gather information necessary to monitor the outcome of their therapy. Monitor the clinical effectiveness and suitability of specific drug delivery systems or administration devices with respect to specific patients and communicate clinically relevant observations and recommendations to prescribers and other health professionals involved in the patients’ care.
ASHP, American Society of Health-System Pharmacists; IV, intravenous Adapted from reference 5.
admixtures are compounded in the pharmacy. USP Chapter <797> defines the processes that are required to provide a highquality environment and the appropriately trained personnel to accomplish the compounding of IV solutions in each practice setting. When a pharmacy prepares admixtures it must be done using specific policies and procedures to operate with a high degree of quality. System-specific training is required for all personnel using the IV delivery system. Appropriate space and additional equipment are required to make certain the system does not encounter unnecessary obstacles.6 In addition, there are specific requirements with respect to the design of appropriate clean rooms and anterooms, the use of gowns and gloves, as well as monitoring and reporting. A published gap analysis tool is available from the American Society of Health-System Pharmacists (ASHP)
to help evaluate pharmacy-compounding programs.6 Several recent market introductions of training modules (ie, a CDROM from ASHP and an online program from Baxter Healthcare) also are available to assist in the training and documentation of pharmacy staff.
Optimizing Pharmacy Processes Consulting groups can assist health systems in evaluating the best approaches. One such group is Baxter Healthcare’s pharmacy services group. This group will consult with a facility and use several analysis and implementation tools to maximize the effectiveness and efficiency of the institution’s IV delivery system. They can also evaluate staffing components, available space and equipment, and policies and procedures already in place, and
Sanborn MS, Moody ML, Harder KA, et al. Second consensus development conference on the safety of intravenous drug delivery systems—2008. Am J Health Syst Pharm. 2009;66:185-192.
Coe CP, Uselton JP. Assuring Continuous Compliance with Joint Commission Standards: A Pharmacy Guide. 7th ed. Bethesda, MD: ASHP, 2008.
Van Hassel T. Evaluating outsourced compounding. PPPMag. 2009;6(1):6-10.
Hicks RW, Becker SC, Cousins DD. MEDMARX Data Report: A Chartbook of Medication Error Findings from the Perioperative Settings from 1998-2005. Rockville, MD: USP Center for the Advancement of Patient Safety; 2006.
American Society of Health-System Pharmacists. Best Practices for Hospital & Health-System Pharmacy 2008-2009. Bethesda, MD: 2008.
American Society of Health-System Pharmacists. The ASHP Discussion Guide on USP Chapter <797>. http://www.ashp.org/s_ashp/docs/files/DiscGuide797-2008.pdf. Accessed October 20, 2009.
Lean Six Sigma and Design for Six Sigma Training. http://www.sixsigmaonline.org/lean-six-sigma/. Accessed October 20, 2009.
Baxter, Vial-Mate, and Mini-Bag Plus are trademarks of Baxter International Inc. ADD-Vantage is a trademark of Hospira Inc.
PHARMACY PRACTICE NEWS • NOVEMBER 2009
with distinct labeling from Baxter. Coming soonâ€Śdistinctive labeling from Baxter. To learn more, contact your Baxter representative or call 1-800-4-BAXTER (1-800-422-9837).
Baxter, Committed to a Safer Healthcare Environment, and the distinctive product label design are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111085 03/09
Up Front 9
Pharmacy Practice News • November 2009
Inspiration, Perspiration Fuel Research Honorees Rural pharmacy, nutrition and medication safety among topics garnering gold stars from ASHP Foundation
he began taking classes at Purdue University in Indiana at the age of 10. Eight years later, already in her fifth year at the university’s School of Pharmacy, she was honored by the president of her parents’ homeland, Syria’s Bashar AlAssad, along with her two high-achieving siblings. At 19, she received her doctorate of pharmacy. Today, the only question for the 24-year-old winner of the American Society of Health-System Pharmacists (ASHP) Foundation’s 2009 Pharmacy Practice Research Award is whether all this success is going to her head. No chance. “I was so humbled just to be nominated,” said Yaman Kaakeh, PharmD, BCPS, the modest and personable clinical assistant professor of pharmacy practice at Purdue. “To hear that we won the award, I was ecstatic. It was a great team effort from my co-authors and me.” The youngest of the ASHP Foundation’s five literature award winners this year, Dr. Kaakeh was honored for a paper published last January in the American Journal of Health-System Pharmacy (2008;65:49-54) on a quick, simple method for verifying the identity and concentration of high-risk IV medications. “Technology in IV medication preparation has been so lacking,” said Dr. Kaakeh. “We’ve had a lot of systems for keeping track of tablets and capsules, but nothing to verify what is in an IV medication besides what the pharmacist says.” While doing her residency in pharmacy practice from 2005 to 2006 at the University of Michigan Health System in Ann Arbor, she and colleagues had access to the Department of Pharmacy Services’ tabletop enhanced photoemission spectroscopy (EPS) device, ValiMed, manufactured by CDEX, Inc. They used it to test seven high-risk drugs compounded in the pharmacy, including vancomycin, lorazepam, morphine, insulin, hydromorphone, gentamicin and epinephrine. They found that the EPS device successfully detected errors departing from the targeted concentration by 20% or more, with a sensitivity of at least 95%. Specificity in distinguishing among test medications at targeted concentrations was 100%. “We were concerned about it impeding work flow, but it added only about a minute of testing time,” she said. And the benefits were substantial: “In the first 18 months, it prevented five serious and potentially deadly medication errors in the University of Michigan. I think the device is especially beneficial in pediatric units, where small dosing errors can have fatal consequences.”
Although admitting that some assume such a precocious achiever must have no life outside of work, Dr. Kaakeh said her parents had always emphasized the importance of leading a balanced life. “I do spend a lot of time with my friends and family,” she said. “I like to play tennis, and I’m an artist too. I do oil painting and charcoal. It’s a lot of fun.”
Support Service at the Regional Medical Center in Memphis, Dr. Dickerson has notched up more than 140 publications, more than 160 professional presentations, and research grants and clinical contracts in excess of $3 million. Along the way, he has trained 42 advanced pharmacy residents and fellows. To this day, one of his proudest
‘I think the [ValiMed IV scanning] device is especially beneficial in pediatric units, where small dosing errors can have fatal consequences.’ —Yaman Kaakeh, PharmD ‘I Wanted To Be Like Mr. Baker’ Having received his doctorate in pharmacy before Dr. Kaakeh was born, Roland N. Dickerson, PharmD, BCNSP, FACN, FCCP, has come quite a long way since growing up in the small city of Plattsburgh, N.Y., an hour south of Montreal.
achievements is research he published with physician James L. Mullen showing that obese patients fared better on low-calorie, high-protein parenteral nutrition than they did on what was then standard treatment, a higher calorie diet designed to maintain weight
‘I wanted to be like Mr. Baker [the local pharmacist], to help people. It was a mom-andpop kind of shop on the corner close to our home.’ —Roland N. Dickerson, PharmD “My parents didn’t always have the money to go to the doctor every time I was sick,” said Dr. Dickerson, winner of this year’s ASHP Foundation award for Sustained Contributions to the Literature of Pharmacy Practice. “Sometimes we’d go to the local pharmacist, back in the 1960s, and he was kind of practicing advanced ambulatory
(Am J Clin Nutr 1986;44:747-755). “People said, ‘You can’t do that, you’ll starve these patients.’ They didn’t think these patients would be able to heal their wounds and fight infections. We showed that they had fewer infections, needed fewer days of feeding and ventilation and lost weight too [Nutrition 2002;18:241-246]. As a result of those
‘Nobody would fund us. They said, “Everybody knows it’s not the lipids causing the problem.” It was very much going against common practice.’ —Kathleen M. Gura, PharmD care,” he said. “If I had a bad bee sting, he’d fix me up. If I had an infection, he’d tell me when it was time to see the doctor. I thought, I want to be like this guy. I wanted to be like Mr. Baker, to help people. It was a mom-and-pop kind of shop on the corner close to our home.” Today, as professor of clinical pharmacy at the University of Tennessee Health Science Center and clinical pharmacist and clinical coordinator of the Nutrition
studies, it’s pretty much the standard of practice in this country now to give low-calorie, high-protein enteral or parenteral nutrition to obese patients, even in the ICU [intensive care unit].” At the tender age of 53, however, Dr. Dickerson insists, “I’ve still got a lot of kick in me.” Having published a paper last year showing that the efficacy of warfarin is compromised when enteral feeding is not temporarily suspended
(Pharmacotherapy 2008;28:308-313), he’s now at work on research to reduce hyperglycemia in ICU patients with diabetes, and to improve stomach emptying in patients with traumatic brain injury. “I still have a lot of things I need to accomplish,” said the father of three, who has been married to his wife Erin for 29 years. “We’re improving patient care just one little project at a time.” Somewhere, Mr. Baker must be smiling.
Challenging Orthodoxy, Saving Lives Kathleen M. Gura, PharmD, BCNSP, FASHP, is another pharmacist who has dared to challenge conventional wisdom on parenteral nutrition. “In July 2002, I had a 16-year-old patient in our transplant unit who was on TPN [total parenteral nutrition] but had a soy allergy,” said Dr. Gura, this year’s winner of the ASHP Foundation’s Drug Therapy Research Award, and adjunct professor of pharmacy practice at the Massachusetts College of Pharmacy and Health Sciences, Boston. “He was unable to eat and developed essential fatty acid deficiency.” Using the Internet, she located Omegaven, a fish oil–based emulsion sold in Europe and Asia. Although normally mixed with standard soybean oil– based emulsion, she used it exclusively. “Within a couple weeks, the child’s condition reversed and he was able to get off TPN,” Dr. Gura said. “That was seven years ago; he’s gone on to graduate high school and college.” Dr. Gura and her colleague, Mark Puder, MD, found themselves wondering whether the fish oil–based emulsion could play a role in treating parenteral nutrition–associated liver disease, a rare but potentially deadly complication. In a mouse model, they found it quickly reversed the liver dysfunction. They then sought funding for a clinical trial. “Nobody would fund us,” she said. “They said, ‘Everybody knows it’s not the lipids causing the problem.’ It was very much going against common practice.” Thanks in part to the support of famed oncologist Judah Folkman, MD—himself no stranger to skepticism—they finally received funds from their facility, Children’s Hospital in Boston. In 2004, a surgeon there asked them to try the fish oil–based emulsion on a 6-month-old patient awaiting a liver and bowel transplant. The treatment worked as hoped. Since then, with funding from the March of Dimes and two orphan drug grants from the FDA, they have
see INSPIRATION, page 10
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INSPIRATION continued from page 9
continued testing the fish oil-based emulsion. Last year, they published a paper showing the benefits of the treatment. The paper appeared in the journal Pediatrics (2008;121;e678-e686). In September, another paper was published in the Annals of Surgery (2009;250:395-402). “We’re up to 130 patients treated with this protocol,” she said. “The FDA has been extremely, extremely supportive. They’re allowing other hospitals to import the drug. But we still get kids transferred
here from other places. Although the drug is effective, it’s the total care of the patient that’s important.” Married for more than 25 years (to another pharmacist, of course), with two daughters, Dr. Gura credits the support of her family and colleagues at Children’s Hospital. “A lot of time has been spent over the years,” she said. “You see a lot of authors on our latest papers. It takes a team.”
Helping Hospitals in the Wilds Of Minnesota When Timothy P. Stratton, PhD, BCPS,
‘If you’re admitted on Saturday evening at 10 p.m. and your physician writes up a medication order, it wouldn’t get reviewed by a pharmacist until Monday morning without [an Internet-based, remote pharmacy] program like this.’ —Timothy P. Stratton, PhD FAPhA, was asked to help evaluate an after-hours pharmacy coverage program for hospitals in remote northeast Minnesota, he knew just what the pharmacists up there were dealing with.
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“My first job after pharmacy and graduate school was in Sitka, Alaska, a town of 7,000 hardy souls in the southeast panhandle,” said Dr. Stratton, now professor of pharmacy practice at the University of Minnesota College of Pharmacy in Duluth. “I would go into the hospital in the morning, fill the patient bins, go to the drug store for six hours, return to the hospital again, and then be on call all night. Frankly, I burned out.” When eight rural hospitals belonging to the Wilderness Health Care Coalition in northern Minnesota received a $1.3 million federal grant to implement an after-hours, remote pharmacy order entry system with St. Luke’s Hospital in Duluth, Dr. Stratton led the team evaluating the program. “Some of those critical-access hospitals have a pharmacist for as little as one hour a day; others have one during weekdays, but not on nights or weekends,” he said. “So if you’re admitted on Saturday evening at 10 p.m. and your physician writes up a medication order, it wouldn’t get reviewed by a pharmacist until Monday morning without a program like this.” The Internet-based system permitted pharmacists at St. Luke’s to review prescriptions from 200 or more miles away just as they would if the order were coming from down the hall. “It’s just a very long hallway,” quipped Dr. Stratton. “Once the pharmacist verified an order, he would punch a button at St. Luke’s that would release the medication from a Pyxis or an AccuDose up in Bigfork or Deer River.” In the first 20 months of the project, the evaluation documented more than 700 pharmacist interventions from St. Luke’s. The messages most often prevented a drug from being administered to a patient who had a contraindication or prevented an excessive dose of a drug from being administered. “The best story we got was from a little hospital at Moose Lake,” Dr. Stratton said, “where an intravenous medication had been ordered for a pediatric patient, and had originally been written as a 10-fold overdose. The tertiary pharmacist at St. Luke’s caught it and wouldn’t let it be released until the prescriber changed it.” Dr. Stratton’s colleagues on the program, and co-winners of the ASHP Foundation’s Award for Innovation in Pharmacy Practice, were Marcia M. Worley,
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Awards PhD, assistant professor in the university’s Department of Pharmacy Practice and Pharmaceutical Sciences; Mark Schmidt, BS, chief information officer of SISU Medical Systems in Duluth; and Michael Dudzik, BS Pharm, MHA, director of pharmacy at St. Luke’s. Their award-winning paper on the program was published in the American Journal of Health-System Pharmacy (2008; 65:1727-1734).
A Study That Cost Only Time Can a pharmacy student conduct a study without a penny in funding, yet reach findings of clinical significance for the care of patients? Joshua T. Swan decided to find out. While studying toward his PharmD degree at the University of Mississippi, he spoke with his mentor, Daniel M. Riche, PharmD, assistant professor of pharmacy practice and medicine, about his interest in undertaking a study. He was referred to a rheumatologist at the university’s school of medicine, Vikas Majithia, MD, who suggested he conduct a meta-analysis of prior studies on treatments for patients with class V membranous lupus nephritis. “Systemic lupus erythematosus has a renal component,” said Dr. Swan, who obtained his PharmD in May. “There are five different classes of severity. When you get to class V, there’s this membranous type. Normally, patients are leaking out 3 g of protein per day. Historically, there’s been controversy over whether to treat these patients with immune suppression or steroids.” With published clinical trials varying in design, limited in numbers of patients, and often lacking randomized controls, Dr. Swan conducted as thorough a review of the literature as possible, even e-mailing authors of prior studies to obtain original data when possible. After identifying and analyzing 21 studies, he concluded that immunosuppressive therapy resulted in a significantly higher rate of partial or total remission than did steroid therapy alone. Dr. Swan presented the finished paper in February at the Southern Regional Meeting of the Southern Society for Clinical Investigation. “That was kind of cool—I was the only pharmacist there,” he said. After the paper won the meeting’s Centocor Scholar Award in Rheumatology, Dr. Swan decided to submit it to the Journal of the American Society of Nephrology. First, however, he combined data from a newly published randomized trial, which had likewise found immunosuppressive therapy to be significantly more beneficial than steroids alone. Now in the process of a revision requested by the journal, his original manuscript has received
Conducting a meta-analysis ‘is a way to get involved in research without being clinically licensed to practice, and it doesn’t require any funding. It was a really good way for me to participate and do something meaningful.’ —Joshua T. Swan, PharmD the ASHP Foundation’s Student Research Award. “I am truly humbled,” he said. “Getting into academia as a clinical pharmacy researcher—that’s my pie-in-
the-sky dream.” First, however, Dr. Swan wants to complete his postgraduate year-1 residency at Methodist Hospital in Houston. At 24 years old and already in
his second year of marriage to his high school sweetheart, Samantha, he encouraged other pharmacy students to consider meta-analysis as a fruitful type of study that costs nothing but time—lots and lots of time. “I’ve put in hundreds of hours,” he said. “But it is a way to get involved in research without being clinically licensed to practice, and it doesn’t require any funding. It was a really good way for me to participate and do something meaningful.” —Dan Hurley
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12 Up Front
Pharmacy Practice News • November 2009
Pain Speeds Functional Aging Process
ndividuals who describe themselves as having persistent pain demonstrated functional limitations commensurate with healthy individuals two to three decades older, according to the results of a new cross-sectional study. According to the investigators, this is the first study to measure the effects of pain on loss of function as it relates to age. The association between significant pain and functional disability was seen in patients as young as their early 50s. Researchers from the University of California, San Francisco, led by Kenneth Covinsky, MD, professor of medicine and Edmund G. Brown Sr., distinguished professorship in geriatrics in the Department of Medicine
of the Division of Geriatrics, used data from the 2004 Health and Retirement study (N=18,531; age <50) to gauge age-related functional ability. For the purpose of this study, significant pain was defined as moderate or severe intensity pain experienced by an individual “most of the time.” Function was assessed using four domains: mobility (e.g., ability to walk one mile), stair climbing (e.g., ability to ascend one flight), upper extremity tasks and activities of daily living (ADLs; e.g., bathing, dressing, eating, with or without assistance). Adjustments were made for demographics, socioeconomic factors, comorbid medical conditions, depression, obesity and
health-related habits such as smoking. The investigators found that 24% of study participants reported significant pain. In all four domains, subjects with significant pain had much greater functional disability than individuals of a similar age without pain. Mobility in individuals in the 50 to 59 age range, for example, differed greatly between the significant and nonsignificant pain groups, with 9% of participants in the former saying they were able to run or jog a mile compared with 37% in the latter. Moreover, 4% of 80- to 89-year-olds with no pain felt they could jog one mile
(adjusted odds ratio [AOR], 2.85; 95% confidence interval [CI], 2.20-3.69). Similar results were seen for stair climbing (AOR, 2.84; 95% CI, 2.48-3.26), upper extremity tasks (AOR, 3.96; 95% CI, 3.43-4.58) and ADLs (AOR, 4.33; 95% CI, 3.71-5.06). “Participants with pain were similar in terms of their degree of functional limitation to participants two to three decades older,” wrote the authors. The results appear in the Journal of the American Geriatrics Society (2009 Aug 4 [Epub ahead of print]).
HBV Vaccination Tames Hepatocellular Carcinoma
universal hepatitis B virus (HBV) vaccine program, launched in Taiwan in July 1984, has yielded a dramatic reduction in the incidence of hepatocellular carcinoma (HCC). Researchers reported a 70% reduction in the risk for HCC among those who received the vaccine compared with an unvaccinated control group. The results recently were reported in the Journal of the National Cancer Institute (2009 Sep 16 [Epub ahead of print]). HBV, a major cause of HCC, is common in Taiwan. The authors of this study, made up of researchers from around Taiwan and the Taiwan Hepatoma Study Group, aimed to determine if the national HBV vaccine program offered protection against HCC beyond early childhood. Additionally, they sought to identify predictors of HCC in vaccinated cohorts. Investigators mined data from two
national HCC registries and identified 1,958 patients who were aged 6 to 29 years at the time of HCC diagnosis between 1983 and 2004. These records were analyzed to compare HBV immunization characteristics during infancy, and prenatal maternal hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) serostatus among vaccinated and unvaccinated birth cohorts. The authors identified significantly fewer cases of later HCC among HBV vaccinated compared with unvaccinated newborns (64 HCC cases in 37,709,304 person-years vs. 444 HCC cases in 78,496,406 personyears among vaccinated and unvaccinated subjects, respectively). Poisson regression models revealed an age- and sex-adjusted relative risk for HCC of 0.31 for vaccinated subjects (P<0.001).
Among those vaccinated for HBV, the risk for developing HCC was associated with incomplete HBV vaccination (odds ratio [OR], 4.32; 95% confidence interval [CI], 2.34-7.91); prenatal maternal HBsAg seropositivity (OR, 29.50; 95% CI, 13.98-62.60); and prenatal maternal HBeAg seropositivity (OR, 5.13; 95% CI, 2.24-11.71 for those administered hepatitis B immunoglobulin at birth; OR, 9.43; 95% CI, 3.54-25.11 for those who did not receive hepatitis B immunoglobulin). The authors concluded that “the prevention of [HCC] by this HBV vaccine extends from childhood to early adulthood. Failure to prevent hepatocellular carcinoma results mostly from unsuccessful control of HBV infection by highly infectious mothers.” —Cynthia J. Gordon, PhD
Racial Link to HBV Recurrence Noted
he recurrence rate of hepatitis B virus (HBV) infection after liver transplantation appears higher among white patients than among Asian and black patients. This is according to a study published in the September issue of Liver Transplantation, which reported four-year HBV recurrence rates that were three times higher in whites than in Asians and blacks. The authors of the study described the finding as “surprising,” especially in light of three earlier studies that reported similar or higher HBV recurrence rates among Asians (Transplantation 1994;57:1393-1395; Hepatology 1997;25:223-225; Hepatology 2001;34:126-132). “This finding is inexplicable and needs to be validated,” wrote the authors of the current study, who included investigators from California Pacific Medical Center, San Francisco, and the National Institutes of Health Hepatitis B Virus Orthotopic Liver Transplantation Study Group. The study included 274 patients (116,
white; 135, Asian; 23, black) from 15 centers in the United States who were listed for liver transplant because of HBVrelated liver disease. Recurrence rates of HBV were significantly higher among white liver transplant recipients, at 19% compared with 7% in Asian patients and 6% in black patients (P=0.043 for both). Notably, the difference in HBV recurrence occurred “despite similar HBeAg [hepatitis B envelope antigen] and HBV DNA status (at listing and at transplant), use of antiviral therapy pre-transplant, occurrence of virological breakthrough/ confirmed genotypic resistance to antiviral therapy pre-transplant and use of antiviral and [hepatitis B immune globulin] prophylaxis post-transplant.” A Cox regression analysis of the data revealed that HBeAg status at listing was the only factor significantly associated with HBV recurrence post-transplant (P=0.003). Other outcomes examined by the study authors were similar among the groups. The likelihood of undergoing transplantation one, three and five years after listing was 48%, 57% and
63% for whites; 48%, 58% and 66% for Asians; and 53%, 75% and 88% for blacks. A total of 24 patients died while on the transplant wait list, including 15 (13%) whites, six (4%) Asians and three (13%) blacks, with the probability of wait list mortality similar in all three groups at one, three and five years after listing (P=0.15). After transplantation, 19 patients had died at a median follow-up of 31 months (seven, white; 11, Asian; one, black). The probability of survival at five years after transplantation was similar among all groups (89% for whites, 85% for Asians and 94% for blacks; P=0.93). Hepatocellular carcinoma recurrence was the only predictor of post-transplant mortality. The authors concluded that the “finding of a higher rate of HBV recurrence among Caucasians needs to be validated in other studies,” leaving the door open to further research. —Cynthia J. Gordon, PhD
FDA Approves Asacol HD for Moderately Active Colitis
sacol HD, mesalamine delayedrelease tablets from Procter & Gamble Pharmaceuticals, indicated for the treatment of moderately active ulcerative colitis (UC), has been approved by the FDA. The approval was based on evaluations from the ASCEND (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA [4.8 g/d, 800 mg tablet]) studies. In six-week clinical studies of moderately active UC flares, Asacol HD at 4.8 g per day helped many patients reduce their UC symptoms, including number of bowel movements and rectal bleeding, for some as early as three weeks. Asacol HD decreased the number of trips to the bathroom (i.e., number of bowel movements) in approximately three out of four of patients by six weeks and decreased rectal bleeding for approximately 80% of patients by six weeks. The recommended dose of Asacol HD for adults is two 800-mg tablets, three times per day, with or without food, for a total daily dose of 4.8 g. Asacol HD is the newest addition to Procter & Gamble’s gastrointestinal product line, which also includes Asacol 400 mg delayed-release tablets, the most prescribed oral 5-ASA therapy, according to information derived from IMS National Prescription Data. If for any reason a patient is dissatisfied with the first course of therapy, Procter & Gamble will refund the receipted cost of the original prescription. Receipted cost includes only the amount actually paid by the patient. Procter & Gamble will not refund costs covered by third-party payers, including Medicaid.
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Pharmacy Takes Center Stage Game shows, morning TV spots are all fodder for annual professional outreach to public
ealth-system pharmacists stepped out from their largely behind-thescenes roles in October to celebrate the profession and to educate the communities they serve about the safe use of commonly prescribed medications. In the process, these ambassadors also encouraged physicians, nurses and other institutional caregivers to use more pharmacy services and to learn about the less visible skills the profession brings to the table. Among them: pharmacy’s often high-technology approach to the delivery of drug therapy, keen efficiencies, quick processes and measurable safety practices that promote cost-effective patient care. Interviews with experts at the American Pharmacists Association (APhA), which heads American Pharmacist Month, and the American Society of Health-System Pharmacists (ASHP), which leads National Hospital & Health-System Pharmacy Week (the third week of October), underscored why this annual celebratory period for pharmacy makes a difference for pharmacists, student pharmacists and technicians, and their multiple audiences—inpatients, outpatients, discharged patients, caregivers and their families. “These observances serve the important purpose of raising the awareness of patients about the vital role that pharmacists play on the health care team,” said Kasey K. Thompson, PharmD, vice president of policy, planning and communications at ASHP. “Equally important, these activities also affirm the work of the pharmacy staff and their efforts to ensure that medication use at their practice sites is safe and effective.” For his part, Ed Hamilton, PharmD, FAPhA, the current president of APhA
Johns Hopkins Hospital pharmacists dressed up as unit-dose medications for a theme party during National Hospital & Health-System Pharmacy Week.
(2009-2010 term) and director of pharmacy at Winter Haven Hospital Regency Center for Women and Infants, Winter Haven, Fla., wants to honor “where we’ve come from, and continue to progress to where we want to go, to provide continuity of care. Although we practice pharmacy today in silos—the hospital, the community, the nursing home and other settings—we can help improve outcomes if we use technology like electronic records to capture and share information, and communicate with each other as patients pass back and forth between us.” Dr. Hamilton said the outreach efforts also serve as “a platform to spotlight what we do, and let other decision mak-
During American Pharmacist Month in October, students from St. John’s University School of Pharmacy appeared on “Good Morning America” to promote the APhA’s “Know Your Medicine, Know Your Pharmacist” awareness campaign.
ers know we are capable and available to do more to advance patient safety, monitor lab values, collaborate on medication doses and protocols with physicians and nurses, and consult with patients.”
Medication Lists are Crucial If the October spotlight helps close the circle between patients and pharmacists in different settings, it benefits everyone, suggested Sharon Corbitt, director of external communications, APhA. For example, one aspect of APhA’s ongoing campaign, “Know Your Medicine, Know Your Pharmacist,” stresses how having a current medication list on hand—especially for elderly, chronically ill, multiplemedication patients—facilitates the task of emergency responders and hospital staff doing medication reconciliation. “Consumers should be sharing their list with all of their health care providers to minimize the risk for improper dosing, duplicating medications and harmful drug interactions and side effects,” said Kristen Binaso, RPh, CCP, FASCP, senior director-corporate alliances at APhA, and a pharmacist at Target. Yet a newly released Harris Interactive survey commissioned by APhA found that only 28% of Americans carry their current medication list at all times. Half of those who don’t (49%) said they “never thought about it,” and another one-third (36%) “have no desire or need to carry the list.” Moreover, “although pharmacists are the medication experts, 77% of consumers don’t know their pharmacists’ name, and only 40% have asked their pharmacist questions about their health
care needs in the past year,” explained Ms. Corbitt. Recognizing that such distance exists between pharmacists and community residents who one day may land in their health system’s beds as patients, or arrive as outpatients, hospital pharmacy teams across the United States have made community outreach a significant part of their October pharmacy spotlight events. Pharmacy directors and other event organizers interviewed by Pharmacy Practice News said they saw the public as their primary audience, at least as central as their internal hospital teams. To that end, Sibley Memorial Hospital, in northwest Washington, D.C., was due at press time to host a two-hour Medication Safety Fair at a local church during one day of the National Hospital & Health-System Pharmacy Week. Two pharmacists were to be on hand to review medication lists, discuss potential interactions, answer questions and reinforce the importance of keeping a current list with you at all times. “My grandparents don’t keep their lists. I keep telling them. This issue touches everyone,” said Trinh Le, MS, RPh, director of pharmacy at the 328-bed nonprofit hospital, who planned this event with a case coordinator. “We see ourselves as group educators. It’s not about us. It’s about helping everyone else. We tell them, ‘we don’t want to see you wind up in the hospital,’” she added, noting the fair ran all day in the hospital a year ago and drew positive feedback. “People in our community are well educated. They’ll ask us good questions, and we’ll hopefully help prevent adverse reactions with their medications, herbs, OTC [over-the-counter] drugs and foods.” On a broader scale, Ms. Binaso represented APhA on a blitz of 18 national and regional media interviews on Oct. 1. Also, student chapters of ASHP and APhA donned their white coats and gathered by the outdoor settings of the “Today Show,” the “Early Show” and “Good Morning America” that same day, seeking to attract the anchors and gain some airtime, which has happened in the past. Additionally, APhA past president Jan Engle, PharmD appeared on a segment of “The Oz Show” on Wednesday, Oct. 14, discussing medication errors. On a local level, APhA employees were encouraged to visit their community pharmacists to thank them for their service.
A Spring Awakening To Medication Safety The public also gets another dose of Sibley’s Medication Safety Fair in the
see CENTER STAGE, page 14
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spring, when the central topic usually is the safe storage of medication. To Ms. Le, however, the timing of the October-based fair signifies her department’s focus on community, at a time when hospital peers would anticipate an internal focus instead. “Our goals are multiple this week—to teach our community about medication safety, and to educate hospital staff about what pharmacy does so they can rely on us more as part of the medication management team,” she said. “We’re lucky because our 22 pharmacists are decentralized [the 20 technicians are not]. We have visibility on the floors because we do clinical rounds. Because we also have pharmacists assigned to the medical-surgery and intensive care units, and Sibley Renaissance, our orthopedic rehabilitation inpatient facility, most physicians and nurses already know our roles.” Still, pharmacy plies nurses with candy when they tour the central pharmacy in the basement during this week, to get a sense of the order, the processes, the technology and dedication to safety that color the pharmacy. “Their usual reaction “is ‘wow, you’re really busy.’” Although the weeklong celebration is low key, it is noticed through e-mails sent directly to the entire hospital staff, and coverage in the hospital’s monthly newsletter. Planned within the pharmacy is a staff breakfast and lunch, and special recognition for the pharmacy technicians.
Johns Hopkins Hospital: Let The (Pharmacy) Games Begin A pharmacy committee charged with infusing fun into the week’s education and outreach has turned to games as an effective teaching tool. The collaborative effort represents the central pharmacy, the six outpatient pharmacies and the five satellite pharmacies throughout the nearly 1,000-bed Johns Hopkins Hospital, in Baltimore, explained Yvonne Czyz, PharmD, MBA, clinical pharmacist and pharmacy educator. At display tables staffed by pharmacists and technicians—which are set up for two days outside of the high-traffic main cafeteria, for three days outside an outpatient pharmacy and for one day within an outpatient pharmacy—passersby are drawn in by: • A pharmacy Jeopardy game, dressed up with a television monitor and laptop, which “reinforces key questions we felt people needed to learn about pharmacy and safe medication practices,” said Dr. Czyz. • A look-alike medication quiz. Participants look into a clear pillbox and guess which is the candy and which is the medication. They also look inside a drinking glass and guess which is the
Powerade and which is the Windex. This reinforces Poison Control Center handouts dispensed at the table, which include instructions and contact information. “People who stop by open up to us. We hear lots of personal stories and make that important connection,” added Dr. Czyz, who has run these pharmacycentered games previously, with good effect. “Many families of inpatients stop by the cafeteria table, and we hear their concerns about a loved one in a compromised health condition. At the outpatient pharmacies, we see the patients
‘Although pharmacists are the medication experts, 77% of consumers don’t know their pharmacists’ name, and only 40% have asked their pharmacist questions about their health care needs in the past year.’
themselves. We always try to guide them in the right direction, and back to their permanent care providers.” Monitors by the elevators and the cafeteria, a poster board mounted on an easel by the table, and write-ups in the hospital-wide and pharmacy department newsletters, promote the helpful
information available, plus other events scheduled such as: • Medication Brown Bag Days, where pharmacists review medications that people bring in. • Leg Health Day, where certified staff members discuss OTC compression stockings or support hosiery. “This is
The risks associated with cattle thrombin may stay with patients long after surgery
Patients with antibodies to cattle thrombin products should not be re-exposed due to the risk of developing postsurgical immune-mediated coagulopathy.22 In a recent clinical trial, 1 in 6 surgical patients with likely prior exposure to cattle thrombin had antibodies to cattle thrombin.33 Minimize these risks with RECOTHROM RECOTHROM, the only recombinant human thrombin, is 100% free 4,5 of cattle plasma and as effective as cattle thrombin.4,5 In a phase 3 study of RECOTHROM compared to cattle thrombin, adverse events were reported with similar frequency in both treatment groups, and no reported adverse events were considered causally related to antibody formation in either group. Limited data (n=6) exist regarding re-exposure to RECOTHROM.
Rethink your thrombin
Indication: RECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. Important Safety Information: For topical use only—do not inject directly into the circulatory system. Potential risk of thrombosis if absorbed systemically. Do not use for the treatment of massive or brisk arterial bleeding or in patients with known
hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins. No speci¾c adverse events have been established as adverse reactions causally related to RECOTHROM administration. In a clinical study comparing RECOTHROM to bovine thrombin, adverse events were reported with similar frequency in both treatment groups. The most common event was incision site complication. Limited data (n=6) are available on repeat exposure to RECOTHROM.
Up Front 15
Pharmacy Practice News • November 2009
Events aimed at health care staff, food service, retail and construction workers who stand or sit all day long and want to improve blood circulation or prevent swelling,” said Dr. Czyz. Because the Hopkins pharmacy team is spread out and numbers a couple of hundred, the committee arranged theme parties “so everyone could feel they have a chance to participate. Each area of pharmacy chooses a theme, which builds camaraderie,” she noted, recalling one prior year’s winning team dressed up as unit-dose medications. There’s a three-foot-tall trophy and
bragging rights at stake, too.
The Cleveland Clinic Embraces Public Education, Staff Recognition David Kvancz, MS, RPh, chief pharmacy officer, The Cleveland Clinic, Ohio, thinks the right balance for the week includes heavy doses of patient outreach and staff recognition, plus a subtly expanded visibility into what pharmacy does day in and day out. To that end, he has empowered Mandy Leonard, PharmD, BCPS, RPh, assistant director for pharmacotherapy services, and man-
Please see Brief Summary of full Prescribing Information on next page. References: References: 1. 1. Ness Ness P,P, Creer Creer M, M, Rodgers Rodgers GM, GM, et et al; al; the the Recognition, Recognition, Evaluation Evaluation and and Treatment Treatment of of Acquired Acquired Coagulopathy Coagulopathy Consensus Consensus (RETACC) (RETACC) Panel. Panel. Building Building an an immune-mediated immune-mediated coagulopathy coagulopathy consensus: consensus: early early recognition recognition and and evaluation evaluation to to enhance enhance post-surgical post-surgical patient patient safety. safety. Patient Patient Saf Saf Surg. Surg. 2009;3(1):8. 2009;3(1):8. 2. 2. Thrombin-JMI Thrombin-JMI [package [package insert]. insert]. Bristol, Bristol, TN: TN: King King Pharmaceuticals, Pharmaceuticals, Inc.; Inc.; 2007. 2007. 3. 3. Singla Singla NK, NK, Ballard Ballard JL, JL, Moneta Moneta G, G, Randleman Randleman CD CD Jr, Jr, Renkens Renkens KL, KL, Alexander Alexander WA. WA. AA phase phase 3b, 3b, open-label, open-label, single-group single-group immunogenicity immunogenicity and and safety safety study study of of topical topical recombinant recombinant thrombin thrombin inin surgical surgical hemostasis. hemostasis. JJ Am Am Coll Coll Surg. Surg. 2009;209(1):68-74. 2009;209(1):68-74. 4. 4. Chapman Chapman WC, WC, Singla Singla N, N, Genyk Genyk Y,Y, et et al. al. AA phase phase 3,3, randomized, randomized, double-blind double-blind comparative comparative study study of of the the ef¾ ef¾cacy cacy and and safety safety of of topical topical recombinant recombinant human human thrombin thrombin and and bovine bovine thrombin thrombin inin surgical surgical hemostasis. hemostasis. JJ Am Am Coll Coll Surg. Surg. 2007;205(2):256-265. 2007;205(2):256-265. 5. 5. RECOTHROM RECOTHROM [package [package insert]. insert]. Seattle, Seattle, WA: WA: ZymoGenetics, ZymoGenetics, Inc.; Inc.; 2009. 2009. RECOTHROM RECOTHROM isis aa registered registered trademark trademark of of ZymoGenetics, ZymoGenetics, Inc. Inc. ©2009 ©2009 ZymoGenetics, ZymoGenetics, Inc. Inc. All All rights rights reserved. reserved. RT264-00, RT264-00, July July 2009 2009
ager of the Drug Information Center, to evolve the celebration program these past five years into a multifaceted event. For example, a table staffed by pharmacists near the cafeteria for a day or two will be filled with lots of useful carry items—medication list cards, magnets and pill organizers imprinted with the phone numbers of the health system’s 10 nonprofit retail pharmacies open to patients and employees. One-on-one conversations at the table, as well as separate brown bag events, will help keep people on course with their medications. The department also developed an
To learn more, call 1-888-784-7662 or visit www.RECOTHROM.com
educational PowerPoint presentation that will roll through 52 flat-screen monitors in the health system’s main skyway connecting different parts of the campus. About 20 slides in length, the presentation highlights the pharmacy staff, the services it provides and outcomes for several of its programs. A few examples from the narrative: “We dispense a medication dose every 4.3 seconds. We prepare over 1,000 IV admixtures a day. We manage over 2,200 anticoagulation patients per month. We answer between 200 and 250 questions a month in the
see CENTER STAGE, page 16
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION
16 Up Front
Pharmacy Practice News • November 2009
RECOTHROM Thrombin, topical (Recombinant)
Events Rx Only The following is a brief summary of the full prescribing information for RECOTHROM Thrombin, topical (Recombinant). INDICATIONS AND USAGE RECOTHROM Thrombin, topical (Recombinant), is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. RECOTHROM may be used in conjunction with an absorbable gelatin sponge, USP. DOSAGE AND ADMINISTRATION For topical use only. DO NOT INJECT.
with absorbable gelatin sponge. The amount required depends upon the area of tissue to be treated.
CENTER STAGE continued from page 15
Drug Information Center. On any given day, Cleveland Clinic has over 8,000 visitors to the campus.” Also new is a short video (about four minutes) that presents a thematic program for the pharmacy department for the next few years. “The theme of the video is ‘Pharmacy Cares,’ along with subthemes that reflect how we are committed, accountable and responsible for excellence in every service area or job function we have,” Dr. Leonard said. “Our previous theme spoke to our culture of change and innovation.”
cal pharmacist on the critical care team. To encourage discussion with inpatients about medications they receive at the hospital or take at home, CoxHealth purchased tent cards from ASHP (part of the Just Ask campaign) to be placed on meal trays this week. “Ask the nurse to find us,” the cards instruct. “If enough do, and the outreach seems beneficial, we may look to continue this program yearround,” she added. The Saving Grace program, also launched in October, could have a longer life at CoxHealth if people respond well to pharmacy residents’ efforts to promote the program. The department used its internal print shop to print forms
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS Do not inject directly into the circulatory system. Do not use for the treatment of massive or brisk arterial bleeding.
‘Along with our administration, we say “what if ” to improving the quality of care and efficiencies, and decreasing costs. We’re always working toward higher levels of patient safety.’ —Ed Hamilton, PharmD
any components of RECOTHROM, or hamster proteins. WARNINGS AND PRECAUTIONS Potential risk of thrombosis if absorbed systemically. potential for allergic reaction. ADVERSE REACTIONS
RECOTHROM to bovine thrombin,1 adverse events were reported with similar frequency in the two treatment groups, and the most common events reported were incision site complication, procedural pain, and nausea.
human thrombin. Antibodies against bovine thrombin product were not tested either group did not lead to any adverse events such as excessive bleeding.
To report SUSPECTED ADVERSE REACTIONS, contact ZymoGenetics, Inc. at 1-888-784-7662, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS
The decentralized department has visibility with more than 350 employees, including about 20 clinical specialists who round with physicians, close to a dozen nursing unit-based pharmacists, and satellite pharmacists in oncology, pediatrics and intensive care units. Technicians are on the floors regularly, stocking Pyxis cabinets and delivering medications. To recognize high achievers across this spread-out team, monthly awards are overseen by the volunteer Pharmacy Awards Council, and culminate in a series of five annual awards presented at a luncheon during this celebratory week. The awards acknowledge excellence in supporting world-class service, the department mission, promoting the profession of pharmacy, education and research and preceptoring. The twist to these awards is that a colleague makes every nomination, using a link on the department’s Web site. Last year, there were 99 nominations, “an active process,” Mr. Kvancz said. There also will be a special pinning ceremony for pharmacy technicians who are certified by the state of Ohio, a requirement by April 2010. And all department employees will receive a gift, a foldable chair; in past years, people received logoed jackets, coolers and lunch boxes.
CoxHealth: An ‘Out-of-the-Box’ Approach At CoxHealth, a health system of three hospitals, a long-term care facility and 50 physician clinics in Springfield, Mo., “out-of-the-box thinking” colors this week for the decentralized department of 54 pharmacists and 64 technicians, said Ashley Bartelsmeyer, PharmD, clini-
covering a patient’s medical history, medications list, electrocardiograms, and blood work and lab results. The purpose is to have people fill them out, keep them all together in the supplied baggie with name sticker and affix them to their refrigerator at home. A corresponding sticker goes on their front door, “in case emergency responders are ever needed, they can just grab it and go,” Dr. Bartelsmeyer said. “It will be very helpful for them, and for our Emergency Department teams at the hospital trying to do medication reconciliation.” The initial audiences will be discharged patients and clinic patients. “We’ll want our emergency teams to look for these when first-responding,” she said. At informational tables in the hospital’s lobby, pharmacists will discuss different topics each day, such as medications, poison prevention and the primary roles that health-system pharmacists play on the patient-care team. Because CoxHealth has gone to bedside bar-code administration, the pharmacy automation team will be on hand to “demonstrate the safety procedures implemented this past year. The public isn’t aware of this or other behind-thescenes contributions of pharmacy.” Physicians and nurses often show a similar awareness gap regarding the processes behind medication orders, how they get filled and reach the floor, Dr. Bartelsmeyer noted. “They think it should happen extremely fast. However, once they tour the pharmacy, they understand why our standard is ‘within an hour’ for a routine medication and ‘within 15 minutes’ for stat orders. If we say ‘a medication is in the robot,’ they know what we mean,” she added. Therefore, tours one day of the week
Up Front 17
Pharmacy Practice News • November 2009
Events (with coffee and donuts on morning tours and ice cream on evening tours) are designed to open many eyes about the robot, the compounding areas, the narcotic vault, the IV room and more, she explained. The pharmacy staff itself receive either a fun T-shirt that reads, “Do not shake or agitate the pharmacy staff ” or a polo with an embroidered CoxHealth logo. There are bake-offs—“we love food”—and lunches from different drug companies. Technicians recognized on National Technician Day may have the best deal, however: the choice of a
15-minute massage from the Massage Therapy Department or a gift certificate to a nearby eatery.
Two Decades of Outreach At Winter Haven Hospital Dr. Hamilton recalled “various pharmacy celebrations during each of the past 20 years” at the facility. The streak continues this year, as “the profession continues to evolve from being product-centered to being patient-centered, where we fully utilize our skills as health care providers to help patients manage their medications better.”
Pharmacy also will distribute medication-safety handouts, along with the nurses’ favorite from last year: Take Five candy bars, inside Ziploc bags, with sheets displaying the five rights of medication administration—drug, dose, route, time and patient. Following the theme of American Pharmacist Month, “Know Your Medicine, Know Your Pharmacist,” the pharmacy also will “encourage all hospital employees to pick a community pharmacy near their home as selectively as they’d pick a physician,” he said. At press time, the Winter Haven Hospital was planning several lunches to
CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION
Privigen®, Immune Globulin Intravenous (Human), 10% Liquid Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. WARNING: ACUTE RENAL DYSFUNCTION/FAILURE Use of Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death.1 Patients at risk of acute renal failure include those with any degree of pre-existing renal insufﬁciency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Privigen does not contain sucrose. For patients at risk of renal dysfunction or failure, administer Privigen at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]). 1 INDICATIONS AND USAGE Privigen is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the treatment of the following conditions. 1.1 Primary Humoral Immunodeﬁciency Privigen is indicated as replacement therapy for primary humoral immunodeﬁciency (PI). This includes, but is not limited to, the humoral immunodeﬁciency in common variable immunodeﬁciency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeﬁciencies. 1.2 Chronic Immune Thrombocytopenic Purpura Privigen is indicated for the treatment of patients with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts. 3 DOSAGE FORMS AND STRENGTHS Privigen is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion. 4 CONTRAINDICATIONS Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. Because it contains the stabilizer L-proline, Privigen is contraindicated in patients with hyperprolinemia. Privigen is contraindicated in IgA-deﬁcient patients with antibodies to IgA and a history of hypersensitivity. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Severe hypersensitivity reactions may occur (see Contraindications ). In case of hypersensitivity, discontinue the Privigen infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. Privigen contains trace amounts of IgA ( 25 mcg/mL) (see Description ). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Privigen is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction (see Contraindications ). 5.2 Renal Failure Ensure that patients are not volume depleted before administering Privigen. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Privigen. For patients judged to be at risk of developing renal dysfunction, administer Privigen at the minimum infusion rate practicable (see Boxed Warning, Dosage and Administration [2.3]). 5.3 Hyperproteinemia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Privigen and other IGIV product treatments. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events.2 5.4 Thrombotic Events Thrombotic events may occur following treatment with Privigen and other IGIV products.3-5 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Privigen at the minimum rate of infusion practicable (see Dosage and Administration [2.3]). Weigh the potential risks and beneﬁts of IGIV against those of alternative therapies in all patients for whom Privigen therapy is being considered. 5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently with Privigen (see Adverse Reactions [6, 6.1]) and other IGIV product treatments. Discontinuation of IGIV treatment has resulted in remission of AMS
celebrate and show appreciation for its pharmacy staff of 50. “It’s a time to feel good about your profession and to celebrate. It’s a natural instinct to want to do well and be appreciated,” added Dr. Hamilton. “The week also brings focus to what we do, and creates opportunities to identify new things we could [achieve]. Along with our administration, we say ‘what if’ to improving the quality of care and efficiencies, and decreasing costs. We’re always working toward higher levels of patient safety.” —Al Heller
within several days without sequelae.6 AMS usually begins within several hours to 2 days following IGIV treatment. AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting (see Patient Counseling Information ). Cerebrospinal ﬂuid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. 5.6 Hemolysis Privigen may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.7-9 Hemolytic anemia can develop subsequent to Privigen therapy due to enhanced RBC sequestration and/or intravascular RBC destruction.10 Hemolysis, possibly intravascular, occurred in two subjects treated with Privigen in the ITP study (see Adverse Reactions [6, 6.1]). These cases resolved uneventfully. Six other subjects experienced hemolysis in the ITP study as documented from clinical laboratory data. Monitor patients for clinical signs and symptoms of hemolysis (see Patient Counseling Information ). If these are present after Privigen infusion, perform appropriate conﬁrmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. 5.7 Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients following IGIV treatment.11 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions (see Patient Counseling Information ). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient’s serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. 5.8 Volume Overload The high-dose regimen (1 g/kg/day for 2 days) used to treat patients with chronic ITP is not recommended for individuals with expanded ﬂuid volumes or where ﬂuid volume may be of concern (see Dosage and Administration [2.2]). 5.9 Transmissible Infectious Agents Privigen is made from human plasma. Based on effective donor screening and product manufacturing processes (see Description ), Privigen carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered to be extremely remote. No cases of transmission of viral diseases or CJD have been associated with the use of Privigen. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare professional to CSL Behring Pharmacovigilance at 1-866-9156958. Before prescribing Privigen, the physician should discuss the risks and beneﬁts of its use with the patient (see Patient Counseling Information ). 5.10 Monitoring: Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If signs and/or symptoms of hemolysis are present after an infusion of Privigen, perform appropriate laboratory testing for conﬁrmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. 5.11 Interference With Laboratory Tests After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test. 6 ADVERSE REACTIONS The most serious adverse reaction observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject. The most common adverse reactions observed in >10% of clinical study subjects with PI were headache, pain, nausea, fatigue, and chills. The most serious adverse reactions observed in clinical study subjects receiving Privigen for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects. Six other subjects in the ITP study experienced hemolysis as documented from clinical laboratory data (see Warnings and Precautions [5.5, 5.6]). The most common adverse reactions observed in >10% of clinical study subjects with chronic ITP were headache, pyrexia/hyperthermia, and anemia. 6.1 Clinical Trials Experience Because different clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical studies and may not reﬂect the rates observed in practice. Treatment of Primary Humoral Immunodeﬁciency In a prospective, open-label, single-arm, multicenter clinical study, 80 subjects with PI (with a diagnosis of XLA or CVID) received Privigen intravenously every 3 or 4 weeks for up to 12 months (see Clinical Studies [14.1]). All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. Subjects ranged in age from 3 to 69; 57.5% were male and 42.5% were female. The safety analysis included all 80 subjects, 16 on the 3-week schedule and 64 on the 4-week schedule. The median doses of Privigen administered intravenously ranged from 200 to 888 mg/kg every 3 weeks (median dose 428.3 mg/kg) or 4 weeks (median dose 440.6 mg/kg). A
18 Operations & Management
Pharmacy Practice News • November 2009
Making Medications More Affordable for Patients Anaheim, Calif.—Establishing a lowcost pharmacy within a university setting and helping patients enroll in prescription assistance programs are two ways pharmacists can help low-income, uninsured or underinsured patients get their needed medications. Pharmacists with the University of Oklahoma School of Community Medicine in Tulsa and with Duquesne University’s Mylan School of Pharmacy in Pittsburgh presented their cost-saving
ideas last month at the American College of Clinical Pharmacy’s annual meeting. In Tulsa, where more than 18% of the adult population is uninsured, the University of Oklahoma and the St. John Health System Medical Access Program provided funding for three years for a 20-hour per week pharmacy providing prescription services and medication therapy management services. The STEP (Safety, Tolerability, Efficacy and Price) pharmacy, which opened in March, is
total of 1038 infusions of Privigen were administered, 272 in the 3-week schedule and 766 in the 4-week schedule. Of the 1038 infusions, 435 were administered to females and 603 to males. Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related adverse events (AEs) that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered. Temporally associated AEs are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. In this study, the upper bound of the 1-sided 97.5% conﬁdence interval for the proportion of Privigen infusions temporally associated with one or more AEs was 23.8% (actual proportion: 20.8%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 397 (a rate of 0.38 AEs per infusion), reﬂecting that some subjects experienced more than one AE during the observation period. Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Privigen infusion or within 72 hours after the end of an infusion, irrespective of causality. Table 2: Adverse Events Occurring in >5% of Subjects With PI During a Privigen Infusion or Within 72 Hours After the End of an infusion, Irrespective of Causality Adverse Event Subjects (%) [n=80] Infusions (%) [n=1038] Headache 35 (43.8) 82 (7.9) Pain 20 (25.0) 44 (4.2) Fatigue 13 (16.3) 27 (2.6) Nausea 10 (12.5) 19 (1.8) Chills 9 (11.3) 15 (1.4) Vomiting 7 (8.8) 13 (1.3) Pyrexia 6 (7.5) 10 (1.0) Cough 5 (6.3) 5 (0.5) Diarrhea 5 (6.3) 5 (0.5) Stomach discomfort 5 (6.3) 5 (0.5) *Excluding infections.
Of the 397 temporally associated AEs reported for the 80 subjects with PI, the investigators judged 192 to be related to the infusion of Privigen (including 5 serious, severe AEs described below). Of the 187 non-serious AEs related to the infusion of Privigen, 91 were mild, 81 were moderate, 14 were severe, and 1 was of unknown severity. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (29% of subjects), pain (14% of subjects), nausea (11% of subjects), fatigue (11% of subjects), and chills (11% of subjects). Sixteen subjects (20%) experienced 41 serious AEs. Five of these were related severe AEs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature) that occurred in one subject and resulted in the subject’s withdrawal from the study. Two other subjects withdrew from the study due to AEs related to Privigen treatment (chills and headache in one subject; vomiting in the other). Seventy-seven of the 80 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia. During this study, no subjects tested positive for infection due to human immunodeﬁciency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V). Treatment of Chronic Immune Thrombocytopenic Purpura In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less received a total of 2 g/kg dose of Privigen administered as 1 g/kg intravenous infusions daily for 2 consecutive days (see Clinical Studies [14.2]). Subjects ranged in age from 15 to 69; 59.6% were female and 40.4% were male. Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56.1%) subjects received premedication with acetaminophen and/or an antihistamine. Table 3 lists the temporally associated AEs that occurred in more than 5% of subjects with chronic ITP during a Privigen infusion or within 72 hours after the end of a treatment cycle (two consecutive infusions) with Privigen, irrespective of causality. Table 3: Adverse Events Occurring in >5% Subjects With Chronic ITP During a Privigen Infusion or Within 72 hours After the End of a Treatment Cycle*, Irrespective of Causality Adverse Event Headache Pyrexia/hyperthermia Nausea Epistaxis Vomiting Blood unconjugated bilirubin increased Blood conjugated bilirubin increased Blood total bilirubin increased Hematocrit decreased
Subjects (%) [n=57] 37 (64.9) 21 (36.8) 6 (10.5) 6 (10.5) 6 (10.5)
Infusions (%) [n=114] 41 (36.0) 22 (19.3) 6 (5.3) 6 (5.3) 6 (5.3)
4 (7.0) 3 (5.3)
4 (3.5) 3 (2.6)
located within the university’s family medicine clinic. Its primarily genericonly formulary was developed around four chronic diseases—asthma, diabetes, hypertension and dyslipidemia. The formulary stocks about 50 medications focused on chronic health needs; most medications cost $3 for a 30-day supply. Every patient is counseled by the pharmacist, and there are low literacy aids available to help explain how to use insulin or asthma inhalers.
Three subjects experienced three serious AEs, one of which (aseptic meningitis) was related to the infusion of Privigen. One subject withdrew from the study due to gingival bleeding, which was not related to Privigen. Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase, and a decrease in hemoglobin level within two days after the infusion of Privigen. Two of the eight subjects were clinically anemic but did not require clinical intervention. Four other subjects with active bleeding were reported to have developed anemia without evidence of hemolysis. In this study, there was a decrease in hemoglobin after the ﬁrst Privigen infusion (median decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29. Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, 12 (21.4%) developed a positive DAT during the 29-day study period. 6.2 Postmarketing Experience Because postmarketing reporting of adverse events is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. Evaluation and interpretation of these postmarketing reactions is confounded by underlying diagnosis, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance. Privigen Postmarketing Experience Adverse reactions reported during worldwide postmarketing use of Privigen do not differ from what has been observed in clinical studies with Privigen and from what is known for IGIV products. General The following mild to moderate reactions may occur with the administration of IGIV products: headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, ﬂushing, skin reactions, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, myalgia, arthralgia, and changes in blood pressure. Immediate hypersensitivity and anaphylactic reactions are also a possibility. The following adverse reactions have been identiﬁed and reported during the post-approval use of IGIV products.12 Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test Musculoskeletal: Back pain Gastrointestinal: Hepatic dysfunction, abdominal pain General/Body as a Whole: Pyrexia, rigors 7 DRUG INTERACTIONS Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, and rubella.13 The immunizing physician should be informed of recent therapy with Privigen so that appropriate measures may be taken (see Patient Counseling Information ). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Privigen. It is not known whether Privigen can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Privigen should be given to pregnant women only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.14,15 8.3 Nursing Mothers Use of Privigen in nursing mothers has not been evaluated. 8.4 Pediatric Use Treatment of Primary Humoral Immunodeﬁciency Privigen was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with PI. There were no apparent differences in the safety and efﬁcacy proﬁles as compared to those in adult subjects. No pediatric-speciﬁc dose requirements were necessary to achieve the desired serum IgG levels. The safety and effectiveness of Privigen have not been established in pediatric patients with PI who are under the age of 3. Treatment of Chronic Immune Thrombocytopenic Purpura Safety and effectiveness of Privigen have not been established in pediatric patients with chronic ITP who are under the age of 15. 8.5 Geriatric Use Clinical studies of Privigen did not include sufﬁcient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Use caution when administering Privigen to patients age 65 and over who are judged to be at increased risk of developing renal insufﬁciency (see Boxed Warning, Warnings and Precautions [5.2]). Do not exceed recommended doses, and administer Privigen at the minimum infusion rate practicable. Manufactured by: CSL Behring AG Bern, Switzerland
* Two consecutive daily infusions.
Of the 183 temporally associated AEs reported for the 57 subjects with chronic ITP, the investigators judged 150 to be related to the infusion of Privigen (including the one serious AE described below). Of the 149 non-serious AEs related to the infusion of Privigen, 103 were mild, 37 were moderate, and 9 were severe. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (65% of subjects) and pyrexia/hyperthermia (35% of subjects).
US License No. 1766 Distributed by: CSL Behring LLC Kankakee, IL 60901 USA
Based on June 2009 revision.
Data presented at the meeting showed that in the first nine weeks of operation, pharmacists provided 218 prescriptions for 93 unduplicated clients, with a refill rate of 20.4%. Diabetes (31.2%) and cardiovascular conditions (29.4%) accounted for 60.6% of prescriptions filled. In one diabetic patient, they estimated a potential cost savings of $6,744 annually by substituting STEP-approved medications. Additional data show that in the first four months, the pharmacy saw about 250 patients and dispensing has increased by 500%, according to Darrell L. Willyard, PharmD, the STEP pharmacy manager. Additionally, 25% to 30% of the patients return for refills, added study co-author Janet Gaskins, resident education specialist, “which is a substantial number for us. “The indigent population is very mobile, and they’re not very responsive to adherence to medications,” Ms. Gaskins said. “This shows we are meeting their needs and in a way that allows them to take their medications. Eighty percent of the patients we see now are return patients.” Dr. Willyard said he very actively works with patients’ doctors to substitute generic medications whenever possible. “The patients appreciate it. If I call and get them switched from something that costs $100 a month to $3 a month, I get a lot of ‘God blesses.’ ” Dr. Willyard now plans to bring medical and pharmacy students in to the pharmacy for rotations.
Prescription Assistance Programs Can Help In Pittsburgh, pharmacists at Duquesne have taken a different approach to helping their patients receive affordable medications, by helping enroll them in manufacturer-sponsored prescription assistance programs (PAPs). In a recent study, they evaluated the cost savings of pharmacist-assisted enrollment into PAPs in an ambulatory care setting. They also estimated the costs associated with missed opportunities of not using the PAPs. Autumn L. Runyon, PharmD, assistant professor of pharmacy practice, and colleagues evaluated 148 enrollment applications for PAPs between March 1, 2008, and Feb. 28, 2009, from patient records at the Catholic Charities Free Health Care Center, a local clinic. They documented the names of medications, quantity of drug, and number of refills. The cost savings of using a pharmacist was calculated based on the usual & customary (U&C) charge for each medication applied for. The U&C charge, representing the “cash” price of each medication,
Operations & Management 19
Pharmacy Practice News • November 2009
‘The patients appreciate it. If I call and get them switched from something that costs $100 a month to $3 a month, I get a lot of ‘God blesses.’ ” —Darrell L. Willyard, PharmD
was obtained from a local pharmacy; the U&C charges for all applications were then totaled. The missed opportunity costs were calculated by totaling the clinic’s charges for medications that could have been obtained via PAPs during the same time period. Dr. Runyon and her team estimated the annual cost savings from implementing pharmacist-assisted PAPs totaled nearly $182,792. The missed opportunity cost of not using the pharmacist-assisted PAP totaled about $20,998. Most community pharmacists are not familiar with PAPs, she said, but they can bring huge cost savings to patients. For example, GlaxoSmithKline’s Bridges to Access program offers a voucher that allows patients to get the first two months of asthma inhalant medication for $10. “So a therapy that might cost a patient $600 a month they could get for $10, and then for free after that. “Pharmacists in every setting are coming into contact with patients who are uninsured or low-income. This is just one of the resources available.” Every major manufacturer has a PAP, Dr. Runyon says, as do some smaller companies. They work in various ways, with some companies mailing the drugs to patients’ homes and others providing vouchers that can be used at a pharmacy. Dr. Runyon said in all of her work with PAPs, she has only come across about one in 25 drugs that is not covered, and usually in that case there is a therapeutic alternative or generic substitute. Pharmacists should be aware that filling out the applications can be timeconsuming at first. Most forms require a physician and patient signature, a copy of the prescription and some documentation of the patient’s finances. Applications are reviewed within four to six weeks, she says, although many companies can provide medications quicker in an urgent situation. She recommends checking manufacturer’s Web sites, or the site www. needymeds.org, which compiles a list of available PAPs and includes links to coupons and PDF files of the applications.
ASHP, Other Sources For More Help Sandra Leal, PharmD, director of clinical pharmacy for El Rio Health Center in Tucson, Ariz., and past president of the Association of Clinicians for the Underserved, said additional information on PAPs can be found on the Ameri-
can Society of Health-System Pharmacists’ Web site: http://www.ashp.org/
Import/PracticeandPolicy/PracticeResourceCenters/PatientAssistancePrograms.aspx. She also suggests pharmacists at
health care sites serving largely lowincome populations consider the federal 340B Drug Pricing Program, which limits the cost of covered outpatient
drugs to certain federal grantees, federally qualified health center look-alikes and qualified disproportionate share hospitals. The Pharmacy Services Support Center provides free assistance to Health Resources and Services Administration grantees and other eligible health care sites in optimizing the value of the 340B program. For more information, visit http://pssc.aphanet. org or call 1-800-628-6297. (For more information on the 340B Drug Pricing Program, see page 50.) —Karen Blum
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20 Operations & Management
Pharmacy Practice News • November 2009
Leadership in Action
Portfolio Life—Where Can It Take You? O
ver the past several months, we have been analyzing David Corbett’s book, “Portfolio Life, The New Path to Work, Purpose and Passion After 50.”1 I have also shared the impact this book has had on my own life. Tomorrow is my 56th birthday. Today, my family—including my grandchildren, the pride of my life—celebrated my special day. As I have related to you in past columns, I have completed Corbett’s suggested self-examination, looked at my inner life, reflected on my passions and gifts, written my “life plan,” even taken a new job with a new organization. When I first came up with the idea of writing several columns based on Corbett’s book, I felt as though I was taking a risk. I was not sure if my idea had merit. I did not know if this topic would be of interest to other people. Are others questioning the balance of their life (like me), evaluating everything (like me)? Do they need a shot in the arm (like I did)? The upshot surprised me. I had no idea of the impact that this topic might have on so many people. Readers wrote
in [See Pharmacy Practice News, September, page 4]. And I learned that revealing my story had encouraged others to expose their own. So what have I learned through the process? Well, Annette Simmons in her book “The Story Factor”2 is right. It’s the personal stories that grab people, that turn the abstract into reality. It’s the personal stories to which people can relate. So now, I’d like to turn the attention to your story. To recap, author David Corbett outlines a step-by-step process to counteract imbalance, with a combination of what he calls the five “elements”: 1. working in the form you want; 2. learning and developing; 3. making time for personal pursuits and recreation; 4. enjoying family and friends; and 5. giving back to society. When balanced, Corbett contends, each of those elements will help us live authentic, realized lives. In this column, I also challenged you to write your life plan by identifying your five elements and by listing five
‘Life goals need to be heartfelt aspirations and hopes that define our values and how we want to live our lives. These goals are our compass.’
goals for each element. I identified the following five areas of my life that I find the most important: 1. my employment work life; 2. my professional/organizational life; 3. my spiritual life; 4. my family and personal life; and 5. mentoring young people. As Corbett states, “Two things happen as people shift from a career perspective to a portfolio perspective. They begin to take a broader view of their lives, beyond defining themselves in terms of their work. And they learn to pay attention to the issue of balance, to the interplay of parts that make up a whole life.” In essence, the portfolio is meant to probe deeply beneath the surface of our lives, penetrating the core fabric of who we are.
A Life of Mentoring I have identified my goals for the foreseeable future. There is a lot that I would like to accomplish before I formally retire. I’ve even given thought to what I would like to do when I do retire. For example, I would still like to be active in the pharmacy profession. I admire those past presidents who are retired, yet still attend the ASHP (American Society of Health-System Pharmacists) summer meeting and the House of Delegates. It is a joy to speak with them about their current pursuits and how they stay active in the profession. I would like to be a lifelong mentor of others, both in the professional realm and in my personal realm of friends and family. Having a long-term perspective and planning for the future also is a “Quadrant II” activity in the time-management matrix in Stephen Covey’s book “The Seven Habits of Highly Effective People.”3 This means that it is not urgent, but it is important. As I think about the activities that I do now that will afford me the opportunities in the future, they all seem to fall into the category of networking and influence. Building a wide network of people through current interactions— with integrity and service—will enable a future that consists of options. Corbett echoes this in his book. I have always been a proponent of the adage “attitude is everything.” Corbett lists five habits of attitude: 1. be optimistic and embrace change; 2. see things in a new light; 3. take it slow, as the boss of your life; 4. do what you want to do to create change; and 5. cultivate an attitude of curiosity.
Accepting Failure Being the perfectionist that I am,
“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Caritas Christi, Boston, Mass. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ caritaschristi.org.
Ernest R. Anderson Jr., MS, RPh
I have a fear of failure. What I am learning, however, is that I need to overcome that fear and accept that failure is a product of trying new things in my life. Many years ago, I had to overcome the fear of public speaking. Now I actually enjoy getting up in front of a large crowd and communicating a particular topic. Corbett also identifies five helpful paths to a new mindset. They are: 1. go with your strengths and leverage them; 2. create and develop new paths; 3. go with your gut; 4. don’t fear failure; and 5. connect with others. So, as I evaluate what I want to do in the coming years it involves presenting to others, perhaps even as a motivational speaker, mentoring others, building networks of people, making a difference in the lives of others. I think reflection is a part of the aging process. When I was just getting started in my career, I always charged ahead without reflection. As I currently take stock, I reflect back, and then look forward, answering the question of what choices I should make that will help me achieve my goals. Life goals need to be heartfelt aspirations and hopes that define our values and how we want to live our lives. These goals are our compass. After all, we have to manage our own lives—no one else will do it for us. So let me end this series by encouraging you to let your mind roam. Dream, visualize where you want to go and who you want to be. Imagine your life five or 10 years from now. What will it look like? What is your passion, your energy, your purpose, your calling? My overall habit of the mind is to share what I know with others, to help others with a genuine sense of caring and interest, while not looking for anything in return. I hope that these columns have gotten you thinking. If I have connected with you, I’d love to hear your story. Keep in mind, as hockey great Wayne Gretzky once said, “You miss 100% of the shots you never take.” I wish you well.
Referencess 1. Corbett D. Portfolio Life: The New Path to Work, Purpose and Passion After 50. New York, NY: Wiley; 2007. 2. Simmons, A. The Story Factor. New York, NY: Perseus Publishing; 2001. 3. Covey SR. The Seven Habits of Highly Effective People. New York, NY: Fireside/Simon & Schuster; 1989.
BRIEF SUMMARY: For full prescribing information, see package insert.
Skin and subcutaneous tissue disorders (Common, >1 to <10%, dose dependent): Prolonged administration of high dosages of hydroxyethyl starch may cause pruritus (itching) which is an undesirable effect observed with all hydroxyethyl starches.
For administration by intravenous infusion. Initial U.S. Approval: 2007
Investigations (Common, >1% to <10%, dose dependent): The concentration of serum amylase can rise during administration of hydroxyethyl starch and can confound the diagnosis of pancreatitis. At high doses the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and in a decrease of hematocrit. [see Interference with Laboratory Tests (5.3)]
To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@ hospira.com or FDA at 1-800-FDA-1088 or electronically at www.fda.gov/medwatch.
6.2 Adverse Reactions in Clinical Trials Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug may not reflect the rates observed in practice.
(6% HYDROXYETHYL STARCH 130/0.4 IN 0.9% SODIUM
INDICATIONS AND USAGE
Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is indicated for the treatment and prophylaxis of hypovolemia. It is not a substitute for red blood cells or coagulation factors in plasma. 4
The use of Voluven® is contraindicated in the following conditions: •
known hypersensitivity to hydroxyethyl starch [see General Warnings and Precautions (5.1)]
fluid overload (hyperhydration) and especially in cases of pulmonary edema and congestive heart failure
renal failure with oliguria or anuria not related to hypovolemia
patients receiving dialysis treatment
severe hypernatremia or severe hyperchloremia
WARNINGS AND PRECAUTIONS
5.1 General Warnings and Precautions Anaphylactoid reactions (mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema) have been reported with solutions containing hydroxyethyl starch. If a hypersensitivity reaction occurs, administration of the drug should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved. [see Adverse Reactions (6)] Fluid status and rate of infusion should be assessed regularly during treatment, especially in patients with cardiac insufficiency or severe kidney dysfunction. In cases of severe dehydration, a crystalloid solution should be given first. Generally, sufficient fluid should be administered in order to avoid dehydration. Caution should be observed before administering Voluven® to patients with severe liver disease or severe bleeding disorders (e.g., severe cases of von Willebrand´s disease). 5.2 Monitoring: Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation. 5.3 Interference with Laboratory Tests Elevated serum amylase levels may be observed temporarily following administration of the product and can interfere with the diagnosis of pancreatitis. At high dosages the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in hematocrit. 6
6.1 Overall Adverse Reaction Profile From the accumulated clinical development experience, expected adverse reactions after administration of Voluven® occurring in less than 10% of patients are as follows:
Immune system disorders (Rare, >0.01% to <0.1%): Products containing hydroxyethyl starch may lead to anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema). In the event of an intolerance reaction, the infusion should be discontinued immediately and the appropriate emergency medical treatment initiated. [see General Warnings and Precautions (5.1)]
During clinical development, 471 patients were exposed to and a total of 768 patients received the hydroxyethyl starch 130/0.4 drug substance contained in Voluven® at different concentrations (2%, 4%, 6%, or 10%) and at cumulative doses of several mL up to 66 L1). The mean duration of treatment with hydroxyethyl starch 130/0.4 was 3.9 ± 3.3 days, mean cumulative doses were 3338 ± 3695 mL, and the longest follow-up period was 90 days. In the US trial, 100 patients undergoing elective orthopedic surgery were treated either with Voluven® (N=49) or hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) (N=51) for intraoperative volume replacement. Mean infusion volumes were 1613 ± 778 mL for Voluven® and 1584 ± 958 mL for hetastarch.
Adverse reactions observed in at least 1% of patients: In the US trial comparing Voluven® with hetastarch, a possible relationship to Voluven® was reported in five cases in a total of three patients (aPTT elevated, PT prolonged, wound hemorrhage, anemia, pruritus). A possible relationship to hetastarch was reported in five patients (three cases of coagulopathy; two cases of pruritus). The three coagulopathy cases in the hetastarch group were serious and occurred in patients receiving more than the labeled ceiling dose (20 mL/kg), whereas no serious coagulopathy occurred in the Voluven® group. 6.3 Postmarketing Experience The following adverse reactions have been identified during the postapproval use of Voluven® and other types of hydroxyethyl starch solutions. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
8.4 Pediatric Use In one trial, children including newborns to infants (<2 years) undergoing elective surgery were randomized to receive Voluven® (N=41) or 5% albumin (N=41). The mean dose of Voluven® administered was 16 ± 9 mL/kg3). Voluven® may be given to premature infants and newborns only after a careful risk/benefit evaluation. The safety and efficacy of Voluven® have not been established in the age group of 2 to 12 years. Use of Voluven® in children >12 years is supported by evidence from adequate and well-controlled studies of Voluven® in adults and by data from children <2 years old. Dosage in children should be adapted to individual patient colloid needs, taking into account underlying disease, hemodynamics and hydration status. [see Pediatric Dose (2.2)] 8.5 Geriatric Use Of the total number of subjects in clinical studies of Voluven® (N= 471), 32% were 65 years old and older while 7% were 75 and older. No overall differences in safety or effectiveness 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. 8.6 Renal impairment Voluven® is mainly excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Volume status, infusion rate, and urine output should be closely monitored. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. [see Pharmacokinetics (12.3)] 10 OVERDOSAGE As with all plasma volume substitutes, overdosage can lead to overloading of the circulatory system (e.g. pulmonary edema). In this case, the infusion should be stopped immediately and if necessary, a diuretic should be administered. [see General Warnings and Precautions (5.1)] 15 REFERENCES 1)
Neff TA, Doelberg M, Jungheinrich C, et al. Repetitive large-dose infusion of the novel hydroxyethyl starch HES 130/0.4 in patients with severe head injury. Anest Analg 2003; 96 (5): 1453–9
Kozek-Langenecker S. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology 2005; 103 (3): 654-60
The safety profile from postmarketing experience of Voluven® is not different from the profile obtained from clinical trials performed using the product.
Lochbühler H, Galli C, Hagemann H. Hydroxyethyl starch HES 130/0.4 in paediatric surgery: results of an explorative, controlled, multicenter safety study. Crit Care 2003; 7 (Suppl 1):, P107
Based on spontaneous reporting of hypersensitivity reactions, urticaria, bronchospasm, or hypotension were the most frequently reported serious adverse drug reactions for patients treated with Voluven®.
Jungheinrich C, Neff T. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinetik 2005; 44 (7): 681-699
Jungheinrich C, Scharpf R, Wargenau M, et al. The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment. Anesth Analg 2002; 95 (3): 544 – 51
Leuschner J, Opitz J, Winkler A, Scharpf R, Bepperling F. Tissue storage of 14C-labeled hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 after repeated intravenous administration to rats. Drugs R D 2003; 4 (6): 331-8
Gandhi SD, Weiskopf RB, Jungheinrich C et al. Volume replacement therapy during major orthopedic surgery using Voluven® (hydroxyethyl starch 130/0.4) or hetastarch. Anesthesiology 2007; 106:1120-1127
With the administration of hydroxyethyl starch solutions, disturbances of blood coagulation can occur depending on the dosage2). 8
USE IN SPECIAL POPULATIONS
8.1 Pregnancy Pregnancy Category C. Voluven® has been shown to cause embryocidal or other adverse effects in rats and rabbits when given in doses 1.7 times the human dose. There are no adequate and wellcontrolled studies in pregnant women. Voluven® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The type of hydroxyethyl starch present in Voluven® had no teratogenic properties in rats or rabbits. At 5 g/kg of body weight per day, administered as a bolus injection, fetal retardations and embryolethal effects were observed in rats and rabbits, respectively. In rats, a bolus injection of this dose during pregnancy and lactation reduced body weight of offspring and induced developmental delays. All adverse effects were seen exclusively at maternal toxic doses due to fluid overload. [see Toxicology (13.2.1)] Fertility studies on directly exposed animals have not been conducted.
16 HOW SUPPLIED/STORAGE AND HANDLING Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) for intravenous infusion is supplied in the following primary container and carton sizes: Polyolefin bag (freeflex®) with overwrap: 500 mL Carton of 15 x 500 mL NDC 0409-1029-01 Store at 15° to 25°C (59° to 77°F). Do not freeze.
8.2 Labor and Delivery Information on the use of Voluven® during labor or delivery is unknown.
Manufactured by: Fresenius Kabi Norge AS, P.O. Box 430, NO-1753 Halden, Norway
8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Voluven® is administered to a nursing woman.
Distributed by: Hospira, Inc. 275 North Field Drive Lake Forest, Illinois 60045 USA Made in Norway Reference EN-1597
Pharmacy Practice News â€˘ November 2009
Contemporary Management Of Hyponatremia JOAN M. STACHNIK, PHARMD, BCPS Clinical Assistant Professor Department of Pharmacy Practice College of Pharmacy University of Illinois Medical Center at Chicago Chicago, Illinois
yponatremia, a common electrolyte imbalance, generally is defined as a serum sodium concentration of less than 135 mEq/L.1 Patients with acute or moderate to severe
hyponatremia may present with neurologic signs and symptoms and may be at risk for long-term complications. However, even patients with mild, chronic forms of the disorder may be at risk for significant morbidity, making recognition and appropriate treatment essential.2-4
Classification and Epidemiology Hyponatremia can be classified by rate of onset, as either acute (ie, rapid-onset) or chronic, and by the degree of sodium deficitâ€”mild (125130 mEq/L), moderate (115-125 mEq/L), or severe (110-115 mEq/L). Estimates of the prevalence of hyponatremia vary, ranging from less than 1% to 45%, depending on the setting and population studied. High rates of hyponatremia have been reported in hospitalized patients, with 35% to 45% experiencing low sodium levels following certain surgical procedures.5,6 In a retrospective study, Hawkins et al reviewed laboratory records of 120,137 patients for whom serum sodium was recorded, along with patient age, gender, and location of care. Among those patients in a hospital setting (36%), 6,227 (14%) who had normal sodium levels before hospitalization developed hyponatremia after admission.6 In another study of 8,142 patients with normal serum sodium levels before admission to an intensive care unit (ICU), 917 (11%) developed hyponatremia within a median of 2 days.7 The prevalence of hyponatremia also has been assessed in the outpatient setting. Among patients in the community or ambulatory care clinics, rates of hyponatremia have been reported at 7.2% (1,730 of 24,027) and 21% (11,100 of 52,860), respectively.6 Certain disease states, such as cirrhosis and heart failure, may be associated with higher rates of hyponatremia. Klein and colleagues found that 256 of 943 (27%) patients with heart failure in the OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) study had hyponatremia.8 (The
study was designed to determine the relationship between serum sodium levels and clinical outcomes in patients with heart failure.) Similarly, in a trial by Gheorghiade and colleagues evaluating the effects of drug therapy for hyponatremia in patients with heart failure, 9,368 of 47,647 (20%) patients had hyponatremia at study entry.9 Borroni and colleagues conducted a prospective study to determine the effects of hyponatremia on hospital outcomes of patients with hepatic cirrhosis.10 The authors reported that hyponatremia was present in nearly 30% (57 of 191) of enrolled patients.
The Clinical Burden Hyponatremia has been associated with significant morbidity and mortality, regardless of severity.1 Sajadieh conducted a communitybased study evaluating serum sodium levels as an indicator of the risk for death or cardiovascular events (eg, myocardial infarction). The study included 671 patients with an average age of 64.5 years.4 The rate of death or myocardial infarction among patients with normal-range serum sodium levels (>137 mEq/L) was 14.1% (86 of 609), compared with 27.4% (17 of 62) for patients with serum sodium levels less than 137 mEq/L (a more conservative definition of hyponatremia used by the authors), and 42.8% (6 of 14) for patients with sodium levels less than 134 mEq/L. Mild hyponatremia may also increase the risk for falls and fractures, especially in the elderly.1,2,11 In one series of patients admitted for hip fractures secondary to a fall, Kengne reported 13% (67 of
513) to have mild asymptomatic hyponatremia (with mean serum sodium levels of 131 mEq/L), compared with 3.9% (20 of 513) in a similar group of patients without a fracture.12 Although the exact mechanism of how hyponatremia may contribute to falls is unclear, it has been suggested that low sodium levels may cause impairment of both gait (balance and posture) and attention compared with normal sodium levels.11 The effects of hyponatremia on hospitalized patients also have been evaluated. One large prospective trial compared the outcomes of more than 98,000 patients during a 3-year period based on serum sodium levels.3 Patients with hyponatremia had higher in-hospital and 1- and 5-year mortality rates compared with those with normal-range sodium levels. For hospitalized hyponatremia patients, the higher mortality rate translated to an adjusted hazard ratio [HR] of 1.47 (95% confidence interval [CI], 1.33-1.62), and occurred regardless of whether the hyponatremia was classified as mild, moderate, or severe. The effects of hyponatremia were more pronounced among patients with circulatory system disorders (eg, cardiovascular disease), metastatic cancer, and disorders related to the musculoskeletal system (HRs of 2.19, 1.78, and 2.10, respectively, for in-hospital mortality). Evidence suggests that patients with hyponatremia who are hospitalized for pneumonia also may be at risk for poorer outcomes.13 Although mortality was not increased, these patients had significantly higher rates of mechanical ventilation (odds ratio [OR], 1.75; 95% CI, 1.13-2.69) and ICU admissions
see HYPONATREMIA, page 24
Pharmacy Practice News • November 2009
HYPONATREMIA continued from page 23
(OR, 1.58; 95% CI, 1.20-2.08), along with longer hospital stays (7.6 vs 7.0 days; P<0.001) compared with those who had pneumonia but were not hyponatremic. These hyponatremia-associated complications also resulted in higher hospital costs (median of $7,086 vs $5,732; P=0.001). The risk for mortality among patients with liver disease may be increased in the presence of hyponatremia.14 In a study involving nearly 14,000 patients with severe liver disease awaiting liver transplant, the risk for death increased by 5% for every unit decrease in serum sodium when levels were between 125 and 140 mEq/L. Research has found that as the serum sodium decreased, the risk for mortality increased. In addition to the effects of hyponatremia on general health, hyponatremia has a significant economic impact.15 The cost of treatment for hyponatremia in the United States, either in inpatient or outpatient settings, has been estimated to be between $1.6 billion and $3.6 billion annually.
Mechanisms of Water-Sodium Balance Balance of both water and sodium is important for the regulation of plasma osmolality and blood volume.1 Water in the body is divided between the extracellular (approximately 40%) and intracellular (approximately 60%) compartments.16 Sodium (along with its associated anions) is the major determinant of the osmotic pressure and volume of extracellular fluids (ECFs); therefore, any changes in total body content of sodium can effect changes in ECF osmolality. Similarly, intracellular osmotic pressure is primarily determined by potassium. Normally the osmolality of the intracellular fluid (ICF) and ECF is the same, maintained by the free exchange of water between the 2 compartments and a balance of the solutes sodium and potassium (referred to as effective osmoles).1,17 However, changes in the osmolality of the ECF will influence this free-water exchange between the 2 compartments. Hypertonicity of the ECFs (as with an excess of sodium) will result in a decrease in ICF volume (ie, a shift in free water to the extracellular compartment); hypotonicity (as with low sodium) will cause an increase in ICF volume (ie, a shift in free water to the intracellular compartment). This increase in ICF volume is especially important in cerebral tissues, where an increase in cell volume can result in significant cellular damage. Other mechanisms also can affect water and sodium balance. Water retention or metabolism is controlled primarily by arginine vasopressin (AVP or antidiuretic hormone), a peptide produced by the pituitary in response to osmotic and nonosmotic changes.18-20 An increase in plasma osmolality results in stimulation of AVP secretion by osmoreceptors in the anterior hypothalamus, causing antidiuresis and reabsorption of water into the circulation. This, along with stimulation of thirst, results in a decrease in water excretion and an increase in water intake.1,18,20 When plasma osmolality is below a biologically preset threshold (approximately 280 mOsm/kg), AVP levels usually are undetectable, allowing for excretion of free water and normalization of osmolality.19,20 Secretion of AVP also is stimulated via a more potent nonosmotic mechanism—arterial stretch
baroreceptors—in response to a reduction in blood pressure or blood volume of approximately 8% to 10%. Although osmotic mechanisms generally control AVP secretion over nonosmotic mechanisms, under certain pathophysiologic conditions, such as cardiac failure or liver cirrhosis, pressure and volume responses for AVP secretion predominate and allow for elevated AVP levels despite low plasma osmolality, resulting in hyponatremia.
Causes of Hyponatremia Hyponatremia usually results when there is a loss of balance between intake and excretion of water, or from renal or extrarenal sodium loss.21 Initial evaluation of a patient with hyponatremia generally includes plasma or serum osmolality and volume status to determine the type of hyponatremia and to identify possible causes (Tables 1 and 2).17,22 Plasma osmolality, which is normally between 280 and 295 mOsm/kg with normal hydration, can determine whether the hyponatremia is isotonic, hypertonic, or hypotonic.
Hypotonic Hyponatremia Hypotonic hyponatremia is the most common type seen and also is associated with critical illnesses.23 It can be further classified based on extracellular fluid status (including urine osmolality and sodium) as hypovolemic, euvolemic, or hypervolemic.22 Hypovolemic hyponatremia results in reductions in both total body water (decreased extracellular fluid) and, to a certain extent, total body sodium.17,22 Urine osmolality is elevated
(>450 mOsm/kg). Urine sodium measures can give an indication as to the cause of water and sodium loss. Urine sodium of less than 10 to 20 mEq/L suggests extrarenal loss, such as diarrhea, vomiting, excess sweating, or blood loss.1,23 High urine sodium levels (>20 mEq/L) indicate renal loss of sodium and water as a cause, such as diuretic use, adrenal insufficiency, or certain nephropathies. Euvolemic hyponatremia presents with clinically normal ECF volume and is the most common of the hypotonic hyponatremias.17,23 Although total body water is increased, it is not enough to cause edema, making the patient appear clinically euvolemic.1 Euvolemic hyponatremia is most commonly the result of the syndrome of inappropriate antidiuretic hormone (SIADH), where water intake exceeds excretion by the kidney. Urine osmolality is generally higher than 100 mOsm/kg and urine sodium levels are high (>20 mEq/L). Euvolemic hyponatremia also can result from primary polydipsia (water intake >20 L/d) or very low-solute diets. In this case, urine osmolality would be less than 100 mOsm/L and urine sodium levels low (<20 mEq/L). Hypervolemic hyponatremia is associated with excess total body sodium along with a greater expansion of total body water, resulting in hyponatremia with clinically evident edema.17,23 The increase in total body water results from a reduction in water excretion by the kidneys—a response to a decrease in effective circulating blood volume.1,17 Conditions associated with hypervolemic hyponatremia include heart failure, cirrhosis, and
Table 1. Types of Hyponatremia by Plasma Osmolality17,22,23 Isotonic
Pseudohyponatremia due to an artifactual reduction in sodium
Results from elevation in plasResults from excess ma osmolality due to presence water relative to effective of effective osmoles (eg, glucose, osmoles (solute) in the mannitol, sorbitol) and movement extracellular space of water from intra- to extracellu- Caused by either a lar spaces decrease in total body Result is a reduction in serum solute (depletion) or an sodium with elevated osmolality increase in total body Plasma osmolality >295 mOsm/kg water (dilution)
No movement of water between extra- and intracellular spaces Results from elevation of the nonaqueous, non-sodium portion of plasma by proteins and lipids relative to the aqueous portion with no true reduction in total sodium
Plasma osmolality <280 mOsm/kg
Plasma osmolality = normal range
Table 2. Common Etiologies for Hyponatremia16,17,22 Isotonic
Hypotonic Hypovolemic (Depletional)
Hypothyroidism Nephrotic syndrome
Burns SIADH, syndrome of inappropriate antidiuretic hormone
Pharmacy Practice News • November 2009
Educational review nephrotic syndrome.17 Urine osmolality is higher than 100 mOsm/kg, with a urine sodium concentration of less than 20 mEq/L.1
Table 3. Clinical Signs of Hyponatremia Based on Degree of Sodium Loss24
Clinical Presentation Symptoms of hyponatremia vary greatly, depending on the type and degree of hyponatremia and the rate of onset (Table 3).1,2,24 Hypovolemic hyponatremia typically causes signs of dehydration, such as dry mucous membranes, tachycardia, and hypotension.24 Hypervolemic hyponatremia can cause peripheral or pulmonary edema; these are not present with euvolemic hyponatremia. Symptoms of hyponatremia also differ depending on the degree of sodium loss. Individuals with mild (>125-130 mEq/L) and chronic hyponatremia are generally asymptomatic. However, it has been suggested that symptoms of mild hyponatremia may be too subtle to notice, yet result in significant morbidity among certain patient groups, such as the elderly.2 Moderate to severe hyponatremia or rapid-onset (≤48 hours) hyponatremia may present with neurologic symptoms ranging from confusion, agitation, or impaired mental function to seizures and coma if sodium levels fall to below 115 mEq/L.24,25 The rate of change of sodium levels may be especially important, because a rapid drop in sodium does not allow the cells of the brain time to adapt to the change in osmolality, resulting in cerebral edema as water moves intracellularly.17 Although solutes such as sodium and potassium move from the brain cells to the extracellular space quickly, other solutes (organic solutes such as taurine, creatine, and glutamine) are slower, requiring up to 48 hours to completely compensate for the fluid shift.1,24,25 Onset of hyponatremia over several days, even if severe, allows time for this adaptation process and reduces the risk for cerebral edema.
Treatment of Hyponatremia Treatment of hypertonic or isotonic hyponatremia generally consists of addressing the underlying cause of the sodium decrease.17,23,24 For example, hypertonic hyponatremia secondary to hyperglycemia may resolve with a reduction in blood glucose.24 For isotonic hyponatremia (an artifactual decrease in serum sodium concentrations), appropriate laboratory assessment is needed to determine the true serum sodium concentration.23,24 The following section relates primarily to the treatment of hypotonic hyponatremia.
Sodium Chloride Infusions Because of the risk for cerebral edema and death, acute symptomatic, severe hyponatremia is considered a medical emergency.26 Although prompt treatment is needed, too rapid a correction of serum sodium levels should be avoided because of the risk for osmotic demyelination or central pontine demyelination, a potentially severe neurologic complication.22,24,25,27 However, cerebral edema and severe neurologic symptoms generally can be reduced or stopped with only a small increase in serum sodium—about a 5% increase for cerebral edema and a 3 to 7 mEq/L increase for seizures.25 Therefore, an initial rate of correction of 1 to 2 mEq/L per hour for several hours has been recommended for patients with severe symptoms. This rate can be reduced once symptoms begin to subside or a serum sodium level of 125 to 130 mEq/L (or lower if starting level is ≤100
Mild (serum sodium 125-130 mEq/L)
Moderate (serum sodium 115-125 mEq/L)
Severe (<110-115 mEq/L) or rapid onset (<48 hours)
Impaired mental function Incontinence Coma Seizures
Table 4. Calculation for Rate of Sodium Chloride Infusion1,21,25,26 Formula for Sodium Chloride Infusions
Sodium Content of Infusions
Total body water = weight (kg) x % body water
5% sodium chloride
Change in sodium per liter of infusion = (Infusion sodium content – baseline serum sodium) ÷ (total body water + 1)
3% sodium chloride
Infusion rate = (target serum sodium increase ÷ change in sodium per liter of infusion) administered over desired time
0.9% sodium chloride
0.45% sodium chloride 77 mEq/L
Calculation example 68-year-old man, weighing 60 kg, presents with lethargy and extreme confusion and a serum sodium of 108 mEq/L. Assuming a 3% sodium chloride infusion is appropriate, what infusion rate is needed to increase serum sodium by 5 mEq/L over the next 12 h? Total body water = 60 x 0.6 = 36 L Change in sodium per liter of 3% sodium chloride = (513 – 108) ÷ (36 + 1) = 10.9 mEq/L Infusion rate = 5 ÷ 10.9 = 0.46 L over 12 h or 38 mL/h for 12 hours a
0.6 for men, 0.5 for women, 0.5 for elderly men >70 years, 0.45 for elderly women >70 years.1,25
mEq/L) is achieved. Other researchers have recommended slowing the infusion rate when a sodium level of 118 to 120 mEq/L has been reached and the patient is asymptomatic.22 Regardless, the sodium level should not be increased by more than 8 to 12 mEq/L in the first 24 hours, because correction rates higher than this are associated with an increased risk for osmotic demyelination.21,22,25 Several methods for calculation of the infusion rate for sodium chloride are available. One method calculates the rate of infusion based on total body water, the change in sodium per liter of solution infused, target sodium increase, and the desired rate of sodium correction (Table 4).1,25 (For general management strategies, see Table 5, page 26.) There is some concern regarding the use of hypertonic sodium chloride infusions, such as 3% sodium chloride, for correction of hyponatremia.1 These infusions can rapidly correct serum sodium in emergent situations and may be needed when isotonic infusions are not appropriate, such as in SIADH. However, there is a risk of too rapid a correction with hypertonic solutions, with the potential for osmotic demyelination. The risks and benefits associated with their use should be considered. In nonemergent situations in which patients are asymptomatic or have mild to moderate symptoms, 0.9% sodium chloride may be used to slowly
correct sodium levels as well as replace deficits in ECF volume for those who are hypovolemic.
Fluid Restriction For patients with nonemergent euvolemic or hypervolemic hypotonic hyponatremia, fluid restriction has been recommended, along with identification and correction of underlying causes.1,17,18,21 Fluid intake is usually restricted to no more than 1,200 mL per day, so that urine output and insensible losses exceed intake in order to achieve a negative water balance. For example, in a patient with a urine output of 550 mL per day, with 200 mL of insensible losses, fluid should be restricted to less than 750 mL per day.18
Drug Therapy Conventional Therapies For some patients with chronic forms of hyponatremia, such as hyponatremia secondary to SIADH, fluid restriction may be difficult to maintain, necessitating drug therapy.17,21 Demeclocycline is a tetracycline derivative that inhibits tubular AVP activity, leading to a decrease in plasma osmolality and an increase in serum sodium levels.1,17,21 When used for hyponatremia, the dose ranges from 600 to 1,200 mg daily in divided
see HYPONATREMIA, page 26
Pharmacy Practice News • November 2009
Table 5. General Management Strategies for Hypotonic Hyponatremia1,25,31-33
continued from page 25
doses. Lithium carbonate also has been used and has a similar effect as demeclocyline, increasing water clearance and serum sodium levels. Doses have ranged from 900 to 1,200 mg per day. However, because of its adverse-effect profile and less consistent effects, the use of lithium is limited. Diuretics have been used in the treatment of hypervolemic hyponatremia in addition to fluid restriction to help reduce volume overload in patients with underlying causes such as heart failure.21,24 Although loop diuretics are more potent for producing diuresis, thiazide diuretics are more likely to cause hyponatremia, possibly secondary to impairment of renal diluting mechanisms.28 The risk for hyponatremia is less with loop diuretics, since these agents affect both renal concentrating and diluting mechanisms.29,30
Treatment Sodium chloride infusion
Clinical Issues 3% or 0.9% solution
Rate of correction depends on severity of symptoms but should not exceed 8-12 mEq/L in 24 h to lessen risk for osmotic demyelination
Euvolemic and hypervolemic patients may require hypertonic sodium chloride (3%) to avoid volume overload and worsening of hyponatremia Hypovolemic patients may require 0.9% sodium chloride to replace extracellular fluid
1,200 mL/d or less (intake should be less than urine output and insensible losses combined)
Slow onset Compliance difficult Increase in serum sodium generally small (1-2 mEq/L/d) May require addition of sodium chloride and/or loop diuretics
Arginine Vasopressin Receptor Antagonists The AVP receptor antagonists are a new class of agents recently approved for treatment of hypervolemic or euvolemic hypotonic hyponatremia.31,32 Two agents are available—conivaptan (Vaprisol, Astellas) and tolvaptan (Samsca, Otsuka America). These agents block one or both of the AVP receptors (V2 or V1a). Antagonism of the V2 receptors on the renal collecting tubules and vascular endothelium results in the stimulation of water excretion with no significant increase in solute excretion.17,33 The lack of solute (ie, sodium) excretion by these agents results in increases in serum sodium levels. This effect has been referred to as aquaresis rather than diuresis because there is only loss of free water. Blockade of the V1a receptors, located on vascular smooth muscle cells, may reverse the vasoconstriction mediated by these receptors.17 Tolvaptan is an orally administered AVP receptor antagonist of the V2 receptor and is indicated for treatment of euvolemic or hypervolemic hyponatremia in symptomatic patients who have failed fluid restriction.31 In the SALT-1 and SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2) trials, tolvaptan resulted in greater increases in serum sodium compared with placebo within 8 hours of first treatment among patients with hyponatremia secondary to heart failure, cirrhosis, or SIADH.34 By day 4, significantly more patients had normalization of serum sodium levels with tolvaptan compared with placebo. Conivaptan is a parenteral AVP receptor antagonist of the V2 and V1a receptors also indicated for treatment of euvolemic or hypervolemic hyponatremia.32 In a study involving 84 patients with hypervolemic or euvolemic hyponatremia (serum sodium, 115 to 130 mEq/L) given conivaptan 20 mg as an IV loading dose followed by a 40- or 80-mg continuous infusion per day for 4 days, conivaptan resulted in significantly greater increases in serum sodium concentrations compared with placebo.35 Increases of 4 mEq/L over baseline with conivaptan were seen within the first 24 hours; this effect did not occur with placebo. At 72 hours, increases with conivaptan were 6.9 and 8.8 mEq/L over baseline, whereas serum sodium was increased by 1.9 mEq/L with placebo. In this study and both SALT trials, patients with hypovolemic hyponatremia were excluded from participating.28,35
All fluids need to be restricted
600-1,200 mg/d in divided doses
Slow onset (3-6 d) Expensive Potential for nephrotoxicity, especially with concurrent liver disease
Slow onset Less predictable effects
20 mg IV bolus followed by 20 mg as continuous infusion over 24 h for up to 4 d; up to 40 mg/d may be administereda
Only indicated for euvolemic or hypervolemic hyponatremia Avoid increases of serum sodium >12 mEq/L per 24 h Potential for drug interactions via CYP3A4 isoenzymes
15 mg once daily titrated to a maximum of 60 mg once daily
Only indicated for euvolemic or hypervolemic hyponatremia Therapy should be initiated in the hospital to allow for close monitoring of serum sodium levels Avoid increases of serum sodium >12 mEq/L per 24 h Potential for drug interactions via CYP3A4 isoenzymes
Although higher doses have been used in clinical trials, the maximum dose per product labeling is 40 mg over 24 hours.
Summary Hyponatremia can result in significant morbidity and mortality, making its recognition and appropriate treatment essential. Prompt treatment of hyponatremia is critical if severe sodium deficits are present, or if the onset is rapid, to avoid cerebral edema and progressive neurologic effects. Sodium chloride infusion is the most commonly used treatment for acute hyponatremia. For more chronic hyponatremia, other therapies, such as fluid restriction or agents that inhibit the actions of AVP, can be used.
Coyle JD, Joy MS, Disorders of sodium and water homeostasis. In: DiPiro JT, Talbert RL, Yee CG, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York, NY: McGraw-Hill; 2008: 845-860.
2. Decaux G. Is asymptomatic hyponatremia really asymptomatic? Am J Med. 2006;119(7A):S79-S82.
3. Waikar S, Mount D, Curhan G. Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am J Med. 2009;122(9):857-865. 4. Sajadieh A, Binici Z, Mouridsen M, et al. Mild hyponatremia carries a poor prognosis in community subjects. Am J Med. 2009;122(7):679-686. 5. Berghmans T, Paesmans M, Body J. A prospective study on hyponatremia in medical cancer patients: epidemiology, aetiology and differential diagnosis. Support Care Cancer. 1999;8(3):192-197. 6. Hawkins R. Age and gender as risk factors for hyponatremia and hypernatremia. Clin Chim Acta. 2003;337(1-2):169-172. 7. Stelfox H, Ahmed S, Khandwala F, Zygun D, Shahpori R, Laupland K. The epidemiology of intensive care unitacquired hyponatraemia and hypernatraemia in medicalsurgical intensive care units. Critical Care. 2008;12:R162. 8. Klein L, O’Connor C, Leimberger J, et al. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure (OPTIME-CHF) study. Circulation. 2005;111(19):2454-2460.
see HYPONATREMIA, page 71
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from Otsuka America Pharmaceutical, Inc. First and only oral treatment for clinically significant hypervolemic and euvolemic hyponatremia1
early as 8 hours, and the change was maintained for 30 days
constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%) â‰Ľ
A choice of 2 dosing strengths
To place your order, call your wholesaler or distributor today
15 mg QD 10-count blister pack 30 mg QD 10-count blister pack
For more information about SAMSCA, visit www.samsca.com or call 1-877-726-7220. INDICATION SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH). Important Limitations Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA.
WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM serum sodium can be monitored closely oo rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable
Please see Important Safety Information on following page.
ÂŠ 2009 Otsuka America Pharmaceutical, Inc.
IMPORTANT SAFETY INFORMATION FOR SAMSCA™ (tolvaptan) SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. SAMSCA is contraindicated in the following conditions: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae – During initiation and after titration monitor patients to assess serum sodium concentrations and neurologic status. Subjects with serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic ﬂuid. Fluid restriction during the should generally be avoided. Gastrointestinal Bleeding in Patients with Cirrhosis – Used only when the need to treat outweighs this risk Dehydration and Hypovolemia – In patients who develop medically signiﬁcant signs or symptoms of hypovolemia, discontinuation is recommended. Dehydration and hypovolemia can occur, especially in Co-administration with Hypertonic Saline – Not recommended CYP 3A Inhibitors – Do not use with strong inhibitors of CYP 3A; avoid concomitant use with moderate CYP 3A inhibitors CYP 3A Inducers SAMSCA may need to be increased P-gp Inhibitors Hyperkalemia or Drugs that Increase Serum Potassium – Monitor serum potassium levels in patients levels Pregnancy and Nursing Mothers – SAMSCA should be used during pregnancy only if the potential beneﬁt justiﬁes the potential risk to the fetus. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother. Commonly observed adverse reactions – (incidence ≥ and hyperglycemia (6% vs 1%)
Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following pages.
Reference: 1. Schrier RW, Gross P, Gheorghiade M, et al; SALT Investigators. Tolvaptan, a selective oral vasopressin V2 for hyponatremia. N Engl J Med
Pharmacy Practice News • November 2009
Documenting the Value of ED Pharmacy Services Studies presented at ACCP show improved medication safety, lowered costs and bolstered quality of care Anaheim, Calif.—The addition of an emergency department (ED) pharmacist at the University of Kentucky Medical Center, in Lexington, made a significant difference in the capture of ED medication errors, increasing the number of error reports by 3.5-fold compared with baseline, according to research unveiled at the American College of Clinical Pharmacy (ACCP) meeting in October. When a second pharmacist joined the ED a year later, the number of captured medication errors increased 14.5 times over baseline, the investigators reported. Moreover, pharmacists’ retrospective review of errors reported during three separate six-month periods from 2005 to 2009 found that “pharmacy personnel captured significantly more [medication errors] than other health care personnel (93.3% vs. 6.6%; P=0.001).” Overall, 497 medication errors were reported during the three study periods. Kyle Weant, PharmD, BCPS, clinical pharmacy specialist in emergency medicine/critical care at University of Kentucky HealthCare and lead author, noted that pharmacists’ interventions prevented 79% of the errors from reaching patients. Victor Cohen, PharmD, BCPS, CGP, CMI-V, clinical pharmacy manager in the Department of Emergency Medicine at Maimonides Medical Center, in New York City, said the study demonstrated the impact that pharmacists’ medication-error reporting activities can have on “transparency, accountability and continuous quality improvement” in the ED. The Kentucky HealthCare study was one of several ACCP meeting research reports that added weight to the growing body of evidence that the presence of clinical pharmacists can improve medication safety, lower costs and help bolster overall quality in the ED.1 According to a recent report, more hospitals are assigning pharmacists to their EDs, although the overall proportion remains small at 6.8%.2 Dr. Weant noted that “while we say pharmacists decrease medication errors, one of the most important things we do is notice medication errors.” In the often frantic ED environment, he said, “there is not a lot of time for evidence-based medicine,” so errors often go unnoticed or unreported and they “continue to recur.” When pharmacists at University of Kentucky HealthCare were assigned to the ED and saw what was happening, Dr. Weant said their first reaction was to “target the systems and opera-
tions that could be improved to protect patients” from the harm that medication errors can cause. One of their first projects was to create a better system for distributing medications to boarded patients. “The ED was never built for patients boarding for extended periods,” Dr. Weant said, adding that many of these patients are among the sickest in the hospital. To improve the haphazard distribution system for these patients, the ED pharmacists built a patient-specific bin system to hold the medications until administration. Then they got everyone on board with how the new system would work.
concentration errors, diluent errors and labeling errors,” Dr. Weant said.
Part 2 of a Two-Part Series
Prospective Drug Order Review
For Part 1, visit http://www. pharmacypracticenews.com/fwd/14101.htm
At Mission Hospitals in Asheville, N.C., pharmacists’ prospective review of ED medication orders took off after management assigned four clinical pharmacists and six pharmacy technicians to the hospital system’s two ED units. During a yearlong study that began in January 2008, shortly after the ED program was launched, ED pharmacists verified an average of 874 orders a day, according to Bethany Delk, PharmD, BCPS, the emergency medicine phar-
Eric H. Gilliam, PharmD, and Becky Ferguson, RN, working in the Emergency Department at Robert Wood Johnson University Hospital in New Brunswick, N.J.
‘These investigations show improved quality and improved process of care that ultimately result in improved safety and outcomes.’ —Victor Cohen, PharmD To reduce ordering and dosing errors, the pharmacists created new ED order sets for the hospital’s computerized prescriber order entry (CPOE) system. In addition, they installed automatic pop-up messages to warn admitting physicians when they attempted to write a medication order that duplicated an ED physician’s earlier order. They also revised the ED Pyxis automatic-dispensing cabinets using medication usage data and created drip kits for medications that often took longer to come from the pharmacy. The availability of premixed drip kits with attached labels not only meant faster delivery to patients, it also “decreased
macist who led the study, which was presented at the ACCP meeting. “We have two pharmacists working each day” during a single shift from 11:30 a.m. to 11:00 p.m., Dr. Delk explained. “We verified ‘stat’ orders within a median of 2.2 minutes (mean, 4.2 minutes).” Medication orders tagged in the computerized prescriber order entry (CPOE) system as “now” orders were reviewed almost as quickly: within a median of 2.5 minutes (mean, 4.6 minutes). Dr. Delk noted that Mission Hospitals’ goal for pharmacist review of both “stat” and “now” orders is 15 minutes. For routine orders, she said, the hospital’s goal is two hours, but “we verified
these orders within a median of 5.7 minutes (mean, 9.7 minutes).” Based on these numbers, she said, it appeared that the majority of orders were being reviewed prospectively, which is helping to prevent medication errors and adverse drug events from occurring. “If we verify them quickly, we are able to intervene before they are given,” she noted.
The Joint Commission’s Take While Joint Commission standard MM.4.10 requires prospective pharmacist review of all but a few special categories of hospital medication orders, it allows hospitals greater leeway for emergency departments because of the difficulty of providing pharmacist coverage in many parts of the country. However, even a requirement for retrospective ED order review proved difficult for some organizations and had to be abandoned. During the yearlong study, Mission ED pharmacists also monitored their interventions—a total of 2,057 clinical interventions and 34 physicianordered pharmacy consults. The most frequent were code responses (23% of the interventions), therapeutic recommendations (19%), order clarifications (16%), medication histories (16%) and drug information requests (10%). Because of the hectic ED environment, the pharmacists estimated that they documented only 40% to 50% of their interventions. Using a Thomson Healthcare benchmarking tool, they also calculated the costs averted by their interventions—a total of approximately $420,000. “Even though our documentation was incomplete, we’ve made many clinical interventions, and our clinical role is just going to continue to grow,” Dr. Delk said.
ED-Specific Antibiogram A Success At Robert Wood Johnson University Hospital in New Brunswick, N.J., pharmacists in the ED looked at whether providing physicians with an ED-specific antibiogram would change antibiotic prescribing patterns for the majority of ED patients who were not admitted but discharged into the community. Comparing two three-month periods before and after the ED-specific antibiogram
see ED PHARMACY, page 35
Pharmacy Practice News • November 2009
SEPSIS DELAYS continued from page 1
existing severe sepsis and septic shock order set (as directed by the Surviving Sepsis Campaign) and to decrease intensive care unit (ICU) and hospital mortality, according to lead author Garrett E. Schramm, PharmD, a critical care pharmacist and assistant professor of pharmacy at Mayo Clinic, in Rochester, Minn. “Sepsis is a very large problem,” Dr. Schramm said. “At Mayo Clinic, we have 10,000 admits to the intensive care unit each year, nearly 1,000 of which are related to sepsis. The literature shows that for every hour delay from the onset of hypotension to treatment, mortality increases by up to 8%.” There are approximately 750,000 new sepsis cases each year in the United States, and mortality associated with severe sepsis is as high as 50%, according to the Surviving Sepsis Campaign. The Institute for Healthcare Improvement and the Surviving Sepsis Campaign guidelines recommend that empiric antibiotics be administered to patients within three hours of severe sepsis or septic shock onset in the emergency department (ED) or within one hour for patients hospitalized in the intensive care units or individual floors.
Prospective Study Detailed Dr. Schramm and colleagues conducted a prospective study of all patients admitted to a medical ICU at Mayo Clinic’s Saint Marys Hospital in Rochester, Minn., between January 2008 and June 2009, who had severe sepsis or septic shock and did not receive timely antibiotic therapy. Of 555 patients screened, 48 (8.6%) met the criteria for delayed antibiotic administration, with a median time of 197 minutes. Failure to identify severe sepsis or septic shock was the reason for most of the delay in treatment, accounting for 65.4% of the time lapse (median time, 129 minutes). The second-longest delay resulted from lags between pharmacy processing and antibiotic administration, accounting for 28.6% of the time (median time, 52 minutes). These results led Dr. Schramm and colleagues to actively improve sepsis treatment at the hospital, by educating staff (including residents and nurses) on the warning signs of sepsis, and hastening delivery of antibiotics, vasopressors and fluids to patients. The hospital has established a sepsis response team, so nurses who suspect a patient has sepsis can electronically page a multidisciplinary intervention team that includes a pharmacist. Regarding antibiotics, the pharma-
cy team has created electronic severe sepsis and septic shock order sets in computerized prescriber order entry (CPOE) programs. Menus prompt physicians to choose an antibiotic based on the presumed source of infection, with preformatted choices of antibiotics and dosages (dosing can be adjusted later as necessary). This first dose of antimicrobials comes to the pharmacy as a STAT order, and the label that prints out instructs health care providers to administer the drug within one hour. The CPOE programs also include an order set for fluids, including goals for resuscitation. In addition, the hospital pharmacy now stocks premade norepinephrine in the intensive care units’ Pyxis machines, for easy access by nurses. Preliminary analysis has shown that these steps have dramatically improved compliance with the sepsis campaign guidelines, Dr. Schramm noted.
A Multisite Effort Other hospitals have implemented sepsis programs, too. The Joint Commission recognized a medical management team at Christiana Care in Delaware, in 2008, for its work reducing sepsis mortality. Introducing sepsis resuscitation and critical care management standards throughout the health system starting in January 2005, led to a 49.4% decrease in mortality rates—from 61.7% in 2004 to 24.6% by December 2007. The changes also brought a 34% decrease in average hospital lengths of stay and a 188.2% increase in the proportion of patients discharged to home, according to a report published in the Joint Commission Journal on Quality and Patient Safety (2008;34:187-191). Megan B. Farraj, PharmD, a clinical pharmacy specialist in the medical ICU at the health system, said that before implementing changes, her organization had problems similar to Mayo Clinic’s. During her hospital’s quality improvement efforts, she helped create Sepsis Alert medication kits, containing a single dose of one of 10 antibiotics that were placed in the ED and ICU automated drug dispensing cabinets, so nurses or a rapid response team member identifying the patient could grab the kit. “Although this eliminated waiting times, it brought up risks,” Dr. Farraj said. She and her colleagues put warnings on all kits to check patients for appropriate doses and for medication allergies before administering the drugs. The pharmacists also created an antibiotic selection chart to help residents choose the most appropriate medication for a variety of infections, and included alternatives for patients with allergy to penicillin. They also made up a poster explaining broadversus narrow-spectrum antibiotics, to enable nurses to prioritize the order of antibiotic administration.
Improving Timing Of Antibiotics For Sepsis Patients
he Surviving Sepsis Campaign (SSC) recommends that health care providers begin intravenous antibiotic therapy as early as possible, and always within the first hour of recognizing severe sepsis and septic shock in ICU patients. But antibiotic vigilance shouldn’t end after initiation, according to the SSC guidelines. Antimicrobial regimens should be reassessed after 48 to 72 hours on the basis of microbiological and clinical data, with the aim of using a narrow-spectrum antibiotic to prevent resistance, and reduce toxicity and costs. Here are some additional tips from the SSC Web site: 1. Establish a premixed quantity of broad-spectrum antibiotics to be available in the emergency department and ICU, in order to avoid delays involving pharmacy acquisition of the antibiotic. 2. Infuse antibiotics through multiple lines as available in order to speed delivery of agents. 3. Cover both gram-positive and gram-negative organisms. 4. Consider specific knowledge about the patient’s organism exposure if available, including fungal infection, the setting from which the patient arrived in the ED (e.g., another institution that may harbor a resistant organism), and community and hospital resistance patterns in making choices. 5. Consider double antibiotic coverage for Pseudomonas if clinical suspicion warrants, although there is no evidence-based definitive answer on this issue. For more information, see www.survivingsepsis.org.
The kits proved so popular that the team soon put them throughout the ED, and used their ED clinical pharmacist in the sepsis alert process for consult before medication is administered. —Karen Blum
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Pharmacy Practice News • November 2009
VANCOMYCIN continued from page 1
two groups based on their vancomycin trough levels: group A had troughs of 15 mg/L or lower, and group B had troughs higher than 15 mg/L. Patients on concurrent nephrotoxic medications or who had preexisting renal impairment were excluded from the study. Average vancomycin troughs were 8.9 mg/L for group A and 20.9 mg/L for group B. The researchers documented nephrotoxicity in one of 50 patients (2%) in group A and in 12 of 55 patients (21.8%)
in group B, according to Jenana Halilovic, PharmD, lead author of the study and currently assistant professor at the Thomas J. Long School of Pharmacy and Health Sciences at the University of the Pacific in Stockton, Calif. On average, patients in group B received a higher cumulative dose of vancomycin than group A (average, 22 vs. 17.7 g) and had a longer treatment duration (average, 22 vs. 18 days) and a longer hospital stay (average, 13 vs. eight
days), Dr. Halilovic and her team noted in a presentation at the American College of Clinical Pharmacy’s annual meeting. High er vanc o myci n trough goals of 15 to 20 mg/L are generally recommended for the treatment of serious infections, Dr. Halilovic noted. “Monitor patients closely and be aware of patients at higher risk for kidney problems, including elderly patients and those on nephrotoxins or with preexisting kidney disease,” she said.
A D V E R T I S E M E N T
Postoperative complications: The pharmacist’s role in prevention
In addition, she advised, “Vancomycin trough levels need to be checked at least once a week. Inpatient pharmacists should also be diligent about monitoring patients’ renal function on a daily basis.”
Other Factors To Consider Michael Rybak, PharmD, MPH, professor of pharmacy and medicine and director of the Anti-Infective Research Laboratory at the Eugene Applebaum College of Pharmacy and Health Sciences at Wayne State University, in Detroit, said that although this study and another just published (Clin Infect Dis 2009;49:507-514) indicate that there is some relationship between very high trough levels and nephrotoxicity, there are other factors that may play a role in driving up nephrotoxicity rates. These include known risk factors such as older age in patients who already have lower renal function, and concomitant use of aminoglycosides such as gentamicin. In addition, the definition of nephrotoxicity may affect the frequency at which the adverse reaction is reported. In a recent study of 109 patients at Dr. Rybak’s hospital treated with high-dose vancomycin for methicillin-resistant Staphylococcus aureus, nephrotoxicity rates were about 10%. That study was presented in March 2009 at the European Society of Clinical Microbiology and Infectious Diseases in Helsinki, Finland. Although the rate of nephrotoxicity in the study was lower than recently reported, Dr. Rybak said he still believes that close monitoring of patients on high-dose vancomycin is warranted.
Large Vancomycin Review Offers Some Direction Dr. Rybak served as lead author for a recent review of vancomycin monitoring for the American Society of HealthSystem Pharmacists, the Infectious Diseases Society of America and the Society of Infectious Diseases Pharmacists, published in January in the American Journal of Health-System Pharmacists (2009; 66:82-98). The article recommends that to improve clinical outcomes for complicated infections such as bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia caused by S. aureus, total trough serum vancomycin concentrations of 15 to 20 mg/L are recommended. A patient should be identified as having experienced vancomycin-induced nephrotoxicity only if multiple (at least two or three consecutive) high serum creatinine concentrations (increase of 0.5 mg/dL or ≥50% increase from baseline, whichever is greater) are documented after several days of vancomycin therapy in the absence of an alternative explanation. —Karen Blum
An under-recognized complication, immune-mediated coagulopathy (IMC) can result in: • Signiﬁcant utilization of blood and blood products • Costly studies and consultations • Reoperations for actively bleeding patients • Extended hospital stays Learn how to reduce the risk of this type of complication in July’s supplement to Pharmacotherapy, “The Pharmacist’s Role in the Prevention of Immune-mediated Coagulopathy.” • Developed from a 2008 ASHP Midyear Meeting continuing education n symposium, topics include: “Achieving hemostasis in the surgical ﬁeld” — Bradley Boucher, PharmD, and Oren Traub, MD, PhD “Topical thrombins: beneﬁts and risks” — Christopher Lomax, PharmD, and Oren Traub, MD, PhD “Immune-mediated coagulopathy: a case study” — Joseph Naoum, MD “Thrombin products: economic impact of immune-mediated coagulopathies and practical formulary considerations” — Stacy Voils, PharmD • Available to all concerned professionals in print or online at www.pharmacotherapy.org
©2009 Alpha & Omega Worldwide, LLC
Pharmacy Practice News • November 2009
Critical Care improved quality and improved process of care that ultimately result in improved safety and outcomes.”
ED PHARMACY continued from page 31
was distributed, the investigators found a trend toward a higher rate of sensitive empiric therapy selection among prescribers. Eric H. Gilliam, PharmD, the ED pharmacy resident who led the study and is now the ED pharmacist at the Queen’s Medical Center in Honolulu, said the research was initiated because of a perceived mismatch between the inpatient antibiogram and the antibiotic choices made by the treating physicians. “When we decided to target antibiotic selection,” he said, “we realized that the inpatient antibiogram didn’t really apply to patients coming to the ED and being treated as outpatients.”
References 1. Cohen V, Jellinek SP, Hatch A, Motov S. Effect of clinic pharmacists on care in the emergency department: A systematic review. Am J Health-Syst Pharm. 2009;66:1353-1361.
The University of Kentucky HealthCare emergency medicine team (left to right): Amy Herrington, RN, Penne Allison, RN, Kyle Weant, PharmD, Patty Howard, PhD, RN, Roger Humphries, MD.
2. Pederson CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: Dispensing and administration–2008. Am J Health-Syst Pharm. 2009;66:926-946.
During a yearlong study that began in January 2008, shortly after the ED program was launched, ED pharmacists verified an average of 874 orders a day. Working with the microbiology laboratory, the pharmacists developed an antibiogram specifically for the ED, and at an ED staff meeting, Dr. Gilliam discussed the microbiology data and distributed laminated, pocket-sized reference cards with the ED-specific antibiogram plus tables giving antibiotic dosing and cost data. To carry out the study, which was presented at the ACCP meeting, the pharmacists obtained positive urine culture data for 146 ED patients, 82 during the baseline period and 64 during the postintervention period. The numbers were too small to establish statistical significance, but the researchers did find some trends. For example, the rate of sensitive empiric therapy increased to 43.3% postintervention from an earlier 40.2%. Moreover, prescribers’ antibiotic selection more closely reflected isolate sensitivities, with decreases in the use of fluoroquinolones (62% to 50%) and trimethoprim/sulfamethoxazole (11% to 3.1%) and increases in first-generation cephalosporins (14.1% from 6.1%) and nitrofurantoin (9.4% from 6.1%). The changes reflected the sensitivities of isolates found in the ED urine cultures, particularly the preponderance of E. coli (69%).
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Dr. Cohen commended the investigators for their study projects. “Pharmacists are continuing to push the line further into emergency departments, and their role continues to be accepted,” he said. “These investigations show
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Pharmacy Practice News • November 2009
Drugmaker Files Citizen Petition Against Bovine Thrombin Whether tit-for-tat or patient protection may depend on perspective
early two years after King Pharmaceuticals filed a Citizen Petition with the FDA against ZymoGenetics’ recombinant thrombin product, Recothrom, the tables have been turned. On Aug. 20, ZymoGenetics filed a Citizen Petition of its own against King’s bovine thrombin product, Thrombin-JMI, charging that case reports of adverse events (AEs) continue to accumulate, and that the availability of both human and recombinant products obviates the rationale for keeping the bovine product on the market. Whether the latest action is a simple case of corporate payback or a meritorious attempt to safeguard patient safety is difficult to judge, given the lack of publicly available reports of AEs since King added a new filtration step last year to remove factor V/ Va from its Thrombin-JMI. The additional filtration prompted the FDA to approve revised labeling regarding the product’s purity. On the other hand, King’s prod-
uct received a “black box” warning in 1996—and still retains it—related to the rare risk for severe bleeding or thrombosis, presumably related to the formation of antibodies against bovine thrombin and/or factor Va. The case is further clouded by concerns expressed in recent years by members of Congress that drugmakers have abused the Citizen Petition process by seeking simply to block competitors’ products.
Petition cites 25 adverse events—in 13 million doses. In September 2006, U.S. Sens. Herb Kohl (D-Wis.) and Patrick Leahy (D-Vt.) introduced legislation to prohibit brand-name drug companies from “abusing” the Citizen Petition law by using it to delay the approval of a generic drug by months or years. The
senators noted of the 21 citizen petitions that had been reviewed and ruled on by the FDA between 2003 and 2006, only one had been found to have merit. Jack Howarth, vice president of investor relations for King Pharmaceuticals, based in Bristol, Tenn., said the firm would not comment on the ZymoGenetics action. The petition cited a total of 25 cases of AEs out of 13 million surgeries in which King’s drug has been used, according to company documents. ZymoGenetics insisted that its petition was based only on concerns for patient safety. “Despite almost 20 years of data that patients can have these reactions [to bovine thrombin], it was thought that in the aggregate, the risk–benefit ratio was considered reasonable,” said W. Allan Alexander, MD, medical director of the Seattle-based company. That ratio changed once human and recombinant products became available, he said. Two academic physicians who have published studies on the products have supported the firm’s view. “Most of us who advise them really do believe that a recombinant human protein, or a human protein, is safer and should take care of the iatrogenic effect that still can occur with the bovine product,” said Paul M. Ness, MD, chief of transfusion medicine at Johns Hopkins Hospital in Baltimore and editor of the journal Transfusion. Although Dr. Ness has served in an advisory role to the company, he said he was not involved in ZymoGenetics’ decision to bring the Citizen Petition. Both Dr. Ness and another physician who has consulted for ZymoGenetics conceded that the firm has a commercial interest in attacking a competitor’s product. But they insisted that their own views were based solely on the products’ medical risks and benefits. “There’s no question there’s a commercial interest here,” said Fred Weaver, MD, chief of vascular surgery at the University of Southern California Keck School of Medicine, in Los Angeles. However, Dr. Weaver added, “There are now two other thrombin products with
the same efficacy, and without any risk that we know of on the market. So why do we still need bovine thrombin? It does carry a ‘black box’ warning.” Thrombin, used routinely by surgeons to check oozing blood and minor bleeding from capillaries and small venules, had been available only from a bovine source until 2007, when the FDA approved the first stand-alone human thrombin preparation, Evithrom (Omrix Biopharmaceuticals). In November of that year, King filed a Citizen Petition with the FDA against the pending approval of Recothrom, asserting that ZymoGenetics had submitted insufficient evidence in support of the drug. But in January 2008, the FDA went ahead with the approval. In August 2009, ZymoGenetics reported that it had generated $6 million in second-quarter sales of Recothrom, in line to achieve its 2009 sales forecast of $25 million to $35 million. A paper co-authored by Dr. Weaver in the journal Biologics in December 2008 (2:593-599) pointed out that dozens of reports of AEs related to the use of bovine thrombin have been published since 1989. In fact, the paper noted, “Almost every surgical specialty has had a case study or series of adverse events related to the use of bovine thrombin.” But in January 2008, the FDA approval revised labeling for King Pharmaceutical’s product, stating that a new filtration method had reduced factor Va levels “below the limit of detection of semi-quantitative Western blot assay (<92 ng/mL, when reconstituted as directed).” Even so, the new label states: “The clinical significance of these findings is unknown.” Dr. Alexander conceded that King had reduced the amount of factor Va in its Thrombin-JMI. But, he said, “If you do the calculations, there is still a fair amount of it. Has the purification been related to improved safety? No study’s been done. Nobody knows what the incidence is. Nobody knows what the baseline was. These recent reports of death suggest there has not been a substantial improvement.” —Dan Hurley
Pharmacy Practice News • November 2009
Can Post-Op Epidurals Preempt Phantom Pain? N
umerous medical treatments have been proposed to treat phantom limb pain—often described as a shooting, stabbing or throbbing pain in the area where a limb has been amputated— yet, current strategies frequently are suboptimally effective. A small group of researchers advocate the use of a preemptive analgesic to treat phantom pain; however, the true efficacy of this technique remains controversial. In a recent case report, Antoun Nader, MD, lead author and an anesthesiologist at Northwestern University Feinberg School of Medicine, in Chicago, treated a 48-year-old man for “suspected” phantom pain by placing an epidural catheter at the L2-3 level immediately following left hip disarticulation. The patient had been suffering from pleomorphic cell carcinoma for four years, and had been treated with radiation and chemotherapy. He also was taking pregabalin (Lyrica, Pfizer) and morphine daily. “We decided against placing the epidural in the patient prior to surgery because he presented with high INR [international normalized ratio] and had a fever of 101.5 F,” Dr. Nader said. Patients with a high INR, which tests the ability of blood to clot, are at increased risk for developing epidural hematomas. In addition, this patient’s febrile state meant his risk for infection was elevated, Dr. Nader said. However, in the recovery room, the patient complained of pain originating from the amputated foot, despite opioid administration, Dr. Nader said. “Interestingly, the patient did not complain of foot pain prior to his operation,” he said. In most cases, the presence of severe pain prior to amputation is associated with a higher risk for post-amputation phantom pain, Dr. Nader said. “It’s still tough to say whether the patient’s foot pain was definitely phantom pain. How long does pain need to persist before we can call it phantom pain?” The risks and benefits were discussed again with the patient postoperatively, and both parties decided the benefits of an epidural catheter outweighed the
‘Phantom pain is thought to be a neuropathic pain resulting from functional changes in the peripheral and central pain pathways subsequent to amputation.’
— Steve Cohen, MD
risks. Following the placement of the epidural catheter—which was run with an infusion of 0.2% bupivacaine and hydromorphone—the patient reported a change in pain intensity from 9 (more severe) to 0 (less severe), Dr. Nader said. The catheter was removed three days after the operation, and the patient was transitioned to oral opioids. “Six months after the amputation, the patient still had no recurrence of phantom pain,” he said. The use of analgesics to prevent and treat phantom limb pain has met with limited success. Many of the studies touting its efficacy have not been properly blinded or randomized, said Lone Nikolajsen, MD, an anesthesiologist at the Danish Pain Research Center at Aarhus University Hospital, and author of several studies on the use of epidural catheters to treat phantom pain. “It is my clinical experience that an
epidural treatment attenuates early phantom pain—when the treatment is stopped on the third, fourth or fifth day, the phantom pain may transiently worsen—but I am not convinced that the treatment has any long-term effect on phantom pain,” she said. Theories for the failure of epidural anesthesia to reduce phantom pain include the idea that preexisting pain memory has already occurred, and that long-lasting improvement of neuron communication might not be achievable by merely removing nociceptive input—activity produced in the peripheral and central nervous systems that has the potential to damage tissue and thus can result in pain, Dr. Nader suggested. Because the patient presented with foot pain after amputation, it is possible that there was no pain memory— meaning that the epidural significantly
reduced nociceptive input, thus altering the sensitization that might be involved in phantom pain, said Dr. Nader. “We conclude that newly developed phantom pain in an amputated organ may be treated with an epidural,” he said. Dr. Nikolajsen, however, said that this conclusion might be too strong. Phantom pain almost always is intermittent, she explained, adding, “There is a chance that the phantom pain described by the patient may have ceased without any intervention.” The mechanisms of phantom pain still are not understood entirely, said Steve Cohen, MD, an anesthesiologist at Johns Hopkins School of Medicine in Baltimore, and director of pain research at Walter Reed Army Medical Center, in Washington, D.C., which annually treats hundreds of soldiers with amputations. “Phantom pain is thought to be a neuropathic pain resulting from functional changes in the peripheral and central pain pathways subsequent to amputation,” he explained. “However, it’s likely that a series of mechanisms are involved, including elements in the periphery, spinal cord and brain— making it hard to treat with a single intervention.” Several internal and external parameters, including stress, genetic predisposition, type of amputation and possibly psychological issues influence phantom pain, Dr. Cohen said. The success of a particular treatment option might vary depending on the combination of these factors. “It’s difficult to draw any conclusions from a case report involving only one patient,” he said. “Further studies are needed to understand the underlying mechanisms of pain in amputees.” Eric Nelson, MD, also an anesthesiologist at the Feinberg School of Medicine, presented results of the study at the 2009 annual meeting of the American Society of Regional Anesthesia and Pain Medicine, in Phoenix (abstract 127). —Michelle Grey Campion
Don’t Sing Praises of Arnica montana for Pain, Swelling ANAHEIM, CALIF.—A new study suggests that patients with leg pain shouldn’t run to their alternative practitioners for topical Arnica montana treatments. In the randomized study, 53 patients were given two tubes of cream, one with the active homeopathic remedy and one with placebo. The tubes were marked “LEFT” and “RIGHT” and were identical in appearance. Patients applied the creams immediately after performing a series of calf raises and then rated their pain in each leg using an analog scale over various time points in the three-day study.
The researchers found that pain scores on the legs of patients treated with Arnica were actually higher than those receiving placebo 24 hours after exercise. No other significant differences were found, reported lead investigator Julie D. Adkison, PharmD, of the Memorial Family Medicine Residency Program in Sugar Land, Texas. Based on those results, “it appears that Arnica may actually increase leg pain, at least in the first 24 hours after exercise,” noted Dr. Adkison, whose study was presented at the American College of Clinical Pharmacy annual meeting.
A Leg Up on the Literature On 2007, Samir A. Kousi, PhD, professor of pharmacy at the School of Pharmacy, Wingate University, in Wingate, N.C., wrote a review on Arnica (Am J Health-Syst Pharm 2007;64:2434-2442). Dr. Kousi’s article cited approximately 10 clinical studies of the homeopathic remedy’s impact on pain and swelling. The most common finding was that Arnica, whether used as an oral or a topical agent, was no better than placebo. —David Bronstein
Pharmacy Practice News • November 2009
Gene Assay Predicts Risk for Colon Cancer Recurrence Orlando, Fla.—A recurrence score based on a gene profile may help guide doctors in deciding when to use adjuvant therapy to reduce the risk for recurrence in patients with stage II colorectal cancer (CRC) who have undergone surgery. According to a recent study, a score based on the gene profile not only predicts recurrence risk, but disease-free survival (DFS) and overall survival (OS) as well. Genomic Health plans to launch the tool, Oncotype DX Colon Cancer Assay, based on the gene profile, in early 2010. “This is the first study of a prospectively defined recurrence score that has been validated as a predictor of recurrence in stage II CRC following surgery. We showed that it has independent predictive value beyond previously available measures,” said David J. Kerr, MD, professor of clinical pharmacology at Radcliffe Infirmary, Oxford University, in Oxford, United Kingdom. Presenting the study at the recent annual meeting of the American Society of Clinical Oncology (ASCO; abstract 4000), Dr. Kerr said that the multivariate analysis in which the recurrence score retained significance included mismatch repair, T stage, nodes examined, tumor grade and lymphovascular invasion.
Need for Improvement Because only 70% to 80% of patients with stage II CRC are cured by resection, clinicians have long been interested in trying to identify which patients may benefit from adjuvant chemotherapy. In 2007, investigators published results from the QUASAR study that randomized 3,329 patients, after apparently curative resection of colorectal cancer, to treatment with 5-fluorouracil and leucovorin (5-FU/LV) or observation (Lancet 2007;370:2020-2029). Assuming that the five-year mortality rate without chemotherapy is 20%, the relative risk
High-risk patientsa a
for death translated into an absolute improvement in survival of 3.6% (95% confidence interval [CI], 1.0%-6.0%). Because of the small improvement in survival, treatment cost and significant toxicities associated with 5-FU/LV, use of this therapy has not become standard practice. The concept that recurrence risk is at least partly mediated by genetic vul-
5-FU/LV. For the current validation study, these were subsequently whittled down to seven prognostic genes and six genes predicting therapeutic response. The validation study used tumor blocks collected during the course of the QUASAR study (from 68% of the participants). Gene expression was evaluated by reverse transcriptase-polymerase chain reac-
‘This is the first study of a prospectively defined recurrence score that has been validated as a predictor of recurrence in stage II CRC following surgery. We showed that it has independent predictive value beyond previously available measures.’ —David J. Kerr, MD nerability led investigators to attempt to identify a gene profile that might be useful in predicting recurrence and identifying patients who could benefit from adjuvant chemotherapy. From a multicenter collaborative effort, 48 genes were identified that had a significant association with increased risk for recurrence of CRC. Another 66 genes were found to predict response to
Risk categories are determined according to gene profile.
Risk for Recurrence, %
12 10 5 0
Figure. Comparison of risk for recurrence using gene profile.
tion (RT-PCR) on paraffin-embedded primary colon cancer tissue. Based on a gene profile for recurrence that emerged from analysis of the tissue samples from previously conducted studies, the investigators tested the prognostic value of a prospectively defined recurrence score in an independent set of patients from QUASAR. Similarly, they tested whether a prespecified gene profile that assessed response to 5-FU/LV could predict protection from recurrence.
A Tool Emerges Of 1,490 tumor blocks collected from stage II colon cancer patients in QUASAR, 1,436 met all inclusion and exclusion criteria for the study and were subsequently analyzed by quantitative RT-PCR. When the prespecified range of recurrence scores was stratified into low, intermediate and high risk, the recurrence rate at three years was approximately twice as high in the high- versus low-risk groups (22% vs. 12%). The intermediate-risk group had a recurrence rate of 18% (Figure). In contrast, gene expression predicting response to 5-FU/LV was not validated as a useful tool for identifying patients likely to benefit from this therapy.
The investigators analyzed other predictors of recurrence in the context of the gene signatures and found independent predictive value from mismatch repair deficiency, which was associated with a 69% reduction in the risk for recurrence (hazard ratio [HR], 0.31; 95% CI, 0.15-0.63; P<0.001), and stage T4 tumors, which were associated with a 94% increased risk for recurrence (HR, 1.94; 95% CI, 1.352.79; P=0.005). Going forward, Dr. Kerr suggested that these two factors might improve the clinical utility of the gene profile in identifying patients who might benefit from adjuvant chemotherapy. According to Ed Chu, MD, who was not involved with the study, the study is the first to show that a prospectively defined gene assay can independently predict disease recurrence following surgery in patients with stage II colon cancer. “This multigene assay may help patients at increased risk for disease recurrence and may be most useful in patients for whom conventional risk assessment parameters, such as T stage or microsatellite instability, are uninformative,” commented Dr. Chu. He is chief of the Section of Medical Oncology and deputy director of clinical research at the Yale Cancer Center, Yale University School of Medicine, New Haven, Conn. Although the results from this study are encouraging, other researchers are more cautious in what they actually mean for patients. Charles S. Fuchs, MD, director of the gastrointestinal malignancy program at Dana-Farber Cancer Institute, in Boston, cautioned that “it is too early to know whether this gene profile should be part of routine management.” In particular, although a high recurrence score was able to identify a patient population that had an increased likelihood of a recurrence, no prospective evidence exists that adjuvant treatment with 5-FU/LV or another therapy would have reduced this risk. Studies demonstrating that acting on prognostic information can change the course of disease are needed, he said. Although Dr. Fuchs agreed with the premise that individualized care is likely to improve outcomes in CRC, he noted that few of the “ever increasing number of candidate biomarkers” have been validated in their ability to guide management so that patient outcomes improve. It’s possible, however, that gene profiling could provide greater prognostic value than biomarkers and thus improve patient care. Despite the promise of this gene validation study, Dr. Fuchs said that the benefit of offering adjuvant chemotherapy in high-risk patients still must be proven in a prospective study. —Ted Bosworth
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Pharmacy Practice News • November 2009
Largest Adjuvant ADT Study Generates Surprising Outcomes Orlando, Fla.—Follow-up from the largest study ever conducted in patients receiving adjuvant androgen deprivation therapy (ADT) after radical prostatectomy has generated a surprisingly low relapse rate of prostate cancer. At five years, overall survival (OS) in patients receiving ADT is 95% (90% in high-risk individuals), a rate that is higher than those seen in similar studies. It is not clear, however, whether the low relapse rate can be fully attributed to the therapy, which consisted of a combined androgen blockade of goserelin (Zoladex, AstraZeneca) and bicalutamide (Casodex, AstraZeneca), or whether other contributing variables played a role, such as the relatively high number of individuals considered to be low risk. What the study does do is contribute to data indicating that “prostate cancer patients diagnosed in 1999 through 2007 have improved survival compared with previous decades,” said L. Michael Glodé, MD, professor of medical oncology at the University of Colorado Health Sciences Center, Aurora. The study revealed overall relapse-free survival (RFS) at five years was 92.5%, a promising result at this milestone. Even in the high-risk patients, 87.5% remained relapse-free at the end of five years. Dr. Glodé acknowledged that longer followup is needed to confirm the benefits of ADT after five years. The study, run by the Southwest Oncology Group (SWOG) and presented by Dr. Glodé at the most recent meeting of the American Society of Clinical Oncology (ASCO; abstract 5009), was designed to compare the combination of goserelin and bicalutamide with the same dual-androgen blockade plus mitoxantrone (Novantrone, Serono/OSI Pharmaceuticals) and prednisone as adjunctive treatment after radical pros-
Syringe of goserelin
The study revealed overall relapse-free survival at five years was 92.5%, a promising result at this milestone. tatectomy. The primary end point of the trial, conceived in 1997 and launched in October 1999, was OS with several secondary end points, including diseasefree survival. However, the Data and Safety Monitoring Committee (DSMC) recommended discontinuing the chemotherapy arm in January 2001 because of an increased number of cases of acute myelogenous leukemia (AML). By the time the data were presented at ASCO, there had been five cases of AML among the 487 patients randomized to chemotherapy and no cases in the arm that received ADT alone. The data presented at ASCO were
limited to the 376 patients who were randomized to the ADT-alone arm and had completed at least two years on the protocol. Although all patients might be considered high risk because of adverse pathologic risk factors after surgery, the outcomes were stratified by low-, intermediate- and high-risk categories. Although Dr. Glodé acknowledged these distinctions were “somewhat arbitrary” in the absence of accepted definitions, low risk was defined as positive margins or extraprostatic extension only. Intermediate risk was defined as seminal vesicle invasion of Gleason score of 8 or greater but no positive nodes. High risk was defined by positive nodes. When these risk groups were compared, survival (95%, 96% and 90%, respectively) was appreciably lower only in the highrisk group. For RFS (98%, 91.6% and 87%, respectively), each increase in risk category was associated with about a 5% reduction in the end point. Of the 17 deaths in the study overall, seven were from prostate cancer, four were from another type of cancer, and the remaining six deaths were from noncancer causes of which only one death was cardiovascular, which was considered low for this study group. In the 189 patients for whom there was sufficient follow-up and data on testosterone recovery, the median time for patients to achieve levels at the lower limit of normal was 9.5 months with 28% achieving this outcome by six months, 75% by 12 months and 90% by 18 months. One of the reasons for the high rates of survival may be that 25% of patients were in the low-risk category (approximately 60% were intermediate risk). In reviewing other studies evaluating ADT, Dr. Glodé said that definitions of risk may have varied, but results from previous
studies are not inconsistent with results from the new study. For example, a study that compared immediate with delayed adjuvant androgen deprivation associated immediate treatment with significant improvements in OS (hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.01-3.35; P=0.04), prostate cancer-specific survival (HR, 4.09; 95% CI, 1.76-9.49; P=0.0004) and progression-free survival (HR, 3.42; 95% CI, 1.96-5.98; P<0.0001) at median follow-up of 11.9 years. That study also associated immediate androgen deprivation with statistically significant improvements in progression-free survival (P<0.0001) and prostate cancerspecific survival (P=0.0004). Asked to comment on the study, Joel Nelson, MD, chairman of the Department of Urology at the University of Pittsburgh, suggested that patients with positive margins but no positive nodes might be in a marginal zone of high risk. He offered the term “low high-risk patients,” agreeing that the substantial representation of such patients in the SWOG study may explain the high rates of survival. Overall, these results verify a benefit from androgen deprivation, but Dr. Nelson expressed more interest in the original study objective, which was to compare androgen deprivation with or without chemotherapy. He suggested that he is “very much in favor” of providing adjuvant chemotherapy in highrisk patients based on the available data, but indicated the practice needs validation with controlled evidence. Unfortunately, the data to assess the activity of the chemotherapy arm may be years away, and they will have to clear “an extremely high bar” with high rates of RFS achieved with androgen blockade alone. —Ted Bosworth
FDA Clears Test for Ovarian Cancer
he FDA has cleared OVA1 (Vermillion), a test that can help detect ovarian cancer in a pelvic mass that is already known to require surgery. The test will help guide decisions about what type of surgery should be performed. In 2002, the American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncologists published recommendations for the role of generalist OB/GYNs in the early detection of ovarian cancer, which included a recommendation of patient referral to a gynecologic oncologist when specific indicators of malignancy are present. These recommendations and later reports indicate that patients with ovarian cancer have improved survival when the surgery is performed by gynecologic oncologists as opposed to general gynecologists or surgeons. OVA1 identifies women who will benefit from refer-
ral to a gynecologic oncologist for surgery, despite negative results from other clinical and radiographic tests for ovarian cancer. If other test results suggest cancer, referral to an oncologist is appropriate even with a negative OVA1 result. The new test should be used by primary care physicians or gynecologists as an adjunctive test to complement, not replace, other diagnostic and clinical procedures. OVA1 uses a blood sample to test for levels of five proteins that change as a result of ovarian cancer. The test combines the five separate results into a single numerical score between 0 and 10 to indicate the likelihood that the pelvic mass is benign or malignant. OVA1 is intended only for women aged 18 years and older, who are already selected for surgery because of their pelvic mass. It is not intended for ovarian can-
cer screening or for a definitive diagnosis of ovarian cancer. Interpreting the test result requires knowledge of whether the woman is pre- or postmenopausal. The FDA reviewed a study of 516 patients, including 269 evaluated by nongynecologic oncologists, which compared OVA1 results with biopsy results. When combined with presurgical information, such as radiography and other laboratory tests, results from the OVA1 tests identified additional patients who might benefit from oncology referral who were not identified using presurgical information alone. —Kate O’Rourke
Hem/Onc Pharmacy 41
Pharmacy Practice News • November 2009
Genetic Variations Predict Outcomes in Pancreatic Ca a univariate analysis, Dr. Li reported. Patients were divided into groups based on the number of unfavorable genotypes (defined by their association with poor response, lower likelihood of
Table. Combined Effect of Adverse Genotypes on Survival Number of Adverse Genotypes
Median Survival (mo)
‘We hope to identify a panel of mutations, like Dr. Li has done, that indicate poor response to chemotherapy and poor survival. If we can do this, we can avoid aggressive therapies in those unlikely to benefit.’ —Jennifer Obel, MD resection and shorter survival time). In particular, EXO1, MLH1, TREX1 and TP73 genotypes were significantly associated with clinical outcomes after adjusting for other factors. At a median follow-up of 50 months, median survival for the whole cohort was 21.7 months, but favorable genotypes were associated with longer median survival. For example, median survival for patients with the “good” TP73 GG/GA genotype was 25.5 months, compared with only 7.4 months for those with
chemoradiation at M.D. Anderson. Investigators looked for the presence of 15 single-nucleotide polymorphisms (SNPs) of eight DNA mismatch repair genes; the genes encode proteins that repair chemotherapy-induced DNA damage and enable cancer cells to become resistant to treatment. Five DNA mismatch repair genes were found to be significantly associated with tumor response, six were associated with resectability and 10 were associated with overall survival in
21.6 20 15.5
7.4 TP73 Ex2+ 4G>A AA
TP73 Ex2+4G>A GG/GA
TREX1 Ex14-460C>T CC
EXO1 R354H GG/AA
EXO1 R354H GG
TREX1 Ex14-460C>T TT/CT
TREX1 Ex14-460C>T CC
TREX1 Ex14-460C>T TT/CT
% of Patients With Partial Response/Stable Disease
the “bad” TP73 AA genotype. Similarly, response and resectability rates also were higher for patients with favorable genotypes (Figures 1 and 2). Dr. Li speculated that the observed effects may be related to interference with the ATR/Chk1 signal pathway and failed apoptosis in response to gemcitabine-induced DNA damage. “For example, after neoadjuvant treatment, tumors actually became larger in 27.3% of the TP73 GA/AA genotype carriers versus 5.7% of the TP73 GG carriers,” she noted. The GG carriers had an 83% R0 resection rate, compared with 51.5% of the GG/AA carriers. “We observed that some genotypes had weak effects, but when we combined the genotypes together, we saw a strong effect on each clinical end point,” she continued. “Median survival time diminished as the number of variants increased.” (See table.) “Identifying a panel of genes that are working on the same pathway may help predict treatment response, and identify patients who will benefit from tumor resection,” Dr. Li concluded. According to Jennifer Obel, MD, a gastrointestinal cancer specialist from NorthShore University HealthSystem, Chicago, Dr. Li’s research exemplifies goals for the future of gastrointestinal treatment. “We know that the majority of pancreatic patients will [have recurrent cancer] and die of disease within five years,” she said. “We hope to identify a panel of mutations, like Dr. Li has done, that indicate poor response to chemotherapy and poor survival. If we can do this, we can avoid aggressive therapies in those unlikely to benefit.”
TP73 Ex2+4G>A GA/AA
outcome,” she said. The study included 154 patients with potentially resectable pancreatic adenocarcinomas enrolled in two Phase II trials of neoadjuvant gemcitabine-based
TP73 Ex2+4G>A GG
San Francisco—Certain genetic variations may enable clinicians to predict response to treatment, resectability of tumor and survival in patients with pancreatic cancer, according to a new study. The findings may explain why the disease is deadly in some patients, but indolent in others, said Donghui Li, PhD, professor of gastrointestinal medical oncology at The University of Texas M.D. Anderson Cancer Center, Houston. She presented her findings at the 2009 Gastrointestinal Cancers Symposium (abstract 118). Approximately 30% of patients with resectable pancreatic cancer do not benefit from tumor resection because of rapidly progressive disease. Clinicians, however, have had difficulty identifying which patients will benefit. Factors that influence a patient’s response to gemcitabine (Gemzar, Eli Lilly), which is standard therapy, also are not well defined. Pharmacogenetic studies have shown that genetic variations in drug metabolism and DNA repair affect individual response to therapy. DNA mismatch repair is a critical genome caretaker that guards genomic stability by correcting mismatches generated during DNA replication and recombination. It also triggers apoptosis in cells with severe DNA damage. In vitro studies have shown that cells deficient in DNA mismatch repair are more sensitive to gemcitabine-mediated radiosensitization, Dr. Li explained. “Based on this information, our goal was to determine whether there is an association between genetic variation in DNA mismatch repair and the clinical outcomes of patients and to see if genetic markers can be used for prognosis, or for prediction of therapeutic
Figure 1. Association of genotype with overall survival.
Figure 2. Association of genotype with tumor response to neoadjuvant gemcitabine-based chemoradiation.
Pharmacy Practice News • November 2009
Biologic Pain Drug Shows Promise in Phase II Trial Monoclonal antibody provides good specificity for peripheral pain
Phase II trial of tanezumab (RN624, Pfizer) has shown that the drug significantly improves chronic low back pain and physical functioning with few side effects. Results of the trial were presented at the 2009 annual meeting of the American Pain Society in San Diego (abstract 268). “For any study drug to have a significant effect over another on physical functioning is very unusual,” said Nathaniel Katz, MD, adjunct assistant professor of anesthesia at Tufts University School of Medicine in Boston, and the study’s lead author. (Dr. Katz’s company, Analgesic Research, was a consultant for Pfizer on the design of the trial.) “This is only one trial, but the data that we’ve seen is quite promising.” The drug, a monoclonal antibody against nerve growth factor, likely will be the first biologic agent approved by the FDA specifically for the treatment of pain. In the study, patients with chronic low back pain were randomized to one of three arms along a double-dummy
study design: IV tanezumab 200 mcg/kg and oral placebo (n=88), IV placebo plus oral naproxen 500 mg (n=88), or IV placebo plus oral placebo (n=41). Baseline characteristics, including average low back pain scores, were similar across all three groups. The study’s primary end point was an average score on the Low Back Pain Intensity scale (aLBPI, 0–10) after six weeks. Secondary end points included treatment response (≥30% or ≥50% reduction in aLBPI) and RolandMorris Disability Questionnaire (RMDQ) scores. Patients receiving a single injection of tanezumab scored almost one point lower than patients taking naproxen on the aLBPI scale after six weeks (tanezumab, –3.37; naproxen, –2.54; P=0.004), and almost 1.5 points lower than placebo (–1.96; P<0.001). Tanezumab also performed better than naproxen in secondary outcomes, which included quality-of-life indicators and improvements in physical functioning. Specifically, patients receiving tan-
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The drug, a monoclonal antibody against nerve growth factor, likely will be the first biologic agent approved by the FDA specifically for the treatment of pain. ezumab had a significantly higher rate of treatment response (50% improvement) compared with those receiving naproxen (57% vs. 34%; P=0.0002) and placebo (20%; P<0.001), as well as in RMDQ scores compared with naproxen (–7.70 vs. –4.69; P<0.001) and placebo (–3.93; P<0.001). And importantly for an antibody, the single tanezumab injection “lasted for the full three months of observation,” said Dr. Katz, significantly outperforming naproxen at 12 weeks. Because tanezumab knocks out nerve growth factor, a key protein in the early development of nerves that also sensitizes nerves to pain in adults, the drug does have the potential to cause adverse neurologic events. Investigators found that 11% of patients in the study reported what Dr. Katz characterized as “abnormalities of sensory processing”—tingling, numbness and hypersensitivity to touch— and two or three of these may have been at least partially unresolved at the end of the trial. “The big picture with all of these drugs appears to be the same thing: If you give enough, you get pain relief that lasts for a long time, and if you give more than enough, you get this sensory syndrome,” said Dr. Katz. “It’s going to be very important in the development of all these drugs to figure out whether this adverse effect is always reversible or are there patients in whom this is not reversible.” But relative to other standard treat-
ments for chronic low back pain, experts say that a large, highly specific molecule like tanezumab—one that does not significantly cross the blood–brain barrier, unlike most opioids—has the potential for far fewer significant side effects. “This ability of monoclonal antibodies to so effectively target and bind to only one molecule with extraordinarily high affinity is difficult to achieve with other means, like smaller molecules,” said Patrick Mantyh, PhD, JD, a professor of pharmacology at the University of Arizona, Tucson, and the Minneapolis VA Medical Center, in Minnesota, who first began studying the compound eight years ago. “As somebody who has looked at a variety of other therapies for pain, if that’s all the side effects that these [monoclonal antibodies] have—paresthesia, hypoesthesia—and they’re transient in nature, that’s very impressive and remarkably small given the side effects that other agents such as NSAIDs [nonsteroidal anti-inflammatory drugs] and opiates have,” said Dr. Mantyh. Ultimately, Phase III trials will determine whether the adverse neurologic effects of tanezumab may hinder a wider population of patients with chronic pain from taking the drug, but experts don’t expect that it will. “Most of these patients would be delighted to trade their back pain for some mild tingling of their toes,” said Dr. Katz. —Gabriel Miller
Pharmacy Practice News • November 2009
Recombinant Human Hyaluronidase Helps Hydration in Kids Boston—Recombinant human hyaluronidase-facilitated subcutaneous fluid administration can be used to successfully and safely rehydrate children who present to the emergency department with mild to moderate dehydration, according to research presented at the American College of Emergency Physicians (ACEP) 2009 Scientific Assembly. The standard method for rehydrating children is to administer fluids intravenously, but this can be extremely dif-
ficult, especially in very young, very sick children, Sharon Mace, MD, told Pharmacy Practice News. Dr. Mace is professor of medicine and director of pediatric education and quality improvement at the Cleveland Clinic, in Ohio. Injections of recombinant human hyaluronidase (rHuPh20), an enzyme, allows fluids to be administered subcutaneously, which enables rapid treatment initiation and delivery of IV-like fluid rates which can lead to successful
rehydration in a less invasive, less painful manner, she said. Moreover, rHuPh20 (Hylenex, Baxter) does not carry a risk for anaphylactic reactions because it is a human form of hyaluronidase, Dr. Mace explained. “Hylenex is new, but the technique is old, because we used to give subcutaneous injections using animal forms of hyaluronidase. With the new recombinant form, to my knowledge, there have been no cases of anaphylaxis reported.”
Immune Globulin Intravenous (Human) Flebogamma® 5% DIF For intravenous use only Rx only
BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Flebogamma® 5% DIF is indicated for replacement therapy in primary (inherited) humoral immunodeficiency disorders. DOSAGE AND ADMINISTRATION The usual dose of Flebogamma® 5% DIF for replacement therapy in primary humoral immunodeficiency diseases is 300 to 600 mg/kg body weight administered every 3 to 4 weeks. An in-line filter with a pore size of 15 to 20 microns is recommended for the infusion. Antibacterial filters (0.2 micron) may also be used. Discard unused contents and administration devices after use. The infusion of Flebogamma® 5% DIF should be initiated at a rate of 0.01 mL/kg body weight/minute (0.5 mg/kg/minute). If, during the first 30 minutes, the patient does not experience any discomfort, the rate may be gradually increased to a maximum of 0.10 mL/kg/minute (5 mg/kg/minute). For patients judged to be at risk for developing renal dysfunction or considered to be at increased risk of thombotic/thromboembolic events, it may be prudent to limit the infusion rate to a maximum rate less than 0.06 mL/kg body weight/minute (3 mg/ kg/minute). Reduction in dose, concentration, and/or rate of infusion in patients at risk of acute renal failure, which includes patients over 65, has been proposed in the literature in order to reduce the risk of acute renal failure. CONTRAINDICATIONS Flebogamma® 5% DIF should not be administered to individuals with a history of severe or anaphylactic reactions to blood or blood-derived products. Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Anaphylaxis can occur using Flebogamma® 5% DIF even though it contains low amounts of IgA (typically < 50 μg/mL). Such patients should only receive intravenous immune globulin with utmost caution and in a setting where supportive care is available for treating life-threatening reactions. If patients are known to be intolerant to any component of Flebogamma® 5% DIF, such as sorbitol (i.e., intolerance to fructose), they should not receive the product. WARNINGS Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Flebogamma® 5% DIF does not contain sucrose. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure. Flebogamma® 5% DIF is made from human plasma. As with all plasma derived products, the risk of transmission of infectious agents, including viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The risk that such products will transmit an infectious agent has been greatly reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Biologicals at 888-GRIFOLS (888-474-3657). All patients, but especially individuals receiving Flebogamma® 5% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at risk for the development of inflammatory reactions characterized by fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations may reduce the risk of these types of events. Appropriate supportive care, including immediate access to epinephrine injection, should be available for the management of acute anaphylactic reactions.
Dr. Mace presented data from the INFUSED Peds II Study (Increased Flow Utilizing Subcutaneously Enabled Pediatric Rehydration II Study), an ongoing Phase 4 open-label trial that randomized otherwise healthy children aged 1 month to 3 years with mild to moderate dehydration to subcutaneous rehydration facilitated with rHuPh20 or to IV rehydration. The children were stratified based on body weight (<10 kg and ≥10 kg) and dehydration severity (mild: Gorelick
PRECAUTIONS General: Any vial that has been entered should be used promptly. Partially used vials should be discarded and not saved for future use because the solution contains no preservative. Do not use if turbid. Solution that has been frozen should not be used. Ensure that patients are not volume-depleted before the initiation of the infusion of IGIV. Renal Function: Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing Flebogamma® 5% DIF at a maximum rate less than 0.06 mL/kg (3 mg/kg) body weight/minute. Aseptic Meningitis Syndrome: An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic milliliter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high-dose (e.g., > 1.0 g/kg body weight) and/or rapid-infusion IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. Hemolysis: Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration [See ADVERSE REACTIONS]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis [See PRECAUTIONS: Laboratory Tests]. Thrombotic Events: Thrombotic events have been reported in association with IGIV (See ADVERSE REACTIONS). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [See PRECAUTIONS: Laboratory Tests]. Transfusion-Related Acute Lung Injury (TRALI): There have been reports of non-cardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1 to 6 hours after transfusion. Patients with TRALI may be managed by using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum [See PRECAUTIONS: Laboratory Tests]. Information For Patients: Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians. It is recommended that the lot number of the vials used be recorded when Flebogamma® 5% DIF is administered. Laboratory Tests: Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF in patients judged to have a potential increased risk for developing acute renal failure and again at appropriate intervals thereafter.
Pharmacy Practice News • November 2009
Critical Care score 1 to 2; moderate: Gorelick score 3 to 6) and then randomly assigned to receive rehydration therapy with 20 mL/kg isotonic fluid over one hour and additional fluid as needed for up to 72 hours, with either rHuPH20-facilitated subcutaneous or IV rehydration. For use of rHuPH20, 1 mL was administered subcutaneously through an angiocatheter or a needle that was placed in the upper back or other suitable region, Dr. Mace explained. This was immediately followed by subcutaneous isotonic fluid administration. The study’s primary end point was the
total volume of fluids administered at a single infusion site. An interim data analysis on 74 patients (37 randomized to subcutaneous and 37 randomized to IV rehydration) showed that the mean total volume infused over a single site was 374 mL for subcutaneous rehydration versus 491 mL for IV rehydration. Mean total fluid volume adjusted by duration of infusion was 445 mL for subcutaneous rehydration versus 419 mL for IV rehydration. In addition, health care providers considered 92% of patients randomized to rHuPH20-facilitated rehydration to
Following infusion of Flebogamma® 5% DIF, there may be a transitory rise of various antibody titers that may result in misleading positive results in serological testing. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum. Pregnancy Category C: Animal reproduction studies have not been performed with Flebogamma® 5% DIF. It is also not known whether Flebogamma® 5% DIF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Flebogamma® 5% DIF should be given to a pregnant woman only if clearly needed. Drug Interactions: Antibodies in Flebogamma® 5% DIF may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration. Pediatric Use: The above mentioned clinical trial with Flebogamma® 5% DIF enrolled only a very limited number of children (0) and adolescents (3) with primary humoral immune deficiency, a number insufficient to fully characterize and establish the efficacy and safety in pediatric patients. Geriatric Use: Subjects over 65 are at increased risk of renal failure with IGIV treatment. For these subjects, and for any other subjects at risk of renal failure, the infusion rate of Flebogamma® 5% DIF should be limited to < 0.06 mL/kg/min (3 mg/kg/min). Adverse Reactions Increases of creatinine and blood urea nitrogen (BUN) have been observed as soon as 1 to 2 days following infusion of IGIV. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment. Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, proximal tubular nephropathy, and osmotic nephrosis. Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate [See DOSAGE AND ADMINISTRATION] must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Adverse reactions may occur more frequently when a high infusion rate is used, the treatment is the initial exposure to immunoglobulin, the immunoglobulin product has been changed to that of a different manufacturer, or there has been a long interval (more than 8 weeks) since the previous infusion. Slowing or stopping an infusion usually results in the prompt disappearance of symptoms. Post-Marketing: The following adverse reactions have been identified and reported during the postapproval use of IGIV products. Respiratory
Cardiovascular Neurological Integumentary Hematologic General/Body as a Whole Musculoskeletal Gastrointestinal
Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiac arrest, thromboembolism, vascular collapse, hypotension Coma, loss of consciousness, seizures, tremor Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, bullous dermatitis Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test Pyrexia, rigors Back pain Hepatic dysfunction, abdominal pain
Because post-marketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently. Adverse events were reported in a study of 46 individuals with primary humoral immunodeficiency diseases receiving infusions every 3 to 4 weeks of 300 to 600 mg/kg body weight. Forty-three (94%) subjects experienced at least 1 adverse event
be successfully rehydrated, compared with 76% who were rehydrated intravenously. They also rated subcutaneous rehydration as much easier to perform, with 97.3% of those who used the subcutaneous route for rehydration reporting ease of use, compared with 67.6% of those who used the IV route. Serious adverse events were reported in six patients. Of two patients who received IV hydration, one had a case of ongoing dehydration, and the other had a rotavirus infection. Of the four patients given subcutaneous hydration, there was one case each of Kawasaki dis-
irrespective of the relationship with the product, and these subjects reported a total of 595 adverse events. None of the 46 subjects who participated in this study discontinued the study prematurely due to an adverse experience related to the study drug. One subject had treatment-emergent bronchiectasis, mild, ongoing, after infusion #10; and one subject had recurrent moderate leukopenia after the 7th and 12th infusions. No adverse events occurred with an incidence of > 2% on a per infusion basis. Table 1. Adverse Events Occurring with an Incidence of > 15% Adverse Event
Number of AEs
Combined Bronchitis Cough and productive cough Diarrhea NOSa Headache NOS and sinus headache Nasal congestion Injection site reaction NOS Pyrexia Arthralgia Sinusitis NOS Pharyngitis Upper respiratory tract infection Wheezing and asthma aggravated
19 10 14 46 11 13 27 11 38 9 24 24
Number of Subjects with AEs 14 10 9 16 7 7 17 7 20 8 15 10
Percent of Subjects with AEs 30 22 20 35 15 15 37 15 44 17 33 22
ease, pneumonia, pyrexia and gastroenteritis. “All serious adverse events were mild or moderate in severity and none were considered to be related to study treatment,” Dr. Mace said. Children who had received subcutaneous infusions had mild local reactions at the site of infusion, usually localized swelling or redness. “These were expected.” All children who received subcutaneous rehydration had at least one infusion site reaction, versus 89.7% of those who received IV rehydration. Erythema and swelling were also more common in the subcutaneous group. All the localized reactions were of mild severity and resolved within one hour after the infusion was stopped, Dr. Mace reported.
A Skeptic Comes Around Robert J. Kuhn, PharmD, associate director of pharmacy services for the Kentucky Childrens Hospital at the University of Kentucky, in Lexington, told Pharmacy Practice News that he was once very skeptical of using rHuPH20-facilitated subcutaneous rehydration, but admitted that he is now completely won over.
a. NOS = not otherwise specified The total number of AEs (regardless of attribution) reported whose onset was within 72 hours after the end of an infusion of Flebogamma® 5% DIF was 216. There were a total of 709 infusions, resulting in a rate of 0.305 (95% confidence interval 0.225 to 0.412) temporally associated AEs per infusion. There were 144 infusions (20.1%, 1-sided 95% upper bound confidence interval = 24.4%) associated with 1 or more AEs that began within 72 hours after the completion of an infusion. Table 2. Summary of Infusions with Mild, Moderate, and Severe TreatmentRelated Adverse Events Severity of AE Mild Moderate Severe
No. Infusions 58 25 1
Adjusted % a with AE 7.9 3.6 0.1
Confidence Intervalb 10.4 4.9 0.3
a. Adjusted % = average of the % of infusions with a treatment-related adverse event for each individual subject. b. The 95% upper bound for the adjusted % of infusions for which at least 1 treatmentrelated adverse event was reported was derived by using the t-statistic. The number and percent of subjects with treatment-emergent rises in AST or ALT are in Table 3. Table 3. Number (%) of Subjects with Treatment-Emergent Rises in AST or ALT (N = 46) Laboratory Test AST ALT
Assessment Criteria Above 3x the ULNa Above 3x the ULN
n 3 1
% 6.5 2.2
a. ULN = upper limit of normal. None of these subjects had a concomitant treatment-emergent rise in total bilirubin. Reported adverse reactions with Flebogamma® 5% DIF and other IGIV products include: headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing, rash, arthralgia, and edema, often beginning within 60 minutes of the start of the infusion. Rarely, Immune Globulin Intravenous (Human) can induce a severe fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with IGIV. In the case of shock, the current standard medical treatment for shock should be implemented. Manufactured by INSTITUTO GRIFOLS, S.A. Barcelona - Spain U.S. License No. 1181 Distributed by GRIFOLS BIOLOGICALS INC. Los Angeles - CA 90032 Phone: 888-GRIFOLS (888-474-3657)
‘I am somewhat of a doubting Thomas, but I have been converted. Appropriately used, this is very effective.’ —Robert J. Kuhn, PharmD “We’ve only used it in six or seven babies, where we have difficulty getting peripheral vein access, even with experienced IV nurses. I am somewhat of a doubting Thomas, but I have been converted. Appropriately used, this is very effective. “We’re getting into flu season, and especially in light of an impending H1N1 outbreak, treating children in the hospital, getting them rehydrated and sending them home (when appropriate) is imperative. We don’t use this in every patient but for those kids who need it, it’s a godsend.” Dr. Mace disclosed that she has financial relationships with Baxter, which participated in the study. Dr. Kuhn reported no conflicts of interest. —Fran Lowry
Pharmacy Practice News • November 2009
Aspirin May Not Benefit All Patients With Type 2 Diabetes Barcelona, Spain—Although the American Heart Association (AHA) and the European Society of Cardiology (ESC) recommend routine aspirin for primary prevention in type 2 diabetes patients commencing at diagnosis, data are emerging that this recommendation may not apply to all patients, according to presentations at the 2009 Congress of the ESC. Presenter Peter J. Grant, MD, and his colleagues showed that aspirin treatment could adversely affect lysis time in the presence of poor glycemic control. They suggested that this may be one mechanism for the reduced efficacy of aspirin in some individuals with diabetes, and concluded that aspirin should be used with caution, or even avoided, in individuals with poor glycemic control. Additionally, Dr. Grant, professor of medicine at the University of Leeds in the United Kingdom, said the use of aspirin in patients with diabetes but no cardiovascular disease has been linked to an increase in major bleeding. Thus, he said, no data justify following the AHA guidelines for the administration of aspirin in such patients. Earlier trials also failed to support aspirin’s role in primary prevention for patients with diabetes, although they may have been underpowered to do so, according to presenter Harald Darius, MD, professor of cardiology and intensive
care medicine at Vivantes Medical Center Neukölln, Berlin, Germany. For example, the JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) trial (JAMA 2008;300:2134-2141) showed no significant effect of aspirin on a combined end point of cardiovascular adverse events including fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke and peripheral artery disease. Judy Cheng, PharmD, MPH, professor of pharmacy practice at the Massachusetts College of Pharmacy and Health Sciences and a clinical pharmacist at Brigham and Women’s Hospital in Boston, told Pharmacy Practice News that the findings from JPAD and POPADAD (Prevention of Progression of Arterial Disease and Diabetes), although interesting, are not sufficient at this point to justify a recommendation against the use of aspirin for primary prevention of cardiovascular events in all patients with diabetes. “JPAD was conducted in a Japanese population and we cannot be sure that there is no genetic difference in terms of patient response to aspirin,” Dr. Cheng commented. “Therefore, the data may not necessarily be applicable
to other patient populations. POPADAD may not have enrolled enough patients to have enough power to detect a difference between the two groups.” Additionally, she said, the data presented at ESC that claim that aspirin is not helpful for primary prevention in patients with diabetes and may actually be harmful and cause more bleeding were based on the demonstration that aspirin reduces clot lysis in patients with poor glycemic control only. Furthermore, she said that these findings were not seen in JPAD or POPADAD. “So, this theoretical increase in risk for bleeding may not actually turn out to be clinically relevant. More ongoing studies are needed to further clarify this question.” Congress presenter Carlo Patrono, MD, agreed that randomized trials are needed to provide direct evidence for the efficacy and safety of aspirin for primary prevention in this setting. Dr. Patrono, professor and chair of pharmacology at Catholic University School of Medicine in Rome, noted that diabetes is not only a risk factor for the occurrence of a serious vascular event,
it also is a risk factor for major extracranial bleeding. Therefore, he cautioned, “We should be careful in seeking adequate evidence for efficacy and safety of aspirin in these patients. Two placebo-controlled randomized trials, ASCEND [A Study of Cardiovascular Events iN Diabetes] and ACCEPT-D [Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes], in approximately 15,000 patients with diabetes, are ongoing to address the uncertainty in the balance of benefits and risks of antiplatelet prophylaxis.” There may be mechanistic explanations for the aspirin-resistant thromboxane biosynthesis seen in patients with diabetes, he said. These include cyclooxygenase (COX)-1 glycation, a faster recovery of COX-1 activity because of accelerated platelet turnover in some individuals with diabetes, and enhanced platelet COX-2 expression, which might be associated with platelet turnover. “Our hypothesis is that enhanced platelet turnover may allow sufficient recovery of COX-1 activity during the 24-hour dosing interval to overcome the antiplatelet effect of low-dose aspirin given once daily and limit its clinical efficacy,” Dr. Patrono said. He and his colleagues are investigating this possibility. —Fran Lowry
Patients Reach BP Goals in Pharmacist-Run Hypertension Clinic Anaheim, Calif.—Three out of four hypertensive patients at the San Diego Naval Medical Center were able to reach their appropriate blood pressure (BP) goals within six months of being referred to the medical center’s pharmacist-run hypertension clinic, according to a study presented at the 2009 annual meeting of the American College of Clinical Pharmacy. The study focused on 60 patients referred to the clinic by medical center cardiologists from late 2007 to earlier this year. Nearly half of the study group (47%) was classified as having resistant hypertension, said Kimberly L. Liang, PharmD, the clinical pharmacist who runs the clinic. The study found that 73.4% of the patients (n=44) achieved BP goals recommended by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), compared with a national average of 34%, as reported in JNC 7. Ten of the patients (16.7%) failed to reach their goals but showed improvements in BP, while six had no
improvement. Of these 16 who did not reach their goals, nine had previously been classified as resistant. Dr. Liang and her colleagues were successful in getting their patients’ BP under control even when the goals were lower than normal because of comorbid conditions. Of the patients reaching goal BP (n=44), 16 had a goal of less than 120/80 mm Hg due to comorbidities such as heart failure and severe coronary artery disease. This was the most intensively treated group, averaging 3.2 medications per patient, Dr. Liang said. There were 14 patients with a BP goal of less than 130/80 mm Hg because of the presence of diabetes. The average number of medications in this group was 2.3, according to Dr. Liang. The remaining 14 patients, who had hypertension uncomplicated by severe disease, were able to achieve their BP goal of less than 140/90 mm Hg, using an average of 2.8 medications each. At the hypertension clinic, Dr. Liang practices under a protocol approved by the medical center’s Pharmacy and Therapeutics Committee that allows her
to use her clinical judgment in switching medications and adjusting dosages recommended by JNC 7 and listed in the medical center formulary. For example, she said, if a patient is having side effects from a medication and has exhausted other recommended options, she has the leeway to switch to another medication. “If that is all I have left,” she said, “that is what I would go with. It’s really just looking at the bigger picture and not just focusing on one subset of the guidelines.” Being part of the cardiology treatment team and understanding more of the big picture regarding individual patients has been a factor in Dr. Liang’s success in the hypertension clinic. In addition to working in the hypertension clinic, she also works in the medical center’s heart failure, anticoagulation and asthma clinics.
Team Approach Advocated Deborah S. Minor, PharmD, FAHA, who has reported similar success in her pharmacist-supported hypertension clinic in Mississippi (Pharmacy Practice News July 2009, page 1), stressed that
this team approach facilitates improved care. “All members of the health care team [must] work together with patients at multiple levels to influence and improve communication regarding barriers to hypertension control.” Applauding the San Diego team’s efforts in an interview with Pharmacy Practice News, Dr. Minor, associate professor of medicine at the University of Mississippi Medical Center, in Jackson, said, “the results of the investigators rival those reported in recent clinical trials and most practice-based studies and exceed national blood pressure goals.” She commented further that it is “exciting to see the involvement of pharmacists in hypertension management. Access to, and utilization of, health care clearly influences hypertension awareness, treatment and control. Pharmacists are particularly qualified to provide a patient-centered approach, with attention to the patient’s knowledge, attitudes, beliefs, experiences and educational level.” —Bruce Buckley
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Pharmacy Practice News • November 2009
HEPARIN POTENCY continued from page 1
On Oct. 1, the FDA issued an alert to health care professionals that USP, the nonprofit standards-setting organization, had adopted new manufacturing controls for heparin, including new assays to detect contamination and a modification of the reference standard for the drug’s unit dose to match WHO’s International Standard (IS) used in Europe and other countries for years. Although the new manufacturing controls took effect on Oct. 1 for production, FDA asked manufacturers not to ship the new product until Oct. 8. “The delay will give health care providers and facilities time to learn about the changes and to make adjustments to their pharmacy procedures and dosing practices,” explained John Jenkins, MD, director of FDA’s Office of New Drugs in the alert. “I’m really surprised by the timing because no one seemed to know about this until the last minute,” said Michael Cohen, RPh, president of the Institute for Safe Medication Practices (ISMP) in Horsham, Pa. “This has been known by industry and regulatory folks for some time, but there has not been much communication with the clinical community, the practitioners who are using heparin. I’m sure most of them are still not aware of it,” he told Pharmacy Practice News.
Earlier Troubles With Heparin Following reports in 2007 and 2008 of widespread sicknesses and some 200 deaths from heparin produced in China and intentionally adulterated with oversulfated chondroitin sulfate (Pharmacy Practice News March 2008, page 3), USP issued a revised manufacturing control monograph in June 2008. A second revision was announced in February 2009 and included additional tests for contamination as well as the approximate 10% reduction in apparent potency (range, 7%-12%). It is that second-stage monograph that became effective Oct. 1. Christopher Bryant, PhD, chief scientif-
ic officer for APP Pharmaceuticals LLC, the largest U.S. manufacturer of heparin, said the company began informing clinicians about the impending changes on Sept. 23 and plans to conduct “ongoing education and communication forums” n the near future. “Given these activities, APP feels that clinicians should be adequately prepared for these changes,” Dr. Bryant said. APP said it was to begin shipping lots of new heparin by the end of October. To help pharmacies distinguish the new version, APP, Baxter International Inc. and B. Braun Medical Inc. will add the letter “N” to lot numbers or after the expiration date on their products. Hospira Inc. will designate new heparin by the number “82” or higher at the start of its lot numbers. APP markets heparin in vials; Hospira markets heparin in IV bags, vials and syringes; and Baxter and B. Braun market the drug in IV bags.
Protection Against Shortages To ensure there are no shortages, FDA said wholesalers can continue to supply heparin manufactured under the old standards and health care facilities can administer both old and new heparin to patients. Because of shelf life, the mixture of products could continue for up to three years, APP said, leading some to wonder how facilities will manage the overlap. “If an institution has ‘older’ and ‘new’ lots of medication in its inventory, how will it track the two lots and ensure that the appropriate dosing protocol is used for each?” Dr. Haines questioned. “In most institutions, unfractionated heparin is widely distributed in various locations. If a hospital wants to switch all its inventory when it receives the new lots, it would likely require considerable time and effort to locate and recover all the ‘older’ lots of medications,” he said. (Such difficulties are not theoretical. In 2008, the pharmacists-in-charge at nearly 100 California hospitals were issued unprofessional conduct citations for failing to locate and remove all lots of recalled heparin [Pharmacy Practice
‘I’m really surprised by the timing because no one seemed to know about this until the last minute.’
—Michael Cohen, RPh
News, November 2008, page 1]). Although the USP does not anticipate any “clinical significance” from the new version’s reduced potency, both it and the FDA urge health care providers to monitor patients (including activated partial thromboplastin time and activated coagulation time testing). This is especially important when heparin is administered as a bolus IV dose for immediate anticoagulant effect. The potency change will likely be less significant when the drug is administered subcutaneously because of heparin’s inherently low and extremely variable bioavailability, the FDA added. However, “no one knows for certain unless studies are done, so you can bet there will be some big question marks about the change,” Mr. Cohen said. William E. Dager, PharmD, pharmacist specialist at the University of California, Davis Medical Center, said his concern was not with patients receiving older lots of heparin, but in making sure they get enough of the new formulation. “Institutions, once they change lots, should carefully assess whether they are achieving target goals at 24 and 48 hours and look at the dosing approach used to make sure they are being adjusted to uncover any barriers to reaching those targets,” he told Pharmacy Practice News.
More USP Testing Requirements Tina Morris, PhD, the USP’s vice president of biologics and biotechnology, said the first monograph revision in June 2008 added a capillary electro-
phoresis test, which has been replaced by a strong anion-exchange identity test in the current second-stage revision. Additional tests, including an expanded proton nuclear magnetic resonance assay, have been added to check identity, impurity and potency. Not everyone is concerned about the effects of the heparin potency change. “Heparin products from the U.S. and Europe have been used in Canada interchangeably for years, without any distinction in patient response,” said Ann K. Wittkowsky, PharmD, clinical professor and director of anticoagulation services at the University of Washington School of Pharmacy in Seattle. “It is important that clinicians understand that this change has been made in case any general change in patient response is seen, but in my opinion it is unlikely to be clinically significant,” she said. I do not feel that there is any need for panic or concern.” Regardless, one likely result of all this will be an increase in the ongoing shift to alternative anticoagulants, Dr. Haines predicted. “Given the recalls on unfractionated heparin products that occurred in 2008, many institutions and clinicians had already begun to turn to alternative anticoagulants for a variety of indications,” he said. “The lowmolecular-weight heparins and fondaparinux are simpler to use and haven’t faced similar manufacturing problems. I anticipate use of alternative anticoagulants will continue to rise.” —Ted Agres
Iron Dextran Linked to Allergic Reactions
evere anaphylactic-type reactions—several fatal— have occurred following the parenteral administration of iron dextran injection, according to a MedWatch alert posted on the FDA’s Web site. The drug’s manufacturer (American Regent) and the FDA announced that an existing boxed warning on the drug’s labeling has been updated as a result of the adverse reactions. The warning now recommends that a test dose of iron dextran, which is marketed as Dexferrum, be given to patients prior to therapeutic administration. If no signs or symptoms of anaphylactic-type reactions occur, “administer the full therapeutic dose,” a Sept. 25 Dear Healthcare Professional letter stated. The FDA warned, however, that the test dose does
not eliminate the risk to patients. “Fatal reactions have [occurred following] the test dose of iron dextran injection, even in situations where the test dose was tolerated,” the agency stressed. The risk for developing such reactions is particularly acute in patients with a history of drug allergies, the FDA added. To protect patients, the agency recommended “that resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions be readily available during Dexferrum administration.” Dexferrum is an IV iron preparation that is indicated for the treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible.
The safety labeling changes approved by the FDA also extend to DexFerrum (Luitpold Pharmaceuticals, Inc.) and INFeD (Watson Pharmaceuticals, Inc.) Allergic reactions to iron dextran are nothing new. As far back as 1980, Hamstra et al (JAMA;243:17261731) examined more than 2,000 infusions of iron dextran in 48 patients. The researchers found that 26% of the patients experienced side effects, most of which were mild and self-limited. Approximately 2% were considered to be “severe” allergic reactions and 0.6% were classified as anaphylactoid. The majority of the reactions occurred immediately during the infusion of a test dose. —David Bronstein
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Pharmacy Practice News • November 2009
340B Discount Program: A Primer A
t first glance, the 340B Drug Pricing Program sounds simple: It requires manufacturers to provide outpatient medications to eligible hospitals at a reduced price, in an effort to take some of the sting out of rising drug costs. But there can be some confusion surrounding what “entities” are eligible, which manufacturers are required to participate and the key components of the program. This article, the first in a series, outlines the basics of 340B and answers some common questions that new entities may have. For many hospitals, the first and perhaps most important question is, ‘Just how much can I really save?’ And by extension, are those savings worth the time and effort needed to get up to speed on 340B implementation? Whether that effort is a worthwhile endeavor will be a call each eligible entity will have to make for itself. But the discount can be significant: The 340B price is 20% to 50% of the Average Wholesale Price (AWP), which means those organizations that are participating in 340B have the potential to access outpatient drugs at a significant savings. As for other 340B Program basics, it was established by Section 602 of the Veterans Health Care Act of 1992 and is administered by the Office of Pharmacy Affairs (OPA), a component of the federal government’s Health Resources and Services Administration Healthcare Systems Bureau. OPA has three functions: 1) administering the 340B Drug Pricing Program, through which certain federally funded grantees and other safety net health care providers may purchase prescription medication at significantly reduced prices; 2) developing innovative pharmacy service models and provision of technical assistance to help entities implement effective pharmacy programs; and 3) serving as a federal resource about pharmacy.
Program Eligibility for Health Care Delivery Sites and Patients All programs eligible for the 340B drug discount program are outlined in the 340B statute, and include the following: • Consolidated Health Centers • Black lung clinics • Federally Qualified Health Centers (FQHC) and FQHC look-alikes • Comprehensive hemophilia diagnostic treatment centers • Certified sexually transmitted disease clinics • Native Hawaiian health centers • Certain Children’s hospitals
• Urban Indian organizations • Certain Disproportionate Share Hospitals • Certified tuberculosis clinics • Family planning projects (Title X) • Ryan White Parts A, B, C, D Participation in the 340B Program is voluntary; even if a site is eligible, it must complete the registration forms to enroll in the program. All forms relating to 340B can be found at http://www. hrsa.gov/opa/legalresources.htm. Enrollment deadlines for 340B are quarterly, and all entities applying to the program should note them: Dec. 1
for the Jan. 1 start date; March 1 for the April 1 start date; June 1 for the July 1 start date; and Sept. 1 for the Oct. 1 start date. Once enrolled in 340B, a covered entity may provide outpatient drugs purchased at the 340B price to any of its patients who meet the 340B definition of a patient. For the 340B Program, a person is a patient of the entity if the following conditions are met: • The entity has an established relationship with the patient and maintains records of care. • The patient receives health care from
Part 1 in a Series
his article is the first in a bimonthly series focusing on strategies for getting the most out of the federal 340B Drug Discount Program. Future topics include: • Split billing software. What does it do? How does it work? Plus tips on policies, procedures and practices, staffing, etc. • Optimizing savings. How to achieve full implementation; dealing with formulary changes; and more. • Contract pharmacy arrangements. In-house versus outside, independent consultants; specialty pharmacy considerations. • Innovations in practice. Alternative Methods Demonstration Projects (AMDP); partnering in the community; patient safety collaboratives.
he Health Resources and Services Administration (HRSA) Pharmacy Services Support Center (PSSC) at the American Pharmacists Association has created several resources to explain 340B. For a narrated PowerPoint presentation that explains the basics, go to PSSC’s 340B journey: http://tiny.cc/modules. For informative manuals, financial spreadsheets and other information, view the Resources tab of the PSSC Web site: http://pssc.aphanet.org/resources.htm. Contact PSSC at (800) 628-6297 or e-mail PSSC@aphanet.org for free services that simplify some of the complex steps involved in determining 340B eligibility. PSSC also offers technical assistance, staffs a call center for questions, does policy analysis and helps with networking. For more information on the OPA, visit www.hrsa.gov/opa. For more information on the PVP, visit www.340bpvp.com.
a health care professional employed or contracted with the entity. • The patient must also receive health care consistent with the range of services from the covered entity. • Disproportionate Share Hospitals (DSH) are exempt from this last requirement. ADAP (AIDS Drug Assistance Program) patients are considered patients as long as they are registered as eligible by the state program. An individual will not be considered a “patient” of the entity for the purposes of 340B if the only service received by the individual from the entity is the dispensing of a drug or drugs for subsequent self-administration or administration in the home setting. Additionally, only outpatient drugs are covered under 340B. A site may not use drugs purchased at the 340B price in an inpatient setting. Some manufacturers may choose to offer 340B-like prices to inpatient departments of certain hospitals, but that is a voluntary decision by the manufacturer and not part of the 340B Program. Once enrolled in the program, covered entities must maintain auditable records and may be subject to audit by the manufacturer or the government. These records must show that a site
see 340B PROGRAM, page 52
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Pharmacy Practice News • November 2009
340B PROGRAM continued from page 50
does not resell or transfer 340B drugs to an ineligible site or patients. Reselling 340B drugs or providing those drugs to patients who do not meet the definition of a patient is known as “diversion” and is strictly prohibited by the 340B statute. Finally, covered entities have an ongoing responsibility to notify OPA if there is any change in their eligibility. Some types of covered entities have an annual recertification process, during which
Once enrolled in 340B, a covered entity may provide outpatient drugs purchased at the 340B price to any of its patients who meet the 340B definition of a patient. they certify the accuracy of their OPA database information.
Manufacturer Participation Drug manufacturers that participate in the Medicaid rebate program must also sign a pharmaceutical pricing agreement
that requires them to offer a 340B price to eligible entities for all of the outpatient drugs they manufacture. Savings on 340B prices have been reported to amount to 22%, or often much higher, on the entity’s total drug purchases. The 340B price is at least as low as the price that
state Medicaid agencies pay. The 340B price is actually a “ceiling” price, meaning it is the highest price a participating entity may be charged. However, drug manufacturers are able to offer entities subceiling prices on drugs as well. The data used to calculate the 340B ceiling price is kept confidential. Manufacturers calculate the ceiling price using a formula found in the 340B statute for covered drugs. The definition of a 340B Covered Drug that appears on the OPA Web site is as follows: “An FDA-approved prescription drug, an over-the-counter (OTC) drug that is written on a prescription, a biological product that can be dispensed only by a prescription (other than a vaccine) or FDA-approved insulin.” Medical/surgical supplies (e.g., syringes, IUDs, etc.) are not covered drugs, but manufacturers may voluntarily give clinics a discounted price.
GPO Exclusion One 340B Program requirement specific to DSH is the Group Purchasing Organization (GPO) Exclusion. When a DSH enrolls in the 340B Program, it must opt out of its GPO for outpatient drugs. The GPO exclusion states that the hospital “will not participate in a group purchasing organization or group purchasing arrangement for covered outpatient drugs as of the date of this listing on the OPA Web site.” However, a DSH may participate in the 340B Prime Vendor Program (PVP) to purchase drugs and other items not covered under 340B through the PVP. The PVP is free, but is only available to 340B covered entities and works to negotiate subceiling prices with manufacturers, helps entities access drug distribution solutions, and offers an array of value-added products and services. For more information on the 340B PVP, visit www.340bpvp.com.
Contract Pharmacy and 340B In some cases, 340B entities do not have an in-house pharmacy or other pharmacy option and choose to work with a retail pharmacy in the community to provide 340B pharmacy services on their behalf. In this arrangement, the covered entity and pharmacy work with their legal advisers to create a contract that outlines their working arrangements. It is important to note that the covered entity must own the 340B drugs at all times. —Danielle Mathers
Danielle Mathers is communications manager, HRSA Pharmacy Services Support Center (PSSC). For additional tips on making drugs more affordable, see page 18
New Product 53
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Statement of Ownership
Less time processing. More time practicing. The Pyxis® Medication Communication System helps pharmacists spend less time processing orders and managing inventory. The result? More time with patients. Studies show that drug interventions can increase by at least three times1 when pharmacists are clinically involved with the patient. It’s just one more way CareFusion combines technology and intelligence to help improve safety and efﬁciency. To learn more, visit our website at carefusion.com.
Schumock, G.T., Meek, P.D., Ploetz, P.A., et al. Economic Evaluations of Clinical Pharmacy Services 1988–1995. Pharmacotherapy, 1996: 16(6), 1188-1208. © 2009 CareFusion Corporation or one of its subsidiaries. All rights reserved. Alaris, MedMined and Pyxis is a trademark or registered trademark of CareFusion Corporation or one of its subsidiaries. MC0954
THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES
Clinical Use of Desirudin, a New Subcutaneously Administered Direct Thrombin Inhibitor John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital North American Thrombosis Forum Boston, Massachusetts
Introduction Thrombin is a serine protease that plays a pivotal role in the coagulation process. It is produced via stepwise activation of proenzymes following vascular injury.1 Once formed, thrombin converts soluble fibrinogen to insoluble fibrin. It also stimulates platelets and enhances production of additional thrombin, facilitating blood clot stabilization.1 Higher thrombin concentrations are associated with denser, more rigid clots.2 Indirect anticoagulants, such as unfractionated heparin (UFH) and low-molecularweight heparin (LMWH), are used widely to prevent thrombosis in various patient populations.3,4 Heparins have several clinical limitations, however, including the inability to neutralize fibrin-bound thrombin; an unpredictable dose–response relationship; and the potential to induce immunemediated platelet activation, which can lead to heparin-induced thrombocytopenia (HIT).1,4-6 Direct thrombin inhibitors (DTIs), considered “direct anticoagulants,” have intrinsic activity, offering several advantages over heparins: They do not require plasma cofactors (eg, antithrombin) to exert their effect; they inhibit both free and fibrinbound thrombin; their use is not associated with HIT; and because they have little interaction with plasma proteins, their anticoagulant effects are more predictable than those of heparin.1,4-6 Four DTIs are approved for use as anticoagulants in the United States: desirudin (Iprivask®, Canyon), lepirudin (Refludan®, Bayer HealthCare), bivalirudin (Angiomax®, The Medicines Company), and argatroban (Argatroban, GlaxoSmithKline). They each have different indications and unique pharmacologic properties.3,4 Table 1 shows an overview of these 4 clinically distinct DTIs.7-10 Desirudin is anticipated to be available on the US market in late 2009. It is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing elective hip replacement surgery.10 Desirudin is the only DTI 54
PHARMACY PRACTICE NEWS
approved for subcutaneous administration.7-10 Desirudin may provide benefits related to dosing, administration, therapeutic monitoring, costs, and transition to oral anticoagulant therapy. Clinical studies have shown that desirudin is significantly more effective than UFH and LMWH for preventing thromboembolic events in patients undergoing hip replacement surgery, with equal safety.11,12 Desirudin also has been studied in acute coronary syndromes13,14 and is currently under investigation for use in several other patient populations, including prophylaxis and treatment of thrombosis in patients who have or are at risk for HIT (subcutaneous administration), and for patients undergoing percutaneous intervention (PCI; administration of single IV bolus dose).
Pharmacology DTIs differ in their potency, pharmacokinetic properties, monitoring requirements, and routes of administration.7-10 They often are classified according to potency or thrombin-binding affinity. Univalent DTIs bind only to the active (catalytic) site of thrombin, whereas bivalent DTIs interact with the fibrinogen-binding site (exosite 1) as well as the active thrombin site.1 Desirudin and lepirudin are high-affinity, bivalent DTIs that are recombinant analogs of hirudin, a peptide originally isolated from the salivary glands of medicinal leeches.4 Bivalirudin, also a bivalent DTI, is a synthetic analog of hirudin.4 However, bivalirudin differs from desirudin and lepirudin in 2 important ways. First, bivalirudin has a binding affinity for thrombin that is approximately 100,000 times less than the recombinant analogs3; second, bivalirudin is cleaved by thrombin to inactive metabolites, resulting in an antithrombotic effect that is much more transient.1 Argatroban, a univalent DTI with the lowest relative affinity, also dissociates from thrombin after binding, leaving active thrombin available to facilitate hemostasis.1,3,4 Differences in thrombin-binding affinity may be associated with differences in efficacy among DTIs.15,16 A recent study in a porcine angioplasty model correlated higher thrombin-binding affinity with more potent antithrombotic effects. This suggests that DTIs with high thrombin-binding affinity (eg, desirudin) may be more efficacious than DTIs with much lower binding
affinity (eg, argatroban, bivalirudin).17 This hypothesis is currently being investigated in clinical trials comparing desirudin with argatroban in HIT/heparin-induced thrombocytopenia with thrombosis syndrome (HITTS) and bivalirudin in PCI. These studies are the first prospective clinical trials investigating the safety and efficacy of parenteral DTIs as anticoagulants.
disease.13,14 Doses of argatroban and bivalirudin—the DTIs currently indicated for use during PCI procedures—are calculated based on patient weight and administered via IV infusion. Subsequent doses of these agents may require adjustment according to targeted, activated clotting times.4,7,9 Desirudin currently is being investigated in the PCI setting as a single, fixed-dose IV bolus anticoagulant.
Dosage and Administration Desirudin is the only DTI approved in the United States as a fixed-dose, subcutaneous formulation.7-10 The ability to administer desirudin subcutaneously gives practitioners the flexibility of prescribing the drug on an inpatient or outpatient basis. Other subcutaneously administered anticoagulants (eg, LMWHs) are commonly used for the treatment of venous thromboembolism (VTE) in the outpatient setting. This practice has been strongly associated with shorter hospitalizations, lower treatment costs, and similar outcomes when compared with inpatient management of VTE.18 Additionally, desirudin does not require weight-based dose calculations or continuous infusion as do heparins and the other DTIs.7-10 Medications that are administered via continuous infusion or require weight-based dosing are associated with increased potential for medication errors and adverse events.19,20 Studies show that patients given weight-based therapeutic anticoagulation are frequently dosed without being weighed, or the doses are based on incorrect weight estimations, resulting in dosing errors and increased hemorrhagic complications.19 As a result, subcutaneously administered, fixed-dose desirudin may allow for greater ease of use, flexibility, cost savings, and safety compared with other DTIs. In patients undergoing orthopedic surgery, the recommended dose of desirudin is 15 mg given every 12 hours for up to 12 days. The initial dose of desirudin should be administered 5 to 15 minutes prior to surgery but after any regional block anesthesia. Prescribing information for desirudin currently recommends reduced doses for patients with moderate to severe renal impairment10; however, recent data suggest that desirudin may be used without dose adjustments in patients with moderate impairment.21 IV administration of desirudin has been used in patients with cardiovascular
Monitoring There are numerous clotting tests used to monitor the activity of the various anticoagulants. Because several reagents are available for use with these tests, results may vary and reproducibility of results is uncertain.6 Unlike heparin and the other DTIs, desirudin, as currently indicated, does not require routine monitoring unless increased risk for hemorrhage or renal impairment is present.10 However, if the clinician desires, desirudin can be monitored easily via activated partial thromboplastin time (aPTT). In most dosing situations, there is a linear correlation of desirudin with aPTT.22 The anticoagulant effects of desirudin will be monitored using both aPTT and activated clotting time in a clinical investigation of the comparative efficacy and safety of desirudin, bivalirudin, and UFH in the setting of PCI.7,23
Transition to Oral Therapy The overall coagulation status of patients on DTIs should be monitored closely during transition to oral therapy.10 DTIs are known to have variable, dose-dependent effects on international normalized ratio (INR) values.4 Argatroban has the greatest impact on INR, which can complicate the transition to oral anticoagulant therapy during concurrent treatment,4,16 whereas desirudin and lepirudin have the least effect on INR.16,23 Transitioning to oral therapy may be less complicated with desirudin given its minimal effect on INR and its ability to be administered subcutaneously.23,24
Safety and Tolerability In early clinical trials of desirudin, patients experienced unexpectedly high rates of bleeding compared with heparin.25,26 The daily doses of desirudin used in these clinical trials were approximately 13 times higher than the currently approved
Supported and approved by
dose of desirudin.10,25,26 In recent clinical trials of DVT prophylaxis, safety and tolerability with the currently approved desirudin dose and formulation was similar to UFH and LMWH (enoxaparin).11,12 Furthermore, in the study comparing desirudin to enoxaparin, the rate of serious bleeding in the desirudin group was nearly identical to the rate in the enoxaparin group (1.9% vs 2.0%, respectively), despite desirudin being administered within 30 minutes before surgery, whereas enoxaparin was given the evening before surgery.11 Antibody formation following the administration of recombinant hirudins has been reported. Although a majority of the data available focus on lepirudin, antibody formation with desirudin also has been reported.6,27 Additionally, cross-reactivity with bivalirudin has been observed in approximately 40% of patients with hirudin-induced antibodies. Fatal anaphylactic reactions following administration of hirudins are rare.6
mechanistic and pharmacokinetic properties, desirudin may be a useful alternative to heparin anticoagulants and currently available DTIs. The use and indications of this potent anticoagulant are likely to expand to broader patient populations as results from ongoing studies in patients with HIT/HITTS and those undergoing PCI are reported.
Desirudin is the only DTI indicated for the prevention of DVT in patients undergoing total hip replacement surgery, and the only DTI approved for fixed-dose, subcutaneous administration. Given its desirable
7. 8. 9. 10. 11.
Acknowledgments Editorial support for this article was provided by Peloton Advantage LLC. This article was funded by Canyon Pharmaceuticals Inc. The author received no honorarium or other form of financial support related to the development of this manuscript.
References 1. 2.
Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med. 2005;353(10):1028-1040. Wolberg AS, Campbell RA. Thrombin generation, fibrin clot formation and hemostasis. Transfus Apher Sci. 2008;38(1):15-23. Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and bivalirudin. Best Pract Res Clin Haematol. 2004;17(1):105-125. Hirsh J. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Ed). Chest. 2008; 133(6 suppl):141S-159S. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines (8th Ed). Chest. 2008;133(6 suppl):340S-380S. Greinacher A, Warkentin TE. The direct thrombin inhibitor hirudin. Thromb Haemost. 2008;99(5): 819-829. Angiomax [package insert]. Parsippany, NJ: The Medicines Company; 2005. Refludan [package insert]. Wayne, NJ: Bayer HealthCare; 2006. Argatroban [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008. Iprivask [package insert]. Hunt Valley, MD: Canyon Pharmaceuticals, Inc; 2009. Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a lowmolecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med. 1997;337(19):1329-1335. Eriksson BI, Ekman S, Lindbratt S, et al. Prevention of thromboembolism with use of recombinant hirudin. Results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am. 1997;79(3):326-333. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. N Engl J Med. 1996;335(11):775-782. Antman EM. Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation. 1996;94(5): 911-921. Baroletti S, Piovella C, Fanikos J, Labreche M, Lin J, Goldhaber SZ. Heparin-induced thrombocytopenia (HIT): clinical and economic outcomes. Thromb Haemost. 2008;100(6):1130-1135. Gosselin RC, Dager WE, King JH, et al. Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values. Am J Clin Pathol. 2004;121(4):593-599. McBane RD, Hassinger NL, Mruk JS, Grill DE, Chesebro JH. Direct thrombin inhibitors are not equally effective in vivo against arterial thrombosis: in vivo
evaluation of DuP714 and argatroban in a porcine angioplasty model and comparison to r-hirudin. Thromb Res. 2005;116(6):525-532. 18. Segal JB, Bolger DT, Jenckes MW, et al. Outpatient therapy with low molecular weight heparin for the treatment of venous thromboembolism: a review of efficacy, safety, and costs. Am J Med. 2003;115(4):298-308. 19. Hilmer SN, Rangiah C, Bajorek BV, Shenfield GM. Failure to weigh patients in hospital: a medication safety risk. Intern Med J. 2007;37(9):647-650. 20. Herout PM, Erstad BL. Medication errors involving continuously infused medications in a surgical intensive care unit. Crit Care Med. 2004;32(2): 428-432. 21. Nafziger AN, Bertino JS. Desirudin dosing and monitoring in moderate renal impairment. J Clin Pharmacol. 2009. In press. 22. Verstraete M, Nurmohamed M, Kienast J, et al. Biologic effects of recombinant hirudin (CGP 39393) in human volunteers. European Hirudin in Thrombosis Group. J Am Coll Cardiol. 1993;22(4):1080-1088. 23. Data on file. Hunt Valley, MD: Canyon Pharmaceuticals Inc; 2009. 24. Marbet GA, Verstraete M, Kienast J, et al. Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39393) in healthy volunteers. J Cardiovasc Pharmacol. 1993;22(3): 364-372. 25. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. Circulation. 1994;90(4):1631-1637. 26. Antman EM. Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. Circulation. 1994;90(4):1624-1630. 27. Greinacher A, Eichler P, Albrecht D, Strobel U, Potzsch B, Eriksson BI. Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance. Blood. 2003;101(7):2617-2619.
Table. Comparison of Direct Thrombin Inhibitors Available for Use in the United States Desirudin (Iprivask®)1,10
Anticoagulant for prophylaxis of DVT, which may lead to PE, in patients undergoing elective hip replacement surgery
Anticoagulant in patients with HIT and associated thromboembolic disease to prevent thromboembolic complications
•Anticoagulant for prophylaxis or treatment of thrombosis in patients with HIT •Anticoagulant in patients with or at risk for HIT, undergoing PCI
•SC injection 5-15 min prior to surgery and every 12 h thereafter •Fixed dose •Dose adjustment in renal impairment •IV bolus plus infusion in clinical trials of the medical management of ACS or PTCA •IV bolus only ongoing study in patients undergoing PCI •Not required for most patients •aPTT monitoring for patients at increased risk for hemorrhage and patients with renal impairment
•IV bolus followed by infusion •Dose based on body weight and infusion rate •Dose adjustment based on aPTT monitoring •Dose adjustment in renal impairment
•Anticoagulant in patients with unstable angina undergoing PTCA •Anticoagulant (with provisional use of glycoprotein IIb/IIIa inhibitor) in patients undergoing PCI •Anticoagulant in patients with or at risk for HIT/HITTS, undergoing PCI •IV bolus followed by infusion •Dose based on body weight and infusion rate •Intended for use with concomitant aspirin •Dose adjustment based on ACT monitoring •Dose adjustment in renal impairment
•aPTT ratio prior to use •aPTT ratio 4 h following administration and once daily
•ACT monitoring 5 min after bolus •Additional monitoring required with renal impairment
SC ≈120 min IV ≈60 min
Dosing and administration
•IV infusion •Dose adjustments required based on aPTT monitoring in HIT or ACT monitoring in PCI •IV bolus followed by infusion in PCI •Dose adjustment in hepatic impairment
•aPTT baseline in HIT/HITTS •aPTT monitoring 2 h after initiation and dose changes •ACT monitoring during PCI •Dose adjustment recommended in patients with hepatic impairment ≈45 min
ACS, acute coronary syndrome; ACT, activated clotting time; aPTT, activated partial thromboplastin time; DVT, deep vein thrombosis; HIT, heparin-induced thrombocytopenia; HITTS, heparin-induced thrombocytopenia with thrombosis syndrome; IV, intravenous; PCI, percutaneous coronary intervention; PE, pulmonary embolism; PTCA, percutaneous transluminal coronary angioplasty; SC, subcutaneous a Thrombin affinity based on Ki values reviewed by Warkentin.3
PHARMACY PRACTICE NEWS
56 People in Pharmacy
Pharmacy Practice News • November 2009
FIRST PHARMACIST continued from page 1
And although I may be the one who’s in the spotlight right now, this is an acknowledgment and an honor that all critical care pharmacists can share; it confirms that our physician and nurse colleagues recognize the value of having specially trained pharmacists working alongside them in the ICU. But in some respects, I’ve just laid the groundwork for our success as a profession; our young practitioners also deserve a lot of the credit for critical care pharmacy’s continued growth. They continually do great research, are active in the [CPP] section, and so it’s exciting to see what a motivated group of individuals can achieve.
: What are some of the goals you want to accomplish as SCCM president? A: Certainly there are a lot of challenges facing all organizations right now, given the ongoing impact of the economic crisis. One clear-cut effect has been on SCCM membership: Although we’ve been fairly stable at about 11,000 members, there’s been some attrition. So that’s something I hope to help reverse during my tenure, perhaps by focusing on how effective the team approach is to critical care. All of the key members of the ICU team—nurses, physicians, pharmacists, etc.—really have a stake in SCCM and could benefit from membership. As far as pharmacist members go, I believe we’re at about 1,000 at last count. But we need to do a better job of ensuring that all pharmacists who are members of SCCM also are members of the CPP section. It’s partly a database issue, but perhaps there’s an awareness component as well. So that’s something I plan on hopefully improving. We also encourage new members who are looking for an organization that is highly focused on their practice area.
: What is it about critical care medicine that makes it respond so well to collaboration? A: It’s mostly due to the fact that there are so many complex pieces to the puzzle of providing high-quality care in this setting; no one person or even profession could possibly handle it well. Take drug therapy: I often tease my students that the number of drugs in use when I first began to practice, versus today, well, there’s just no comparison. And it’s not just a case of more medications to track. Newer drugs are far more complicated than what we had to deal with years ago. That plays to our strength as a profession: Pharmacists are indeed the drug experts, and no critical care team should be without one of us to help guide them
‘Pharmacists are indeed the drug experts, and no critical care team should be without one of us to help guide in the safe, proper use of those drugs.’ in the safe, proper use of those drugs. It is a huge, complex challenge. The scientific literature also is exploding, and this is another area where pharmacists can be an invaluable resource. We should be stepping up in those instances to help with journal clubs, drug-use evaluations, analyzing and disseminating drug safety alerts from the FDA, ISMP [Institute for Safe Medication Practices], etc. We already do these things, but we’re a resource that’s probably untapped at many hospitals.
: What are the most important clinical issues and controversies in critical care medicine today? A: There’s so many, it’s hard to narrow them down! But one that is front and center right now is the difficulty we have in accurately dosing medications for obese patients. Given the epidemic of obesity in the United States, this is a problem that’s not going away. At almost every SCCM Congress, we’ve had multiple sessions on obesity and nutrition, drug dosing, you name it—any aspect of managing these patients usually results in packed meeting rooms. So it’s on our radar and we are trying to give our members the information they need to provide safe, effective care to these patients. Sepsis is another clinical challenge that is ever present. The Surviving Sepsis Campaign has led us all to focus on the disorder as a critically important clinical entity. Great strides have been made in properly diagnosing and managing these patients—but at some hospitals more than others. This takes such a coordinated effort between the emergency department, the ICU and a lot of different specialists that I think sepsis is going to be an important focus for quite a while.
: What specific areas of sepsis management are hospitals
handling well, and what areas remain a challenge? A: The best way to answer that would be to look at the Surviving Sepsis Campaign results that Mitchell Levy [MD] presented at the SCCM meeting last year [Pharmacy Practice News, March 2009, page 1]. There was about a 20% improvement in compliance with two crucial sepsis “bundles”—resuscitation and sepsis management—along with an overall 20% reduction in mortality. In general, we were all very impressed with those findings. After all, how many treatment guidelines out there have had a significant impact on mortality? But there’s room for improvement. We still had well more than half of hospitals in that study not complying with the bundles, and fluid optimization seemed to be a real sticking point for many facilities. Also in the study, hospitals seemed to do fairly well with early antibiotic administration. That’s key, because many studies have shown that any delays in getting antibiotics into these patients can really push up mortality rates. From a pharmacy perspective, those delays often are a systems and work flow issue, so we need to do all that we can to create processes that allow these drugs to be administered in a timely fashion. The other major piece of the sepsis puzzle, of course, is how to manage drotrecogin alfa [Xigris, Eli Lilly]. Hospitals are still struggling, despite the data from the PROWESS [Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis] study group [N Engl J Med 2001;344:699709], to use the correct patient selection criteria in deciding when—or if—to administer the drug. Its role is still being debated and continues to be studied. The challenge for the entire patient-care team is to constantly use resources efficiently. The safety and efficacy of tight glyce-
mic control also continues to be debated, and it certainly heats up whenever a major study on the treatment strategy is released, which seems to happen at least once a year. This is an area that needs continued attention. In fact, I spent most of my morning writing SCCM’s new guidelines on managing insulin in the ICU. I can’t divulge too many details because they have not yet been released, but they will stress that insulin infusions should be an important part of our treatment of patients with high glucose levels in the ICU. The challenge—and this is where some of the data are hard to interpret definitively—is to deliver that insulin safely, so that you minimize the risk for hypoglycemia and other side effects. I think it can be done, but many of the negative studies really didn’t achieve tight control, leading to some undue criticism of the practice. But to just ignore glucose levels in ICU patients is not an option. Or even worse, perhaps, is to make mistakes in how you manage those levels. When you look at the literature on tight control and see that in some cases, 20% of the patients in an ICU had blood sugar levels less than 40 mg/dL, that’s outrageous. The No. 1 imperative has to be to use insulin safely, period. Then, you can debate how tightly patients should be controlled, and how aggressive should we get. If you look at the Surviving Sepsis Campaign guidelines, which in a lot of people’s eyes are reasonable, you want to shoot for keeping patients’ blood sugars to less than 150 mg/dL. Some clinicians and patient advocate groups say 180 mg/dL is a better ceiling to shoot for. That can be tough to do in an ICU setting. Whatever the target is, it can be difficult to accomplish without a coordinated team approach. And regardless of the number you pick, you have to do it safely and minimize the chances of hypoglycemia. There is certainly no lack of protocols you can follow to accomplish that.
: Just to keep the safety thread going, in 2007, researchers at Brigham and Women’s Hospital, in Boston, documented 275 medical errors in its cardiac and medical ICUs. Nearly 45% of the errors were deemed preventable, and nearly half of the mistakes involved medications. Extrapolated across the entire U.S. health care system, they said, the errors could be adding $7 billion to the cost of care each year (Crit Care Med 2007;11:2479-2483). Do you think those results indeed translate to other hospitals? If so, what improvements are needed? A: I do think this is an area of continued concern. One obvious answer is to make sure you have a critical care pharmacist practicing in the ICU because the literature clearly shows that when
People in Pharmacy 57
Pharmacy Practice News • November 2009
Kudos From Critical Care Pharmacy Colleagues O
n the eve of Judi Jacobi, PharmD, becoming the first pharmacist to assume the presidency of the Society of Critical Care Medicine, Pharmacy Practice News asked several of her colleagues to comment on her achievement and what it means for the profession.
Joseph F. Dasta, MSc Professor Emeritus Division of Pharmacy Practice and Administration The Ohio State University College of Pharmacy Columbus, Ohio Adjunct Professor University of Texas at Austin College of Pharmacy Austin, Texas
we are part of the health care team, overall quality of care improves. Just look at the work C.A. Bond and Rob MacLaren have done on this recently. In July, they published a paper [Pharmacotherapy 2009;29:761-768] that compared the outcomes of anticoagulation therapy in ICUs with and without critical care pharmacist services. They found that mortality rates in patients with thromboembolic events and bleeding complications was up to 37% higher in the ICUs without clinical pharmacy services, for an odds ratio of 1.41. They also found that lengths of ICU stay were up to nearly 16% higher when pharmacists were not part of the patientcare team, and the extra Medicare charges approached $216,000. Those are pretty compelling data to support what the researchers concluded—that hospitals should promote the direct involvement of pharmacists in the care of ICU patients.
: Which particular caregivers come to mind when you think of your own collaborations in the ICU? A: It’s been variable, based on where I’ve practiced. At my last job, when I worked at St. Vincent Hospital, anesthesia was very visible in the ICU. [Anesthesia providers] came into the unit with postoperative cardiovascular surgery patients and they maintained those patients and managed the ventilator and took care of them for about 24 hours. So there were many opportunities for fabulous collaboration there. In my current job [at Methodist Hospital/Clarian, in Indianapolis], anesthesia is just not as visible in the ICU, so we don’t have as many opportunities. But we do work closely with the anesthesiologists, nurses and respiratory therapists on a sedation committee that focuses on procedural sedation. Accord-
ne of my most memorable encounters was meeting a recent PharmD graduate, Judi Jacobi, in 1981. She had heard Ohio State was offering a critical care pharmacy residency. I was so impressed with her enthusiasm and poise that I said, “We’d love to interview you.” I had already decided she was going to be my first resident. What a year it was for my colleagues and me
ing to Joint Commission rules, anesthesiology is responsible for that type of care, even though they’re not the ones doing it. The committee also includes gastroenterology and cardiology, which are two of our big procedural sedation groups, as well as emergency medicine, critical care, pharmacy and nursing. It is a really effective and neat collaboration and we do education and monitoring of policies, among other things. My guess is that this is an untapped opportunity in many hospitals. As far as other untapped opportunities for collaboration, Clarian has a pain service that is staffed and organized by anesthesia, but pharmacy does not have a huge presence there. Given the recent studies showing how pharmacists can help improve the quality of pain management, this is probably an area that we need to look at.
: Given the debate over propofol that heated up after Michael Jackson died from an overdose of the sedative, do you or your anesthesiologist colleagues have any opinions as to whether the drug should be reclassified as a Scheduled II narcotic? A: Well, there’s an aqueous form of propofol, fospropofol [Lusedra, Eisai Corp.], approved in December , which has been designated as a Schedule IV narcotic [by the Drug Enforcement Administration]. It’s indicated for monitored anesthesia care, but of course that’s kind of where propofol started. And so to me, if a sister compound is a scheduled drug, propofol will unfortunately probably end up there as well.
: Why would that be unfortunate? A: I guess I’m speaking from an ICU work flow perspective. Propofol comes
at the hospital who served as preceptors. My job was to simply point Judi in the right direction and she took care of the rest. On completing her residency, Judi routinely attended the Society of Critical Care Medicine (SCCM) annual meeting. Judi’s enthusiasm for the meeting, coupled with her leadership skills, were a major influence in the formation of the Clinical Pharmacy and Pharmacology (CPP) section of SCCM. It was a pleasure to watch her develop into a skillful clinician, teacher and clinical researcher. Judi became knowledgeable about the operation of a professional organization and was one of the first pharmacists to be appointed to key SCCM committees. She was also a major factor in the
growth of our section by helping us stay focused, first and foremost, on the needs of the patient. Although Judi’s responsibilities within SCCM have grown, she continues to maintain her role as a fulltime critical care pharmacist. I must admit, the year 2010 brings a sense of pride and joy as Judi assumes the role of SCCM president. Not only is she the first pharmacist president, but also the best person for the job, particularly during this volatile time of change in health care. I am overwhelmed with emotion about Judi’s accomplishments following her residency. She is a role model for past, current and future residents and fellows. I knew her visit to Ohio State in the early 1980s would
in small bottles, which we store in automated drug cabinets [ADC] on the unit floor. When we’re using propofol as our primary sedative, we’ll go through several bottles every few hours. When stocks get low, we simply refill the ADC tray with a bunch of propofol bottles, so there’s no downtime waiting for restocking. That’s really critical to meeting the volume needs of the unit. If we had to treat propofol as a controlled substance, however, that quick access would probably be impacted and it could pose some hardships. But at least at our hospital, we have the ADC cabinets on the floor. However, if you practice in a hospital where you have to send up labeled bottles for each patient, and propofol becomes a controlled substance, it becomes even more daunting, because you can’t just send it up on a cart or via pneumatic tubes and leave it on the counter; a host of new policies and procedures would have to be in place. And so from an ICU sedation perspective, the logistics of propofol delivery and the whole inventory control process becomes more challenging if it’s a scheduled compound. Plus, let’s be realistic about Michael Jackson’s death. It was tragic, but would it really have been prevented if propofol were a scheduled narcotic? I don’t think so. His physician was allegedly using the drug so far off-label, that I doubt the drug’s regulatory status would have ultimately stopped him from getting it for his patient. Remember, this is a very powerful, alluring drug to potential abusers, and there have been many cases of physicians and other caregivers getting access to it in hospitals, many to their own demise. Making it a Schedule II narcotic won’t fundamentally change
that; it will make it a bit harder to divert, yes, but staffers bent on abusing it will still have access to it, unfortunately. So scheduling the drug won’t solve much of the abuse issues, but it certainly will negatively impact our ability to use the drug for legitimate purposes.
see COLLEAGUES, page 58
: One last question: At the end of your term, what do you hope to have accomplished? A: We already touched on some of my major goals. One I didn’t mention is infection prevention and control. SCCM is going to be working directly with multiple stakeholders on this topic in the coming year, such as HHS [U.S. Department of Health & Human Services], to help them with their initiatives at infection prevention. For example, we’ll help them develop educational tools to assist practitioners in the prevention of ventilator-associated pneumonia and catheter-related bloodstream infections. And again, those are areas that you need the entire critical care team to focus on, in order to get the best outcomes. I should say that this effort is not limited to SCCM. Actually the critical care organizations as a group are partnering with HHS: ATS [American Thoracic Society], ACCP [American College of Chest Physicians] and AACN [American Association of Critical Care Nurses] all will be very engaged in this process. And that just underscores one of my main messages as SCCM president: We need a team-based, collaborative approach to improving the care of the critically ill, whether we’re talking about the needs of an individual patient or the specialty as a whole. It’s really all about strength in numbers. —Reported and compiled by David Bronstein
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Tudy Hodgman, PharmD, BCPS, FCCM
continued from page 57
Clinical Coordinator Critical Care Specialist Associate Professor of Pharmacy Practice Midwestern University, Northwest Community Hospital Arlington Heights, Illinois
result in something special. She has helped shape the role of the pharmacist in critical care and will soon take the helm of SCCM to help shape the discipline of critical care—accomplishing both by keeping the patient as the primary focus.
Douglas N. Fish, PharmD, BCPS Clinical Associate Professor of Medicine Division of Pulmonary Sciences and Critical Care Medicine Department of Medicine, School of Medicine University of Colorado, Denver
would like to express my sincere congratulations to Judi Jacobi on being the first pharmacist to serve as president of SCCM. Although many pharmacists have served, and continue to serve, in high-profile leadership positions within SCCM, Judi in particular stands out as a true role model and mentor for her colleagues. Her clinical knowledge and experience are impressive, but I have also always admired Judi’s enthusiasm and “can do” attitude. Judi is also famous for her accessibility, always extending a welcoming hand to new practitioners and encouraging them to become actively involved in their profession. For many years, Judi has been a tireless advocate for the role of the pharmacist as an integral part of a multidisciplinary team in the intensive care unit (ICU) setting. Her relentless campaigning for pharmacists to be included as key policy and decision makers also has helped create numerous opportunities for her pharmacy colleagues to make meaningful contributions to SCCM and other professional organizations. Judi, in her modesty, has often been quick to credit others for her achievements and to acknowledge the roles that others have played in the successful evolution of critical care pharmacy as a distinct, well-recognized practice area. Although it’s true that she hasn’t advanced the profession in this area single-handedly, Judi has certainly been a consistent and dominant force in this process. Although I’ve often questioned her love for Big Ten sports, I nevertheless consider myself fortunate to have been counted among Judi’s colleagues over the years. I have learned a great deal from her and she has certainly been a great example for me personally. Congratulations, Judi— you’re very deserving of this honor, and I’m looking forward to a great year with you at the helm of SCCM!
have known Judi for nearly 30 years since she was a resident of Joe Dasta the year before me. Fortunately, I started my residency early in January 1982, so I was able to work side by side with Judi for six months. Even as a resident, Judi’s “light” was evident. She was notably bright, with a voracious appetite for knowledge. It was such an awesome experience to work with her, for she already had so much talent. Judi always had a vision to push our profession further into practices that now define us as critical care pharmacists. I am lucky to have worked with her and some of her colleagues at the beginning of the pharmacy critical care movement, which was initiated by a small group back in the late 1980s and early 1990s within SCCM. It has been such a great experience to see us all work and grow and create this phenomenon within the society. Judi was persistent in helping model and change the role of the pharmacist working within the ICU. Pharmacy now has a great reputation within SCCM because of the hard work of people like Judi, Joe Dasta and Deborah Armstrong [PharmD, FCCM]. What amazing company for me to be able to call friends and colleagues. Judi is a great clinician, an expert in many areas of critical care, and she continues to promote critical care pharmacy services. She has been a residency director for many years, producing a group of practitioners who have gone on to do the same. Despite her successes, Judi is still very down to earth. She has always had that quick wit and ability to talk and work her way into areas not heretofore taken by a pharmacist. I am proud to be her friend and associate. Judi’s achievements have made us all successful.
than to elect a pharmacist as its president? The fact that SCCM chose Judi to fulfill that role makes perfect sense. She recognizes the value of having our profession directly involved treating patients in the ICU, and that’s at least partly due to the fact that she still sees critically ill patients on a daily basis. So this is a particularly poignant, gratifying development. Our current president, Mitchell Levy, MD, returned from the World Federation of Societies of Intensive and Critical Care Medicine, in Perth, Australia, in October, and in a recent Critical Connections column, he recognized what other clinicians are doing around the world to advance critical care practice. Well, Judi is on that same international stage: She is in high demand for her expertise, has participated in several international conferences, and has contacts across the world in other organizations that practice critical care medicine. So she is truly up to the task of leading SCCM. The expertise Judi brings to the table is impressive: She’s one of the foremost authorities in insulin infusion management in the ICU, and she’s also done great work promoting the goals of the Surviving Sepsis Campaign. She still runs her postgraduate training program in critical care pharmacy as well. Being president of SCCM will be just one more example of how Judi can successfully manage a very challenging set of responsibilities. Of course, being in a leadership position is nothing new for Judi. Shortly after the CPP section first formed in the late 1980s, Judi was the first of our group to be elected to a designated seat on the governing council for SCCM. I believe Debbie Armstrong got elected to an at-large position, so we had two pharmacists sitting on the 18-member council at the time, and that was a pretty big deal. I am very grateful to Judi for those efforts, because as she moved on to other roles within SCCM, I now hold the designated seat for our critical care section. I very much feel that I am following in her footsteps and benefitting from the groundwork she’s laid—as have so many others. Sandra L. Kane-Gill, PharmD, MS, FCCM
Steven J. Martin, PharmD, BCPS, FCCP, FCCM
Associate Professor Pharmacy and Therapeutics University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania
Professor and Chairman Department of Pharmacy Practice The University of Toledo Toledo, Ohio
CCM is one of the only clinical organizations to embrace a multiprofessional, multidisciplinary approach to its membership and activities. What better way to demonstrate that collaboration
everal years ago, as a fellow, I was encouraged to join SCCM because it was the leading critical care organization promoting multiprofessional participation in patient care. I have to admit, it was intimidating to join an organization that contained members who conducted many of the studies
that I had read. The fortunate part was that these researchers/critical care practitioners were very approachable, especially Judi. Judi was always willing to provide the mentorship that a new member needed. She encouraged active involvement in the society and she was a great role model by volunteering her own time. She was actively involved in SCCM in many capacities; in particular, she was a council member for some time. Her insight into the organization was instrumental in providing guidance to me and the entire CPP section. Judi’s words and actions speak loudly about her belief in the mission and vision of SCCM. Judi is a role model for all SCCM members with her outstanding leadership. I am excited to see Judi be the first pharmacist president of SCCM because this honor is well deserved and the society will benefit from her leadership. Congratulations Judi!
Brad E. Cooper, PharmD, FCCM SCCM CPP Section Chair Clinical Pharmacist: Critical Care Hamot Medical Center Erie, Pennsylvania
first came to know Dr. Jacobi as a student at Purdue in the early 1980s. At that time, she practiced in an ICU at a community hospital near the Purdue campus, and taught several pharmacotherapy classes for the Purdue School of Pharmacy. I also had the privilege of having my first critical care rotation with Dr. Jacobi as a student. Dr. Jacobi impressed me with her knowledge and work ethic. Her multidisciplinary team had a great amount of respect for her. She served as the ideal role model for me as she has continued to do for many students and residents in critical care. I still recall Dr. Jacobi being referred to by physicians as “the walking PDR.” One of the practice principles that Dr. Jacobi instilled in me was that she always was thinking about her patients (even in the car on her way to work) and how to optimize their therapies. Along with several colleagues, Dr. Jacobi was instrumental in organizing the CPP section of SCCM, and there is no doubt that her work in SCCM has advanced critical care pharmacy practice and the role of the pharmacist on the critical care team. There are many excellent practitioners, researchers and educators, but very few have achieved the level of accomplishment in all three areas like Dr. Jacobi has. Congratulations to Dr. Jacobi, and we sincerely thank you for the many contributions you have made through your hard work for our section!
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The High Price of Proximity to Prescription Drugs For one pharmacist, easy access to medications led to a five-year struggle with addiction
ared Combs, RPh, lives a life of quiet domesticity. When the 37-yearold pharmacist isn’t at work reviewing orders at the University of Kentucky Medical Center in Lexington, he likes nothing better than to spend time with Darcey, his wife of 13 years, and their three young children. Aside from the occasional hunting or fishing trip, he sticks close to home. “My favorite hobby is taking naps,” he says. It wasn’t always this way. From 1996 to 2000, Mr. Combs was locked into a ruinous addiction to drugs and alcohol—a habit fueled by the easy access to narcotics afforded by his work as a pharmacist. Although he’s been clean for nine years now, he still recalls in vivid detail the desperate life he led as a pharmacist-addict. The benders. The blackouts. The lies he told in order to hide his chemical dependency and his diversion of controlled substances from the pharmacies that employed him. Most of all, he recalls the arrests that humiliated his family and almost cost him his marriage, his livelihood and his freedom. Mr. Combs is well aware of the bullets he has dodged and is filled with gratitude for the second chance at life that he’s been given. “Where I am today is very, very grateful,” he said. “Grateful not to be living a life of lies, and grateful to be able to be a husband and a daddy. That was impossible while I was using.” It’s been a hard journey for Mr. Combs, who was born and raised in Hazard, a hardscrabble coal-mining town in southeastern Kentucky. The son of teetotaler
parents who drank only an occasional beer, he nonetheless developed a taste for alcohol at an early age. “I tried drinking in high school, and I liked the way it made me feel,” he said. “I became a
The Impact of Drug Abuse On Pharmacy—and Ways To Survive It
espite their ready access to controlled substances, pharmacists seem to be no more likely than anyone else to become dependent on drugs or alcohol. “Based on the National Survey on Drug Use and Health in 2008, the incidence of alcohol and other drug dependency in the general population is somewhere around 8% to 10%,” said George A. Kenna, PhD, RPh, assistant professor of psychiatry at Brown University’s Center for Alcohol and Addiction Studies in Providence, R.I. “There is no evidence to suggest that the incidence among pharmacists is any higher.” But pharmacists may be less likely than others to acknowledge a drug or alcohol problem. “Denial can be worse with health care professionals because we feel that we know too much to ever become chemically dependent,” said Charlie Broussard, RPh, MEd, a Mainesville, Ohio pharmacist who runs Pharmacy Recovery Network (http://www.usaprn.org), an organization that provides assistance to pharmacists and student pharmacists who are chemically dependent. Mr. Broussard and other experts who spoke with Pharmacy Practice News say it’s critical to acknowledge the problem and get help before things get too bad. “Addicted pharmacists must realize that they have a choice between secrecy and recovery,” said Anthony C. Tommasello, PhD, executive director of the Pharmacists’ Education and Advocacy Council of Maryland. “Secrecy is the friend of the disease and the enemy of recovery. Once they’ve finished treatment, the vast majority of pharmacists are able to return to work.” —David Freeman
weekend drinker with my buddies on the football team. We didn’t see anything wrong with that—although, looking back, I see that I had a problem even then.” Throughout college and later, while
‘One day I took a Lortab and I fell in love. I felt like “Superpharmacist.” I was instantly happy and serene and thought I could take on the world.’ —Jared Combs, RPh
attending pharmacy school, Mr. Combs binged mostly on weekends—except the weekends kept getting longer. “First, I started drinking on Thursday instead of Friday, and before long I was starting to drink on Wednesday.” Eventually, he was getting drunk at least four days a week—drinking beer and sometimes whiskey. As his drinking habit worsened, Mr. Combs began to experiment with prescription drugs, including Vicoden. But his narcotics addiction didn’t begin until 1996, just months after graduating from pharmacy school and shortly after marrying Darcey, his childhood sweetheart. The couple had bought a home just steps from his parents’ house in Hazard, and he was settling into his job as a pharmacist at a local hospital.
Help From a Pill “The pharmacy work was fast-paced, and I was feeling stressed out,” recalled Mr. Combs. ‘One day I took a Lortab and
I fell in love. I felt like “Superpharmacist.” I was instantly happy and serene and thought I could take on the world.” Before long he was filling his pockets with pills before heading home each night. Lortab. Percocet. Tylox. He’d take Xanax and Soma in the evening to help him relax—and Ritalin to help him get started in the morning. Darcey sensed something was wrong. “When I got home from work, she would look at my eyes and know immediately that I was high,” he said. “Then she would give me a disgusted look and go to bed.” Although her reproach pained him, he ignored her desperate pleas to stop using drugs and seek help. Seven months into his job, someone broke into the hospital pharmacy and stole a large quantity of narcotics. Along with other members of the staff, Mr. Combs was asked to take a polygraph test. Although he said he had nothing to do with the burglary, he refused, fearing that his drug habit—and illegal daily diversion of pills—would be revealed. Suddenly the prime suspect in a major felony, he faced intense questioning by the authorities. In the absence of solid evidence, however, no charges were brought against him at that time. The incident seemed to have blown over; his employment at the pharmacy continued, as did his addiction. Before long, he
see HIGH PRICE, page 62
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HIGH PRICE continued from page 60
was using while on the job, sneaking off to the bathroom to crush and snort the pills he pocketed—and eventually using right at the front counter. On July 25, 1997, police showed up at the pharmacy, placed Mr. Combs under arrest and led him away in handcuffs. Unbeknownst to him, the pharmacy had been fitted with hidden surveillance cameras shortly after the burglary, and his drug use had been caught on tape. He was charged with possession of a
‘It’s a misconception that access to controlled substances in a pharmacy is tightly monitored. I could just grab a handful of pills and stick them in my pocket.’ —Jared Combs, RPh
controlled substance, possession with intent to distribute and pharmacy burglary. After spending four nights in jail, Mr. Combs was released to await trial. Suddenly jobless, and facing the loss of his pharmacy license and criminal
charges that could send him to prison for years, Mr. Combs retreated to his home. He did what he could to earn money— mostly washing cars—but spent most of his time drunk. “I drank vodka every day, as hard as I could,” he recalled. “It
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was the only way I could face the day. Darcey’s job as a schoolteacher didn’t bring in enough to cover our expenses, so financially, we were pretty shot.” The case went to trial the following December. But just two days into the proceedings, the burglary and possession charges were unexpectedly dropped. Mr. Combs pleaded guilty to obtaining a controlled substance by deception, and was sentenced to four weekends in jail and three years probation. Although relieved to have avoided real jail time, he worried that even if he somehow managed to hold on to his pharmacy license, he would be unable to find a new job. In fact, he didn’t lose his license— he thinks a backlog at the Kentucky Board of Pharmacy delayed the investigation into his case—and although the notoriety surrounding his case made him unemployable in Hazard, he soon secured a new pharmacy job in Pikeville, about 70 miles away. Things were looking up for Mr. Combs—but only briefly. Within weeks of starting his new job, he reverted to his old ways—and then some. He found various ruses to fuel his addiction, here pocketing a few pills when he filled a prescription, there emptying capsules to get the powder inside (and hiding his tracks by refilling them with acetaminophen). “It’s a misconception that access to controlled substances in a pharmacy is tightly monitored,” he explains. “I could just grab a handful of pills and stick them in my pocket.” Mr. Combs also found ways to outfox the random drug screenings to which pharmacists are subjected; he began snorting Sonata, a Schedule IV controlled substance sleeping aid, in part because it is unlikely to show up in urine drug tests. Once, when he feared his urine would show traces of narcotics, he escaped detection by giving the tester a vial of a friend’s urine. But avoiding detection just allowed his life to spiral out of control. “I started using more and more, and, as I did, I got worse,” he said. “I was having blackouts. Things got so bad that my colleagues at the pharmacy started to notice.” Darcey threatened to leave him.
Denial Starts To Crack In summer 2000, after years of denial, Mr. Combs admitted to his sister during a blackout that he was addicted to drugs and alcohol. She alerted their brother, and on a Saturday in July, Combs’s family staged an intervention. Yet he refused to enter treatment, insisting that he could get better on his own. He joined a 12-step program but seldom went to meetings. As his drug and alcohol abuse continued, the blackouts became more frequent. One night in October 2000, he scuffled with a bouncer at a local bar
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Addiction Medicine and woke up the following morning in jail. Bruised and battered, he knew he had been in a fight but had no recollection of it. Out on bail, he spent an anxious weekend at home—had the police found the bottle of sleeping pills that he had taken to the bar?—and then returned to work on Monday. But trouble soon arrived. “When I saw the uniformed officer and the detective walking toward the pharmacy, I panicked and ran into the office,” he recalled. “They asked if I was Jared Combs. I said ‘yes,’ and then dropped my head and started to cry. Once again I was led out of a job in handcuffs.” Mr. Combs was back in jail. At long last, he had reached the proverbial rock bottom to which addicts eventually descend. Yet he felt strangely upbeat. “I don’t know how to explain it,” he said. “But God gave me a dose of hope. I said out loud that I was an alcoholic and an addict, and that I didn’t have to keep living like I had been. I just felt hopeful.” Mr. Combs left jail and spent 30 days in an inpatient treatment facility. Then he moved into a halfway house in Lexington, where he began another 12-step program—in earnest this time—and worked hard to sober up. Once again, he managed to avoid jail time. But his
Helpful Resources • Pharmacists Recovery Network, http://www.usaprn.org/: A stateby-state listing of treatment resources available to pharmacists and student pharmacists who are chemically dependent. Experts call this the best place to start. • International Pharmacists Anonymous, http://home.comcast.net/~ipa/ipapage.htm: Peerto-peer support for addicted pharmacists. • International Doctors in Alcoholics Anonymous, www.idaa.org/: Despite its name, this site is open to pharmacists as well. • National Association of Boards of Pharmacy, www.nabp.net: Good source of information on pharmacy-related regulations and policies. • National Clearinghouse for Alcohol and Drug Information. http://www.ncadi.samhsa.gov/: The U.S. government’s comprehensive site about chemical dependency and its treatment. —D.F.
pharmacy license was suspended. Six months into his stay at the halfway house, and feeling confident that his newfound sobriety was of a lasting sort, he successfully petitioned the Board of Pharmacy to have his license reinstated. “I had to go in front of them and sit in the hot seat and explain what I had done to overcome my addiction,” he said. Within weeks, he was looking for work. “I interviewed at Samaritan Hospital here in Lexington and, to my dismay, the guy offered me a job. Here I was, a convicted felon living in a halfway house. But he said as long as
I was doing the right thing, he would give me a chance.” Mr. Combs has made the most of the chance. He moved out of the halfway house and bought a home in Lexington, where he moved in with Darcey and the kids. He worked at Samaritan for two years, and then took his current job as a clinical staff pharmacist at the University of Kentucky. Once again, he is surrounded by narcotics, but now—with the help of prayer, his wife’s encouragement and frequent meetings at his 12-step group— he manages to stay clean. On those rare occasions when he feels tempted to start
using again, he thinks back to his days as an addict. “I was always high or drunk,” he said. “All I did was provide an income and take up space. I had no relationship with my wife other than chaos, and my kids used to cry when I held them. Not a day goes by that I am not truly grateful for sobriety.” —David Freeman For more details on Mr. Combs’ experience with substance abuse, see his self-published book, “Incomprehensible Demoralization: An Addict Pharmacist’s Journey to Recovery” (www.xlibris.com).
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Addiction Medicine CASA Chief:
Parents Are the Key to Keeping Kids Prescription Drug-Free I t has been a long and diverse career for Joseph A. Califano Jr., founder and chairman of The National Center on Addiction and Substance Abuse (CASA). He held the position of counsel to the U.S. Army, was a special assistant to Pres. Lyndon Johnson, and served as U.S. Secretary of Health, Education and Welfare under Pres. Jimmy Carter (and was the architect of the first major U.S. antismoking campaign) before starting CASA at Columbia University in New York City in 1992. Donald M. Pizzi, editor of sister publication Pain Medicine News, spoke with Mr. Califano following the release of his 12th book, “How to Raise a Drug-Free Kid: The Straight Dope for Parents” (www.straightdopeforparents.org).
You’ve written numerous books in your career, but I noticed in the release for this one that you are the grandfather of eight children. How personal a book is this for you?
It is very personal. This book is the result of 17 years of work here [at CASA]. I think the most important thing shown by all of the information
we’ve collected over the years is that drug abuse and alcohol abuse is all about kids. Get a child through age 21 without using drugs or tobacco and without abusing alcohol, and that child is home free for the rest of their life in terms of smoking, using drugs or having a drinking problem. And the greatest influence on kids is parents. People talk about movies and music and popular culture, but there is nothing close to parental influence, for better or worse. Parental engagement is key. My own children don’t really understand the world their teenage children live in. It is awash in drugs; every kid will be offered drugs before they get to high school—many of them many times—and some of them in middle school. Parents don’t realize how much power they have. It is essential to communicate with kids, have family dinners, go with kids to watch their activities, take them to religious services—become involved in their lives. Most teens and “tweens” know how difficult that is, with both parents working; for their parents to do these things tells them, “My parents care about me.” If you listen to them as well as talk to them, set limits and
‘Prescription drugs are now [the] fourth [most abused substances among young people] and are gaining fast; they could easily overtake marijuana in the next couple of years.’
‘When I was a kid they talked about locking the liquor cabinet; nowadays many parents should be locking the medicine cabinet.’
Joseph A. Califano Jr., with Lyndon Johnson, in his New York office.
have consequences for breaking limits, then there is a really healthy family relationship. How much of the advice/information from the book comes from personal experience?
Some of it, but the book is very evidence-based. We’ve been surveying teens for 14 years to understand their attitudes and determine the times they are at greater risk. We try to let parents know that these times are the first six months of middle school, the first six months of high school and then the biggest jump in drinking is in the first six months in college. Diversion of prescription drugs to kids is a huge problem, especially because kids don’t always see them as drugs like illicit substances. Does the book discuss the dangers of prescription drugs?
There is a chapter in the book called “What Drugs Are Most Likely to Tempt Your Teen?” Prescription drugs are now fourth and gaining fast; they could easily overtake marijuana in the next couple of years. And you’re right, kids have a perception that these drugs are safer. It’s very important to let them know they are only safe after a doctor prescribes them and if they are used in the way the doctor prescribes them. When I was a kid they talked about locking the liquor cabinet; nowadays many parents should be locking the medicine cabinet. We’ve found that one-third of prescription drugs taken by kids come from their parents, and one-third come from their friends, who are in turn very often getting them from their parents. So, parents need to keep track of their pills; that is very important. The thing is, teens are remarkably sophisticated about these drugs; you have
13- and 14-year-olds who know you get a rush from crushing OxyContin. [Attention-deficit/hyperactivity disorder] drugs are among those most abused by younger teens, but for older teens, it is prescription painkillers. Kids need to be made to understand the dangers of these drugs. Many in the pain management community, although deeply concerned about the misuse of prescription medications, feel the FDA’s policies, such as requiring REMS (risk evaluation and mitigation strategies) and restricting access will actually keep drugs out of the hands of pain patients who really need them. What is your view on this?
We [at CASA] do think there should be risk management plans. We believe that is very important, although I’m not too familiar with the details of [the FDA’s REMS initiative for opioid pain medications]. We also feel every effort needs to be made to formulate these substances so it is difficult to abuse them. But, to your point, we must be careful that with our actions to curb abuse, we don’t end up denying these drugs to people who need them. There are a lot of myths out there about prescription drug abuse. Most people who get painkillers in hospitals never abuse them. If you had to give one piece of advice with regard to keeping kids away from drugs, what would it be?
Parental engagement. We’re releasing results of a survey showing the importance of parental conduct and expectations. Parents can’t just assume their teenagers are going to smoke marijuana no matter what, and thus they don’t bother to talk about it. If they send a clear message of what they expect from their children, believe me, kids get it.
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Pharmacy Practice News • November 2009
Going to School on Meaningful-Use Criteria and BPOC Mark Neuenschwander President, The Neuenschwander Co, Inc. Bellevue, Washington
professor told me his least-favorite line from students is, “When is this assignment due?” He is most inspired by students who take assignments by the throat, understanding that something
greater than grades is at stake. And his heart goes out to those who want to enroll but can’t afford the tuition. Hospitals are waking up to the fact that bar coding at the point of care (BPOC) is no longer a matter of if but when. Onefourth of our nation’s hospitals are already reaping the rewards. Another fourth say they’re in the throes of planning or implementing. Some are eager to move ahead but lack funding. And I’m sure a few are stalling, for whatever reason, until they
hear when the assignment is due. One important hint could come from the Centers for Medicare & Medicaid Services. In 2011, CMS will issue payments to any facility that can demonstrate “meaningful use” of an electronic health records (EHR) system. (The payments are authorized under the Health Information Technology for Economic and Clinical Health Act, a provision of the American Recovery and Reinvestment Act of 2009.) The problem is, what
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exactly does “meaningful use” of an EHR entail? What criteria must we satisfy—by when—to qualify for those incentive payments? And when does BPOC figure into the equation? Based on recent events, it looks like we have a few more months of waiting for clarification. In his update of Oct. 1, 2009, David Blumenthal, MD, who heads the Office of the National Coordinator for Health Information Technology (ONC), wrote: “CMS is expected to publish a formal definition of meaningful use, for the purposes of receiving the Medicare and Medicaid incentive payments, by Dec. 31, 2009. At that time, the public will be able to comment on the definition, and such comments will be considered in reaching any final definition of the term.”
‘Think of BPOC as a synapse— a more reliable conduit between patients and EHRs than manual alternatives.’
• Provides cost savings compared to items purchased separately1 • Offers additional savings opportunities with inclusion in the Baxter Value Incentive Program • Allows easy management of thrombin use • Helps consolidate inventory of multiple products And FLOSEAL [Hemostatic Matrix] are part of a complete hemostasis product line from Baxter. For more information please contact your local Baxter BioSurgery Representative or call 1-800-423-2090.
www.baxterbiosurgery.com GELFOAM PLUS Hemostasis Kit Indications GELFOAM PLUS is intended as a hemostatic device for surgical procedures when control of capillary, venous, and arteriolar bleeding by pressure, ligature, and other conventional procedures is either ineffective or impractical. Thrombin (Human) used without the Gelfoam Sterile Sponge is not indicated for hemostasis. Important Safety Information GELFOAM PLUS should not be used in closure of skin incisions, because it may interfere with the healing of the skin edges. GELFOAM PLUS should not be placed intravascularly, because of the risk of embolization. GELFOAM PLUS is not recommended for use other than an adjunct for hemostasis. GELFOAM PLUS contains thrombin, which is made from human plasma. It may carry the risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. While packing a cavity for hemostasis is sometimes surgically indicated, GELFOAM PLUS should not be used in this manner unless excess product not needed to maintain hemostasis is removed. Whenever possible, GELFOAM PLUS should be removed after use in laminectomy procedures and from foramina in bone, once hemostasis is achieved. This is because GELFOAM Plus may swell to its original size on absorbing ﬂuids, and produce nerve damage by pressure within conﬁned bony spaces. GELFOAM PLUS is not recommended in the presence of infection. There have been reports of fever associated with the use of Gelfoam Sterile Sponge, without demonstrable infection.
FLOSEAL [Hemostatic Matrix] Indications FLOSEAL is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical. Important Safety Information FLOSEAL must not be injected into blood vessels, or allowed to enter blood vessels. Do not apply in the absence of active bleeding. Extensive intravascular clotting and even death may result. Do not use FLOSEAL in the closure of skin incisions because it may interfere with the healing of the skin edges. Do not use FLOSEAL in patients with known allergies to materials of bovine origin. FLOSEAL is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The maximum swell volume of approximately 20% is achieved within about 10 minutes. Excess FLOSEAL (material not incorporated in the hemostatic clot) should be removed from the site of application using gentle irrigation. RX only: For safe and proper use of these devices, please refer to full device Instructions For Use. 1. 2006 IMS Hemostat and Sealant Revenue, Unit, and ASP Sales Data. Baxter, FLOSEAL and ADVANCING SURGERY,ENHANCING LIFE are trademarks of Baxter International Inc. Gelfoam is a registered trademark of Pharmacia & Upjohn Company LLC., used under license. BS1889 4/2008
In the meantime, what’s a hospital to do? Dr. Blumenthal advises being “as familiar as possible with the discussion of meaningful-use criteria to date.” For the most part, discussion of the meaningful use clause has centered on practical elements—what I would call the letter of the regulation. At the beginning of August, the HIT Policy Committee sent their final recommendations1 to the ONC, which was followed by a period of public comment. The recommendations outlined hospital objectives to be achieved by 2011, 2013 and 2015. The elephant in the 2011 column was CPOE—requiring direct entry of at least 10% of all orders. The 2013 objectives upped the ante, requiring CPOE for all types of orders, and then added, “Conduct closed-loop medication management, including eMAR and computerassisted administration.” Many of us had assumed, if not hoped, that these objectives implied bar coding. The latest document released by the ONC suggests our assumptions may be safe. The Summary of Public Comments2 on the Policy Committee’s recommendations, issued Sept. 14, 2009, contains new language under the 2013 Hospital Objectives. “Conduct closedloop medication management” has been replaced with “conduct medication administration using bar coding.” Also noteworthy, although not surprising, is the fact that 64 of the 165 hospital organizations that offered comments said they believed the 2011
Pharmacy Practice News • November 2009
Guest Editorial timeline for CPOE was too aggressive and should be moved further out. None said it should be moved closer in. The ONC is weighing the Policy Committee’s recommendations along with the public’s comments. In the forthcoming formal meaningful use regulation, will CPOE implementation be moved to 2013? If so, might medication bar coding be moved up to 2011? I’d vote for both. It’s difficult for me to visualize meaningful EHRs without BPOC. This proven technology in the hands of caregivers facilitates the critical exchange of information between patients and EHRs. I hold these truths to be self-evident: 1) To be meaningful, EHRs must be accurately, thoroughly and instantly populated with data from the point of care; 2) To be used meaningfully, EHRs must be immediately accessible and consistently relied upon by physicians and nurses at points of care (i.e., to be meaningful, EHRs must be fully fed and faithfully read). Think of BPOC as a synapse—a more reliable conduit between patients and EHRs than manual alternatives. Even the best CPOE systems cannot fix incomplete or inaccurate data that doctors require for treating their patients. While most of the discussion has focused on the letter of the regulation, the doctor’s October update offered a thought-provoking summary of the spirit of the regulation: “By focusing on ‘meaningful use,’ we recognize that better health care does not come solely
from the adoption of technology itself, but through the exchange and use of health information to best inform clinical decisions at the point of care.”3 Welcome or not, CPOE and BPOC have been assigned. Regardless of due dates, neither is an elective. For hospitals that want BPOC but simply can’t afford it, I hope stimulus funding proves to be the aid required. Finally, highest honors go to those hospitals that are asking not, “When is this assignment due?” but, “How soon can we get it done?” I have a feeling they realize there is something greater than stimulus funding at stake.
2. Summary of Public Comments on Meaningful Use of Health IT September 14, 2009 FINAL. http://www.hospitalrx.com/pdf/Summary%20 of%20Public%20Commments%20MU%20 Sept%2014%202009.pdf. 3. October 1, 2009: A Message from Dr. David Blumenthal, National Coordinator for Health Information Technology. http://healthit.hhs. gov/portal/server.pt?open=512&objID=1325&p arentname=CommunityPage&parentid=15&mo de=2&in_hi_userid=11113&cached=true.
Making the Case for INFeD
Many years of clinical use
Iron dextran products are not interchangeable1 deﬁciency anemia2 ® has a BP rating by the FDA and as such, the FDA has not approved any therapeutically equivalent products3 3
Proven safety proﬁle of iron dextran
dextran, dyspnea, hypotension, and neurological symptoms were the most common major adverse drug events (ADEs) – The most common minor ADEs were nausea, vomiting, ﬂushing, and pruritus – INFeD® administrations over 6 months)
(0.6%) receiving 2099 iron dextran injections (0.1%), with no fatalities reported5 – In a retrospective analysis of 61,950 hemodialysis patients, the incidence of reactions to INFeD® requiring resuscitative medications was 0.0016% (5 episodes in 317,097 exposures)6 ® is required prior to the ﬁrst therapeutic dose2
Reprints of Pharmacy Practice News articles are available in minimum quantities of 500. Reprints can be ordered in black & white or 4-color versions and printed on 80-lb. glossy stock.
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Mr. Neuenschwander is co-founder and partner of The TerraPharma Project, LLC, producers of The unSUMMIT for Bedside Barcoding. The next summit, “Mastering the Art of Barcoding,” will take place May 5-7, 2010, in Atlanta. For more information, visit www. unsummit.com.
1. Health IT Policy Council Recommendations to National Coordinator for Defining Meaningful Use Final August 2009. http://www.hospitalrx. com/pdf/FINAL MU RECOMMENDATIONS TABLE.pdf
In the treatment of patients with documented iron deﬁciency in whom oral administration is unsatisfactory or impossible
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The parenteral use of complexes of iron and carbohydrates has resulted in anaphylactic-type reactions. Deaths associated with such administration have been reported. Therefore, INFeD® should be used only in those patients in whom the indications have been clearly established and laboratory investigations confirm an iron deficient state not amenable to oral iron therapy. Because fatal anaphylactic reactions have been reported after administration of iron dextran injection, the drug should be given only when resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available. Test dose is required. INFeD® should be used with caution in individuals with histories of significant allergies and/or asthma, and is contraindicated in patients with hypersensitivity to the product and patients with all anemias not associated with iron deficiency. Allergic reactions may potentially still occur in patients who have previously tolerated test or therapeutic doses of INFeD®, so administration of subsequent test doses during therapy should be considered. INFeD® should be used with extreme care in patients with serious impairment of liver function, and should not be used during the acute phase of infectious kidney disease. Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis, which is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias.
Please see next page for references and brief summary of full Prescribing Information.
© 2009, Watson Pharma, Inc., Morristown, NJ 07960. All rights reserved. NEP5166 10/09
Pharmacy Practice News • November 2009
BIS Monitor Plugs Into Pain Mounting evidence sees role for device in ICU patients San Diego—The bispectral index monitor may find a home in the intensive care unit as a gauge of pain in patients under heavy sedation. A team of Canadian researchers has found that the BIS monitor (Aspect Medical) appears to be more sensitive than other estimates of pain for patients in the ICU who cannot verbalize their discomfort. It also may be more sensi-
tive than a commonly used behavioral measure, the Critical-Care Pain Observation Tool (CPOT), according to the researchers, who presented their findings at the 2009 annual meeting of the American Pain Society (abstract 101). The study adds to a growing body of evidence suggesting that the technology, developed to assess depth of sedation in the operating room, could migrate into
References: 1. Data on ﬁle, Watson Laboratories, Inc. 2. INFeD® medicine. JAMA 7.
T H E O N LY L O W M O L E C U L A R WEIGHT IV IRON DEXTRAN
other areas of the hospital. “None of the physical measures of pain have adequate sensitivity in sedated and intubated patients,” said Yannick Tousignant-Laflamme, PhD, a physical therapist at Sherbrooke University Hospital, in Quebec, who helped conduct the research. The CPOT has been validated as a tool for detecting moderate to severe pain in the ICU, but it is not a
3. FDA, Approved Drug Products with Therapeutic Equivalence Evaluations, 29th Edition. 4. Fletes Am J Kidney Dis 5. Nephrol Dial Transplant J Am Soc Nephrol 8.
Examination of the bone marrow for iron stores may not be meaningful for prolonged periods following iron dextran therapy because residual iron dextran may remain in the reticuloendothelial cells. Bone scans involving 99m Tc-diphosphonate have been reported to show a dense, crescentic area of activity in the buttocks, following the contour of the iliac crest, 1 to 6 days after intramuscular injections of iron dextran. Bone scans with 99m Tc-labeled bone seeking agents, in the presence of high serum ferritin levels or following iron dextran infusions, have been reported to show reduction of bony uptake, marked renal activity, and excessive blood pool and soft tissue accumulation. Carcinogenesis, Mutagenesis, Impairment Of Fertility: See WARNINGS.
BRIEF SUMMARY: For full Prescribing Information, see package insert. WARNING THE PARENTERAL USE OF COMPLEXES OF IRON AND CARBOHYDRATES HAS RESULTED IN ANAPHYLACTIC-TYPE REACTIONS. DEATHS ASSOCIATED WITH SUCH ADMINISTRATION HAVE BEEN REPORTED. THEREFORE, INFeD SHOULD BE USED ONLY IN THOSE PATIENTS IN WHOM THE INDICATIONS HAVE BEEN CLEARLY ESTABLISHED AND LABORATORY INVESTIGATIONS CONFIRM AN IRON DEFICIENT STATE NOT AMENABLE TO ORAL IRON THERAPY. BECAUSE FATAL ANAPHYLACTIC REACTIONS HAVE BEEN REPORTED AFTER ADMINISTRATION OF IRON DEXTRAN INJECTION, THE DRUG SHOULD BE GIVEN ONLY WHEN RESUSCITATION TECHNIQUES AND TREATMENT OF ANAPHYLACTIC AND ANAPHYLACTOID SHOCK ARE READILY AVAILABLE.
Pregnancy: Pregnancy Category C: Iron dextran has been shown to be teratogenic and embryocidal in mice, rats, rabbits, dogs, and monkeys when given in doses of about 3 times the maximum human dose. No consistent adverse fetal effects were observed in mice, rats, rabbits, dogs and monkeys at doses of 50 mg iron/kg or less. Fetal and maternal toxicity has been reported in monkeys at a total intravenous dose of 90 mg iron/kg over a 14 day period. Similar effects were observed in mice and rats on administration of a single dose of 125 mg iron/kg. Fetal abnormalities in rats and dogs were observed at doses of 250 mg iron/kg and higher. The animals used in these tests were not iron deﬁcient. There are no adequate and well-controlled studies in pregnant women. INFeD should be used during pregnancy only if the potential beneﬁt justiﬁes the potential risk to the fetus. Placental Transfer: Various animal studies and studies in pregnant humans have demonstrated inconclusive results with respect to the placental transfer of iron dextran as iron dextran. It appears that some iron does reach the fetus, but the form in which it crosses the placenta is not clear.
INDICATIONS AND USAGE: Intravenous or intramuscular injections of iron dextran are indicated for treatment of patients with documented iron deﬁciency in whom oral administration is unsatisfactory or impossible.
Nursing Mothers: Caution should be exercised when INFeD is administered to a nursing woman. Traces of unmetabolized iron dextran are excreted in human milk.
CONTRAINDICATIONS: Hypersensitivity to the product. All anemias not associated with iron deﬁciency.
Pediatric Use: Not recommended for use in infants under 4 months of age (See DOSAGE AND ADMINISTRATION).
WARNINGS: See BOXED WARNING. A risk of carcinogenesis may attend the intramuscular injection of iron-carbohydrate complexes. Such complexes have been found under experimental conditions to produce sarcoma when large doses or small doses injected repeatedly at the same site were given to rats, mice, and rabbits, and possibly in hamsters. The long latent period between the injection of a potential carcinogen and the appearance of a tumor makes it impossible to measure accurately the risk in man. There have, however, been several reports in the literature describing tumors at the injection site in humans who had previously received intramuscular injections of iron-carbohydrate complexes. Large intravenous doses, such as used with total dose infusions (TDI), have been associated with an increased incidence of adverse effects. The adverse effects frequently are delayed (1-2 days) reactions typiﬁed by one or more of the following symptoms: arthralgia, backache, chills, dizziness, moderate to high fever, headache, malaise, myalgia, nausea, and vomiting. The onset is usually 24-48 hours after administration and symptoms generally subside within 3-4 days. These symptoms have also been reported following intramuscular injection and generally subside within 3-7 days. The etiology of these reactions is not known. The potential for a delayed reaction must be considered when estimating the risk/beneﬁt of treatment. The maximum daily dose should not exceed 2 mL undiluted iron dextran. This preparation should be used with extreme care in patients with serious impairment of liver function. It should not be used during the acute phase of infectious kidney disease. Adverse reactions experienced following administration of INFeD may exacerbate cardiovascular complications in patients with preexisting cardiovascular disease. PRECAUTIONS: General: Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis. Such iron overload is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias that might be erroneously diagnosed as iron deﬁciency anemias. INFeD should be used with caution in individuals with histories of signiﬁcant allergies and/or asthma. Anaphylaxis and other hypersensitivity reactions have been reported after uneventful test doses as well as therapeutic doses of iron dextran injection. Therefore, administration of subsequent test doses during therapy should be considered. (See DOSAGE AND ADMINISTRATION: Administration.) Epinephrine should be immediately available in the event of acute hypersensitivity reactions. (Usual adult dose: 0.5 mL of a 1:1000 solution, by subcutaneous or intramuscular injection.) Note: Patients using beta-blocking agents may not respond adequately to epinephrine. Isoproterenol or similar betaagonist agents may be required in these patients. Patients with rheumatoid arthritis may have an acute exacerbation of joint pain and swelling following the administration of INFeD. Reports in the literature from countries outside the United States (in particular, New Zealand) have suggested that the use of intramuscular iron dextran in neonates has been associated with an increased incidence of gram-negative sepsis, primarily due to E. Coli. Information For Patients: Patients should be advised of the potential adverse reactions associated with the use of INFeD. Drug/Laboratory Test Interactions: Large doses of iron dextran (5 mL or more) have been reported to give a brown color to serum from a blood sample drawn 4 hours after administration. The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium. Serum iron determinations (especially by colorimetric assays) may not be meaningful for 3 weeks following the administration of iron dextran. Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of INFeD and slowly returns to baseline after about 3 weeks.
ADVERSE REACTIONS: Severe/Fatal: Anaphylactic reactions have been reported with the use of iron dextran injection; on occasions these reactions have been fatal. Such reactions, which occur most often within the ﬁrst several minutes of administration, have been generally characterized by sudden onset of respiratory difﬁculty and/or cardiovascular collapse. Because fatal anaphylactic reactions have been reported after administration of iron dextran injection, the drug should be given only when resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available. (See boxed WARNING and PRECAUTIONS: General, pertaining to immediate availability of epinephrine.) Cardiovascular: Chest pain, chest tightness, shock, cardiac arrest, hypotension, hypertension, tachycardia, bradycardia, ﬂushing, arrhythmias. (Flushing and hypotension may occur from too rapid injections by the intravenous route.) Dermatologic: Urticaria, pruritus, purpura, rash, cyanosis. Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea. Hematologic/lymphatic: Leucocytosis, lymphadenopathy. Musculoskeletal/soft tissue: Arthralgia, arthritis (may represent reactivation in patients with quiescent rheumatoid arthritis - See PRECAUTIONS: General), myalgia; backache; sterile abscess, atrophy/ﬁbrosis (intramuscular injection site); brown skin and/or underlying tissue discoloration (staining), soreness or pain at or near intramuscular injection sites; cellulitis; swelling; inﬂammation; local phlebitis at or near intravenous injection site. Neurologic: Convulsions, seizures, syncope, headache, weakness, unresponsiveness, paresthesia, febrile episodes, chills, dizziness, disorientation, numbness, unconsciousness. Respiratory: Respiratory arrest, dyspnea, bronchospasm, wheezing. Urologic: Hematuria. Delayed reactions: Arthralgia, backache, chills, dizziness, fever, headache, malaise, myalgia, nausea, vomiting (See WARNINGS). Miscellaneous: Febrile episodes, sweating, shivering, chills, malaise, altered taste. OVERDOSAGE: Overdosage with iron dextran is unlikely to be associated with any acute manifestations. Dosages of iron dextran in excess of the requirements for restoration of hemoglobin and replenishment of iron stores may lead to hemosiderosis. Periodic monitoring of serum ferritin levels may be helpful in recognizing a deleterious progressive accumulation of iron resulting from impaired uptake of iron from the reticuloendothelial system in concurrent medical conditions such as chronic renal failure, Hodgkins disease, and rheumatoid arthritis. The LD50 of iron dextran is not less than 500 mg/kg in the mouse. Rx Only Revised: August 2008 Product No.: 1001-02
Manufactured for: Watson Pharmaceuticals, Inc. Corona, CA 92880 USA Manufactured by: Patheon Italia S.p.A. Ferentino, Italy 03013 251261 S0808
physiologic assessment. The small study involved nine patients (seven men, two women; mean age, 58 years) undergoing treatment in the ICU at Sherbrooke. Most were receiving sedation with propofol. To evaluate the utility of a portable BIS monitor in assessing pain, the researchers took readings when the patients were resting and therefore considered to be relatively free of acute pain. They also used the device at two times when pain is known to occur in the ICU: when patients were being moved and when they were receiving endotracheal suction. “We know that these procedures provoke pain,” Dr. Tousignant-Laflamme said. In addition to BIS readings, the researchers also recorded patients’ blood pressure, heart rate and CPOT scores during the interventions and at rest. Although heart rate and blood pressure did not change during the painful procedures, the patients’ BIS levels spiked, showing statistically significant increases during movement (P=0.0046) and suctioning (P=0.0003), according to the researchers. BIS readings did not differ from procedure to procedure, nor did the researchers observe a correlation between BIS values and CPOT scores during either intervention. The Sherbrooke team is not the only group using the BIS in the ICU to assess discomfort. Paul Ouellet, PhD(c), a critical care specialist at Edmunston Regional Hospital in New Brunswick, Canada, has been looking into whether the BIS monitor might be a useful tool for measuring pain in patients on mechanical ventilation. Dr. Ouellet and his colleagues are particularly interested in the phenomenon of patient– ventilator asynchrony—such as when the ventilator forces air while a patient is exhaling or vice versa. These episodes are considered likely indicators of distress, he said. In two studies, involving 39 patients, Dr. Ouellet and his colleagues found that patients whose BIS values were between 40 and 60 were much less likely to fall into asynchrony, whereas those whose BIS values rose above 60 were much more likely to do so. The researchers observed a similar pattern with the BIS monitor’s electromyelograph (EMG) readings. A reflection of electrical activity in the frontalis muscle, BIS EMG values have conventionally been considered useless data pollution, Dr. Ouellet said. The pollution part is technically true, he added, because the EMG and electroencephalographic waves overlap between 30 and 50 Hz. But useless, no. “We have
Pharmacy Practice News • November 2009
Pain Medicine Dr. Riker and his colleagues have found that the technology can be useful in assessing pain in sedated patients. In one study, the Maine researchers showed that BIS scores correlated closely with nurse ratings of pain in patients undergoing three uncomfortable procedures in the ICU: removal of a breathing tube, suctioning of the tube and removal of a dressing from the chest. Those results agree with findings from a study published in Intensive Care Medicine (2002;28:211-213) by French anesthesiologists who found that BIS scores
were lower in patients who received alfentanil before undergoing uncomfortable ICU procedures than if the drug was not administered. “There likely is something in the BIS that will help us look at patients and estimate their pain,” Dr. Riker said. “If you’re adequately treated with analgesia and you’re just lying there, not much should happen. But if you’re uncomfortable, there should be some variability and that BIS signal should look like a sawtooth, not a smooth wave.” —Adam Marcus
noticed that whenever the EMG went above 32 db, this is where patients started to have ventilator asynchrony.” Acting on the link, Dr. Ouellet’s clinical colleagues began to administer analgesics—rather than increase sedation perfusion—to patients whose EMG readings topped 32 db. “The EMG would come down, BIS would drop back between 40 and 60 and we didn’t see ventilator asynchrony,” he said.
‘If you’re adequately treated with analgesia and you’re just lying there, not much should happen.’
—Richard Riker, MD This strategy also appeared to shorten the time patients required to emerge from sedation and breathe spontaneously, Dr. Ouellet added, from nearly a day to about three hours. Oversedation affects roughly 50% of patients on mechanical ventilation in the ICU. “We feel with BIS technology, we can prevent oversedation,” he said. “It might be premature to imply that BIS EMG always reflects the preclinical expression of pain,” Dr. Ouellet added. “Nevertheless, the observations we made certainly mandate further investigation, specifically on the expression of pain in noncommunicative patients in ICU.” Dr. Ouellet, who holds an appointment at the University of Sherbrooke but was not associated with the BIS study there, said his group plans to submit its findings for publication in the near future. Richard Riker, MD, director of critical care research at Maine Medical Center, in Portland, said his hospital has used BIS monitors in the ICU since the mid1990s, particularly in patients receiving neuromuscular blockers; to titrate pentobarbital (Nembutal, Ovation) coma for patients in status epilepticus or with elevated neurocranial pressure; and in those undergoing therapeutic hypothermia after cardiac arrest. As with the Sherbrooke group,
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Pharmacy Practice News • November 2009
Practical Changes Reduce PCA Pump Programming Errors Vancouver, British Columbia—There is a simple, yet effective, model for minimizing programming errors in patientcontrolled analgesia pumps, according to a team of Canadian researchers. The investigators used a combination of new technology, education and a system of double checking to reduce the incidence of such errors to almost nil. “A few years ago, I started a database for clinical documentation and research,” said James Paul, MD, director of the acute
pain service and associate clinical professor of anesthesia at McMaster University in Hamilton, Ontario. “Once we started tracking patients, we noticed that PCA [patient-controlled analgesia] programming errors were occurring fairly regularly. Concentration errors were particularly troublesome and fairly common.” Between January 2002 and February 2006, 59 PCA errors occurred in 13,005 patients (average, 1.2 per month). Of these, 21 (36%) were pump programming
errors, by far the most common type of pump error reported. Although the majority (64.4%) of the errors were benign, 30.5% of the incidents caused the patients temporary harm involving either underdosage or overdosage of analgesics. Thirteen incidents resulted in respiratory depression that required intervention. The investigators’ first step to address the errors was to purchase new PCA pumps. “We chose pumps that have a
large display screen,” Dr. Paul said at the 2009 annual meeting of the Canadian Anesthesiologists’ Society (abstract 613809). “The screen shows all relevant parameters at once: drug, concentration, dose, lockout and four-hour limit.” Increased education for the system’s 1,400 nurses was another important component of the program. “[The nurses] used to get a one-hour session on using the pumps,” Dr. Paul told Pharmacy Practice News. “We increased that to six hours. “We also rewrote our preprinted physician PCA orders to include a double check,” he added. “This way, it’s not just a single nurse programming the pump; another nurse has to check it and sign off.” Patients were also counseled on the use of PCA pumps as part of the program. From the implementation of these changes in 2006 to February 2009, the researchers documented a decrease in the incidence of PCA-related errors to 11 (0.5 per month) in 12,193 patients. None of the errors involved mistakes in programming the PCA pumps. “We still have other types of errors that come up,” Dr. Paul said, “but in terms of programming the pump, we haven’t had a single error since we implemented these changes.” Given the improvements born of the program, he advised that institutions with similar problems consider the same types of changes. “I wouldn’t want to recommend any particular pump, but one with a large screen that shows all the programming elements at one time is a must,” Dr. Paul said. “The double check of preprinted orders is actually a recommendation of the Institute for Safe Medication Practices, and education, of course, is a key component.” Eugene R. Viscusi, MD, director of acute pain management at Thomas Jefferson University in Philadelphia, applauded the research and noted that the findings are consistent with those of others who have examined PCA technology. “Whenever possible, PCA solutions should be standardized throughout an institution,” Dr. Viscusi said. “Still, IVPCA remains a complex process with over 130 individual steps and approximately a half-dozen people touching some part of the process.” Dr. Viscusi said his concern is that there are limits to the technology that can handle such a complex process and human error cannot be totally eliminated. He noted, however, that the rate of PCA errors appears to have remained relatively stable in recent years. “Dr. Paul’s findings also underscore the need to have a well-developed, blameless process for reporting medication errors within an institution,” he said. Such a process encourages corrective follow-up actions that prevent
Pharmacy Practice News • November 2009
HYPONATREMIA continued from page 26
9. Gheorghiade M, Abraham W, Albert N, et al. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIME-HF registry. Eur Heart J. 2007;28(8):980-988. 10. Borroni G, Maggi A, Sangiovanni A, Cazzaniga M, Salerno F. Clinical relevance of hyponatraemia for the hospital outcome of cirrhotic patients. Digest Liver Dis. 2000;32(7):605-610. 11. Renneboog B, Musch W, Vandemergel X, Manto M, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71.e1-71.e8. 12. Kengne F, Andres C, Sattar L, Melot C, Decaux G. Mild hyponatremia and risk of fracture in the ambulatory elderly. Q J Med. 2008;101(7):583-588.
Metabol Clin N Am. 2006;35(4):873-894. 24. Smith D, McKenna K, Thompson C. Hyponatremia. Clin Endocrinol. 2000;52(6):667-678. 25. Adrogue H, Madian N. Hyponatremia. N Engl J Med. 2000;342(21):1581-1589. 26. Patel G, Balk R. Recognition and treatment of hyponatremia in acutely ill hospitalized patients. Clin Ther. 2007;29(2):211-229.
29. Spital A. Diuretic-induced hyponatremia. Am J Nephrol. 1999;19(4):447-452. 30. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52(1):144-153. 31. Vaprisol [package insert]. Deerfield, IL: Astellas Pharma US, Inc.; 2008. 32. Samsca [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Co., Ltd.; 2009.
27. Abbott R, Silber E, Felber J, Ekpo E. Osmotic demyelination syndrome. BMJ. 2005;331(7520):829-830.
33. Munger M. New agents for managing hyponatremia in hospitalized patients. Am J Health-Syst Pharm. 2007;64(3):253-265.
28. Sonnenblick M, Friedlander Y, Rosin A. Diuretic-induced severe hyponatremia. Review and analysis of 129 reported patients. Chest. 1993;103(2):601-606.
34. Schrier R, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099-2112.
35. Zelster D, Rosansky S, van Rensburg H, Verbalis J, Smith N. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007;27(5):447-457.
Dr. Stachnik is part of The University of Illinois at Chicago Drug Information Group, a fully integrated medical communication group situated within an academic medical center. The Group focuses primarily on the provision of drug information services, medical writing, and implementation of educational programs, and is staffed by highly trained clinical pharmacists with expertise in these areas.
13. Zilberberg M, Exuzides A, Spalding J, et al. Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study. BMC Pulm Med. 2008 Aug 18;8:16. 14. Kim W, Biggins S, Kremers W, et al. Hyponatremia mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359(10):1018-1026. 15. Boscoe A, Paramore C, Verbalis J. Cost of illness of hyponatremia in the United States. Cost Eff Resour Alloc. 2006 May 31;4:10. 16. Morgan GE Jr, Mikhail MS, Murray MJ. Management of patients with fluid & electrolyte disturbances. In: Morgan GE Jr, Mikhail MS, Murray MJ, eds. Clinical Anesthesiology. 4th ed. New York:McGraw-Hill; 2006:662-688. 17. Verbalis J, Goldsmith S, Greenberg A, Schrier R, Sterns R. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11A):S1-S21. 18. Schrier R, Bansal S. Diagnosis and management of hyponatremia in acute illness. Curr Opin Crit Care. 2008;14(6):627-634.
Your Single Source Solution
19. Ishikawa S, Schrier R. Pathophysiological roles of arginine vasopressin and aquaporin-2 in impaired water excretion. Clin Endocrinol. 2003;58(1):1-17. 20. Rosner M. Hyponatremia in heart failure: the role of arginine vasopressin and diuretics. Cardiovasc Drugs Ther. 2009;23(4):307-315.
21. Ghali J. Mechanisms, risks, and new treatment options for hyponatremia. Cardiology. 2008;111(3):147-157.
22. Douglas I. Hyponatremia: why it matters, how it presents, and how we can manage it. Cleve Clin J Med. 2006;73(suppl 3):S4-S12. 23. Adler S, Verbalis J. Disorders of body water homeostasis in critical illness. Endocrinol
repetition of similar errors. Dr. Viscusi recommended doublechecking programming by two nurses, standard PCA concentrations of equipotent opioids, minimizing the use of custom PCA solutions and considering the use of smart pumps. “Still,” he added, “we may be at the limit of the technology.”
Pharmacy Practice News • November 2009
Post–Kidney Transplant Patients At Risk for Drug Errors Anaheim, Calif.—Yet another study has shown that a computerized prescriber order entry (CPOE) system is not a cureall for medication errors. This time, the technology failed to prevent more than 100 clinically significant drug errors during an audit of an inpatient renal transplant unit. Although half of the errors never reached patients, the near-misses “showed us that we had to improve our drug handling procedures and CPOE system to avoid future errors,”
said lead investigator Kwaku Marfo, PharmD, a transplant pharmacist at Montefiore Medical Center, in New York City. Dr. Marfo said the audit was triggered by the case of a renal transplant patient who was mistakenly given immunosuppressive induction therapy with anti-thymocyte globulin (Thymoglobulin, Genzyme) instead of basiliximab (Simulect, Novartis). “The patient developed a potentially severe reaction to the drug, so we knew there was a pressing need to determine
the extent of the problem,” he said. The investigators prospectively evaluated all drug errors in their renal transplant unit during an initial 10-day period and a 28-day follow-up audit. Each error was evaluated for error type and the potential to cause harm to patients. A total of 103 clinically significant medication errors were detected; 43 occurred during the 10-day audit and 60 during the 28-day audit. The most common drug mishaps involved wrong dose ordered
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and wrong time of drug administration. Thirty-six of the errors reached patients. “Wrong dose” errors most often occurred when a transplant patient’s renal function wasn’t adequately factored into the dosing calculations, Dr. Marfo noted. “On post-op day 1, transplant patients’ renal function is usually still compromised. But on post-op day 4, it often improves significantly,” he explained. “Unfortunately, some physicians didn’t factor in the improved renal function when choosing immunosuppressant and other drug doses.” Most of the “wrong time” errors involved similar breakdowns. With use of tacrolimus (Prograf, Astellas), for example, blood levels must be drawn for therapeutic drug monitoring, Dr. Marfo noted. But if there is poor coordination between the time that blood is drawn for monitoring, the time the drug reaches the unit and the time that a nurse actually administers the medication, “that’s considered a potentially harmful drug error,” he said. As for preventing future occurrences, “We’ve improved our work flow and incorporated CPOE more seamlessly into the drug ordering and dispensing process,” said Dr. Marfo, whose team presented the study at the American College of Clinical Pharmacy annual meeting. The important take-away of the study, he added, “is not to assume that just because you have a CPOE system in place, safe medication use is assured. You need to periodically analyze your work flow and how well it meshes with the technology to ensure optimal outcomes.”
Transplant Pharmacist’s View
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Jill Martin-Boone, PharmD, FASHP, professor of pharmacy practice at the James L. Winkle College of Pharmacy, University of Cincinnati, in Ohio, agreed that the study results underscore the limits of any technology to fix flawed systems or processes. “CPOE is an excellent tool,” she said. “But it’s only one piece of the medication safety puzzle.” The results “also affirm the need to have pharmacists on the organ transplant team,” said Dr. Martin-Boone, who worked for 15 years as an organ transplantation pharmacist at the University of Cincinnati Hospital. “The patients you’re caring for not only have complex diseases; they often go home on eight to 12 medications. So there are both inpatient and outpatient opportunities to demonstrate our medication management expertise.” She also congratulated the researchers for performing the audit and sharing the results. Those proactive steps “show their commitment to continuous process improvement and medication safety.” —David Bronstein
Pharmacy Practice News • November 2009
Before Investing in IT, Take Time To Observe A
s hospitals across the country prepare to embark on unprecedented levels of technology adoption spurred by the American Recovery and Reinvestment Act of 2009, the need to ensure safe, effective implementation has never been greater. But before investing in federally mandated information technology (IT)— namely computerized provider order entry, automated medication administration and electronic medical records— facilities may want to consider a certified observational process to improve medication safety and maximize the returns on each IT dollar invested. In the early 1960s, Kenneth N. Barker, PhD, and colleagues at Auburn University in Auburn, Ala., began evaluating observation as a viable method of detecting and measuring errors in drug administration.1 The observation method proved to have advantages over other data collection processes: self-reports (e.g., interviews and questionnaires), testing and physical evidence (e.g., medical chart review). In particular, recording an error does not require the caregiver to recognize the error, report it or fear disciplinary action. Neither are the facts of the event obscured by the caregiver’s perceptions or communication. Moreover, the effect of the properly trained observer on the observed is minimal, so observational studies may yield more data than other strategies.2 Simply described, an observational study of medication use requires a researcher to accompany nurses who are gathering, preparing and administering drugs. He or she records details of all doses administered, and then compares this information with the doses prescribed. Discrepancies are recorded as errors and reflected in the overall medication accuracy rate. Unless the observer sees that a gross error is about to occur, at no point can the observer intervene in an error because he or she is blind to the order until after the fact.
Standardized Method Is Key One difficulty noted with observational research is the ability to obtain consistent, comparable data because observers interpret what they see or hear differently.3,4 To obtain quality data, a standardized system must be used which is capable of employing observers with proper skills and personality characteristics who are trained, tested and periodically recertified. Additionally, the system must use standard classification of errors and consistent documentation. Only with a standardized system can data be benchmarked and trended across an organization—or various hospitals—despite different processes of medication delivery, varying forms of
technology and diverse cultures. When supported by software designed for standardization, trained observers yield near real-time feedback for clinical process improvement. One proprietary system, AU MEDS, created by MedAccuracy (Lenexa, KS), applies the observational methodology created by Auburn University for hospital use. The software suite includes standardized worksheets to aid in the data collection process and in reviewing the patient’s
medication orders. The software helps observers determine the accuracy rate, errors by drug class, errors by route, clues to root causes and other accuracy measures. Additionally, benchmarking and trending reports allow a hospital to compare its accuracy rate over time and with other hospitals based on similar attributes. Through benchmarking, a hospital derives clues as to which types of medications are the biggest sources of errors and whether an upward trend
Observer inputs observational data into AU MEDS software system.
represents actual errors or merely a spike in voluntary reporting. Point-
see OBSERVE, page 74
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Pharmacy Practice News • November 2009
OBSERVE continued from page 73
of-care data are readily converted to actionable information.
Case Study: Lancaster General Hospital In the late 1990s, the Institute of Medicine’s spotlight on medication safety caught the eye of leaders at Lancaster General Hospital (LGH) in Lancaster, Pa. The 638-bed level II trauma center with a level III neonatal intensive care unit was experiencing rapid growth in patient volume and was actively pursuing ways to improve quality while meeting demand. In 2000, LGH sought to eliminate its handwritten, non-pharmacy-generated, five-day medication administration record (MAR). “Bar coding seemed to be an obvious solution for the organization,” said Rich Paoletti, MBA, RPh, vice president of operations at LGH. “But there wasn’t a lot of information yet about how bar code medication administration [BCMA] would improve the safety of the medication process. We employed the AU MEDS methodology as part of a validation process for a pre- and postimplementation study.” Results of the Lancaster observational study were published in the American Journal of Health-System Pharmacy in March 2007. The direct-observation accuracy rate derived from the observation of approximately 3,100 administered doses before BCMA was 86.5%; after BCMA implementation, the accuracy rate rose to 97%.5
The ‘Hawthorne Effect’ Debunked Yet the 2007 report was just the beginning of lessons learned for LGH throughout the BCMA implementation. The team learned the critical role of ongoing, systematic direct observation for error detection and early identification of noncompliance issues. Contrary to the belief that people will take additional care when they know they are being observed (the Hawthorne effect6), Tina Marie Suess, RN, Bridge System Administrator at LGH does not see this effect impacting their data. “The majority of the nurses are not aware that they are making a mistake. You don’t need the observation method to identify a nurse who is blatantly violating policy—it’s obvious. Observation finds what is not readily apparent— hidden in your systems.” Indeed, multiple studies7-9 suggest that concerns about the effect of the observer on error events are unfounded when the observer is properly trained. Yet initially being observed can be an uncomfortable experience for nurses. Therefore, most observational studies
Observer witnesses medication being administered to a patient at Lancaster General Hospital in Lancaster, Pa.
‘You don’t need the observation method to identify a nurse who is blatantly violating policy—it’s obvious. Observation finds what is not readily apparent—hidden in your systems.’ —Tina Marie Suess, RN of medication administration practices have used disguised-observation techniques; nurses are aware of the observation but unaware of its true purpose.10 Ms. Suess recalls, “In the beginning, everybody was a little guarded. We introduced observation to the nurses while preparing for bar coding implementation. We never told the staff, ‘we’re looking for errors,’ but rather ‘we’re trying to make this process better with new technology and we want to observe you in your element to see what you are doing.’ ” By keeping the process nonpunitive, LGH saw to it that nurses were open to observation. “We never communicate errors to their nurse manager,” Ms. Suess said. “We debrief with the nurse after we observe them. We affirm that they are doing a good job and suggest ways they might improve. When we detect that an error has occurred, we work with the nurse involved to correct it or make sure that we are not going to have that error continue day after day.” From the hospital executive perspective, observation provides an important validation that their technology investment is yielding continuing results. “One of the fallacies associated with implementing BPOC [Barcode Point-of-Care] is that when you’re fully implemented, you are done and won’t it be great!” Mr. Paoletti said. In reality, the implementation starts a deluge of new and unwieldy data about your medication administration process. LGH employs a core team of individuals which includes pharmacy, nursing, risk management and other departments to routinely review observation and system data. “Observation adds to the validity of our system data and helps us prioritize what’s important to do from a process standpoint,” he said. A dedicated medication management team looks at the
process and a clinical medication safety team focuses on associated policy and high-risk drug category issues. Ultimately, the information informs the actions of the [Pharmacy & Therapeutics Committee]. “The problems with the use of medications largely exist beyond the pharmacy,” Mr. Paolettti added. “Yet pharmacy process greatly impacts the nurse at the bedside. You need to see how your medication distribution process might affect your nurses. It’s a tremendous, overwhelming experience to realize everything you need to do in the pharmacy to set the nurse up for success. Until you get outside and see what occurs at the bedside and systematically pull data back to focus on your process, you’re running blind.”
To-do List Is Long, But Needed Dedicating your organization to observation ensures a never-ending to-do list. Ms. Suess pointed to the myriad bedside events that occur under the watchful eyes of observers, despite their primary initial focus on medication administration. “Being out there with nurses reveals so much. We witness their frustrations with technologies and environmental issues. The up-front cost for the AU MEDS software is simply a start—the real work is in fixing the problems that are identified through observation data.” Mr. Paoletti echoed this sentiment. “We dedicate eight hours each week to observation and the data entry portions of managing that process. But be prepared. If you have a broken pharmacy distribution process, observation will quickly illuminate improvement opportunities that carry additional costs. We’ve absolutely increased pharmacist and technician [full-time equivalents] as we’ve moved more preparation work from the nursing floor back to the pharmacy.” LGH’s experience also demonstrates
the role that observation has in ensuring that technology adoption works as expected the first time with user buyin. “Your board members are going to want to have proof that the technology you’ve chosen is doing what it’s supposed to do,” warned Mr. Paoletti. “In this current economic environment, expect a requirement to establish a return on investment [ROI]. How are you going to back it up?” An even more basic benefit than ROI validation is the ability of observational studies to avoid a costly technology implementation debacle. “Often, the nurses around the table helping to plan implementations are not end-user nurses,” Ms. Suess said. “So being out there observing prior to implementation allows your team to truly understand work flow and to build or change policies to support the new way of doing things. “Done right,” she added, “you can avoid reacting on the fly when your users become frustrated with unanticipated issues that should have been worked through long before the technology was put in place.” —Jamie Kelly
References 1. Barker KN, McConnell WE. The problems of detecting medication errors in hospitals. Am J Hosp Pharm. 1962;19:360-369. 2. Flynn EA, Barker KN, Pepper GA, et al. Comparison of methods for detecting medication errors in 36 hospitals and skilled-nursing facilities. Am J Health-Syst Pharm. 2002; 59:436-446. 3. Cohen MR, ed. Medication Errors. Washington, DC: American Pharmaceutical Association; 1999. 4. Dean B, Barber N. Validity and reliability of observational methods for studying medication administration errors. Am J Health-Syst Pharm. 2001;58:54-59. 5. Paoletti RD, Suess TM, Lesko MG, et al. Using bar-code technology and medication observation methodology for safer medication administration. Am J Health-Syst Pharm. 2007;64:536-543. 6. Katz D, Kahn RL. The Social Psychology of Organizations. New York, NY: Wiley; 1966. 7.
Barker KN, Kimbrough WW, Heller WM. A Study of Medication Errors in a Hospital [dissertation]. Fayetteville, AR: University of Arkansas; 1966.
8. Ridge KW. Evaluating Performance in a Hospital Medicines Supply System [dissertation]. Manchester, England: University of Manchester; 1998. 9. Dean BS. A Transatlantic Study of Medication System Errors in Hospitals [dissertation]. London, England: University of London; 1993. 10. Allan EL, Barker KN. Fundamentals of medication error research. Am J Hosp Pharm. 1990;47:555-571.
Ms. Kelly is an independent marketing consultant serving health care information technology vendors. Ms. Kelly and her partner, Mark Neuenschwander, organize the annual unSUMMIT for Bedside Barcoding educational forum. For more information on the 2010 summit, visit www.unsummit.com.
Pharmacy Practice News • November 2009
Weighing the Options for Optimal Chapter <797> Compliance W hen it comes to complying with United States Pharmacopeia (USP) Chapter <797> sterile compounding regulations for IV preparation, there are three basic options for preventing contamination—building a clean room, adding barrier isolator hoods or combining the two technologies. According to several industry experts and pharmacy directors interviewed, there’s no one-size-fits-all approach. Each hospital has to determine the strategy that makes the most sense based on cost, work flow and other highly individual considerations. For the University of Pittsburgh Medical Center (UPMC) Braddock Hospital, the clean-room option was the best fit. The facility invested $100,000 in a 400-square-foot clean room to help comply with the compounding standards. To better prevent errors and deliver more stable products to patients, the 190-bed hospital, which is one of 19 member hospitals of UPMC, also stocks more commercially purchased, premixed IV bags than it did before (see box, this page).
Larger-Scale Strategies Cleveland Clinic, a far larger facility (54,000 annual inpatient admissions and 3.6 million outpatient visits), has developed a 2,200-square-foot compounding suite in the main pharmacy, plus satellites in the cancer and heart centers. The clean-room air quality complies with the USP standards of ISO 7 in the buffer
Why Use More Premixed Solutions?
he move toward using more commercially prepared, premixed IV products has a host of benefits, noted Matthew Schonder, RPh, MBA, pharmacy director at the University of Pittsburgh Medical Center (UPMC) Braddock Hospital: • The IV solutions are made more consistently and under better safety conditions than many hospitals could manage. • There are clear gains in work flow efficiency. Tracking expiration dates, for example, is much simpler with commercial preparations. (Custom compounded solutions can have multiple expiration dates based on such factors as drug type, density and storage temperature.) • Using more premixed IVs helps with USP <Chapter 797> compliance: The regulations stipulate that premixed products should be used, when available, because of the product’s safety benefits. —A.H.
The clean room at Cleveland Clinic’s main pharmacy preparation area.
The clean room at the University of Pittsburgh Medical Center (UPMC) Braddock Hospital.
zones and ISO 5 in the compounding zones (the lower the number, the higher the standard), and helps the 24/7 preparation teams of technicians and pharmacists dispense between 2,200 and 2,500 IV admixtures from the main pharmacy clean room on an average day, noted David Kvancz, MS, RPh, chief pharmacy officer, and Angela Yaniv, PharmD, sterile products manager. Included in Cleveland Clinic’s main pharmacy compounding suite are a main room measuring 18 × 75 feet, where technicians prepare most of the IV admixtures; a glass-enclosed pharmacist work area, where supervisors have good visibility into the ongoing preparation activities; two anterooms (one for gowning and gloving, the other for materials); two hazardous drug rooms with biological safety cabinets; and a nonsterile to sterile compounding laboratory. Between eight and 10 technicians and three pharmacists staff the main clean room during the day, and six technicians and two pharmacists at night. In contrast, anyone on the UPMC Braddock pharmacy team (seven technicians and six pharmacists) can be called on to prepare IV admixtures at any time in its clean room, according to Matthew Schonder, RPh, MBA, pharmacy director. “Although technicians do most of the compounding,” he said, “pharmacists [prepare] specialty items and we run a final quality assurance check on everything: right bag, right drug, right dosage, etc.—it’s all on the pharmacists’ shoulders.” Mr. Schonder concedes that his staff “prefers to sit and work at hoods rather than stand and work in our clean room,” and they are “less comfortable wearing masks and gowns over what they used to wear. But they do enjoy the solace of working in that space uninterrupted, and they’ve adapted because we all want to improve the products we make. Our people are learning to adhere to remov-
ing jewelry and makeup.” Yet, he opted for an open-architecture, hood-free clean room because “with hoods, you can clean and replace the filters that trap particulates, and you can clean the work surfaces, but you can never get behind the hoods to clean the area.” That lack of access for cleaning is a problem, “because dust and residue collect from the admixture process over the years,” Mr. Schonder said. “Hoods can weigh thousands of pounds, and they’re bolted in place.”
A Helping Hand Neither facility built its compounding areas alone. Despite their vastly different scales, both Cleveland Clinic and UPMC Braddock needed to take measures to comply with stringent USP Chapter <797> standards (practically all hospitals do some compounding, sources said), and turned to HWI Clean Rooms, Pittsburgh, an outside designer-builder that specializes in sterile compounding pharmacies in hospitals. (Link in the Tips box provides a partial source list for planning, designing, building, testing and maintaining clean rooms.) The clean-room experiences at UPMC Braddock and Cleveland Clinic are still too fresh to have documented improvements in patient, pharmacist and technician safety; IV sterility; or the efficiencies in preparing admixtures—mostly because baseline records of sterility and efficiency were not kept previously, and safety measures are still difficult to link directly to the clean room. Yet the pharmacy chiefs at both health systems are satisfied. They knew once they opted for clean rooms, they would be best served by a firm specializing in USP standards and compliance rather than by a general contractor. Demonstrating that point, Mr. Kvancz described how two of the Cleveland Clinic’s clinical areas designed and built by HWI “went up problem-free.” In the
hospital’s cancer center, in contrast, “the general contractor took the lead role— HWI was just a subcontractor—and there were inordinate problems,” including design and work flow issues; lack of an air monitoring system; multiple fingerpointing between the general contractor, subcontractors and HWI, etc. Mr. Schonder of UPMC Braddock recounted how “jaws dropped when these national standards were passed on us. The regulations were daunting when we first saw them. Teleconferences frequently had dozens of pharmacy directors asking how to comply. As a profession we never thought IV prep was a problem area. Pharmacists aren’t trained to get involved in construction. We felt measures we were taking were sufficient, since universities generally didn’t focus on it, and preparing IV admixtures had been a learned task on the job.”
Clean Rooms, Hoods or Both? Because the new clean room at UPMC Braddock was designed specifically without hoods and is not designed for mixing chemotherapy products, patients are referred to a specialty sister facility for any chemotherapy admixtures. “If you mix chemo, you need a vertical flow hood or barrier isolator, so the user is shielded from the aerosolization of vapors,” Mr. Schonder said. In contrast, once he goes forward with a clean room in approximately a year, Tom Van Hassel, RPh, MPA, director of pharmacy at 330-bed Yuma Regional, in Yuma, Ariz., intends to include barrier isolator hoods within that environment because “clean rooms are a great idea, and what everyone wishes could be true. I agree with the concept. But when people go in and out on a routine basis, you destroy that integrity. Larger facilities might have enough dedicated staff that can spend 15 minutes gowning, gloving, washing and dressing to go in
see COMPLIANCE, page 78
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Basic Immunology Abul K. Abbas, Andrew H. Lichtman
This is a readable and concise introduction to the workings of the human immune system, with emphasis on clinical relevance. The format makes learning easy with short, easy-to-read chapters, color tables, key point summaries and review questions in every chapter.
2 ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com. We can supply any medical book in print, so if you donâ€™t find the book you want, e-mail your request with billing information to RMcMahon@ McMahonMed.com. If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@ McMahonMed.com.
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Clarke's Analysis of Drugs and Poisons (3rd ed.) Anthony C Moffat; M David Osselton; Brian Widdop
This practical manual and standard reference work provides the definitive source of analytical data for drugs and poisons. It is intended for use primarily by scientists faced with identifying and quantifying these substances in body fluids, tissue samples and pharmaceutical and industrial products.
Clinical Pharmacy in the United States: Transformation of a Profession Robert M. Elenbaas, PharmD, FCCP; Dennis B. Worthen, PhD
Clinical Pharmacy in the United States: Transformation of a Profession is a comprehensive account of the evolution of clinical pharmacy and is an insightful must-read for anyone who cares about the profession of pharmacy.
Exploring Medical Language: Text, Audio CDs and Mosby's Dictionary 7th Edition Package Myrna LaFleur Brooks
This valuable, money-saving package includes Exploring Medical Language, 7th Edition, Audio CDs for Exploring Medical Language and Mosby's Dictionary of Medicine, Nursing & Health Professions.
Focus on Safe Medication Practices Melanie J. Rantucci; Ian Stewart; Christine Stewart
Focus on Safe Medication Practices gives an overview of the risks associated with various types of medication incidents and preventive strategies. It is designed as an adjunct to comprehensive training in communication skills and dispensing procedures to improve patient safety. The book provides an overview as well as specific examples of medication incidents and prevention strategies.
For Doctors Only: A Guide to Working Less & Building More Christopher R. Jarvis, MBA; David B. Mandell, JD, MBA; Jason M. Oâ€™Dell, CWP; Claudio A. DeVellis, JD, CPA
For Doctors Only teaches doctors how to perform efficiently so they can get more out of a medical practice. More specifically, For Doctors Only will help doctors protect their personal and practice assets from lawsuits, taxes and bad investments while showing them the secrets to building wealth through the leverage of people, assets and effort.
How to Write a Paper (4th ed.)
Managing Anticoagulation Patients in the Hospital: The Inpatient Anticoagulation Service
George M. Hall
This bestselling guide provides clear instructions on getting published in biomedical journals. Now in its fourth edition, How to Write a Paper has been fully revised and updated to include all aspects on writing each section of a structured paper incorporating the latest information on open access, electronic publication and submission. Written by editors of leading medical journals as well as publishing experts, this guide is relevant and easy to use for any novice writer wanting to publish in journals.
The first guide to providing systematic anticoagulation care in inpatient settings, this new resource will be welcomed by all pharmacists who practice in or are developing, implementing and maintaining an inpatient anticoagulation service.
Medication Errors (2nd ed.)
Pharmacotherapy: A Pathophysiologic Approach (7th ed.)
Michael R. Cohen
Medication Errors is the most comprehensive, authoritative examination of the causes of and means to preventing medication errors in print. Cohen and two dozen other experts on the subject dissect the problem in 23 chapters, three more than the first edition.
Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee
Pharmacotherapy: A Pathophysiological Approach uses evidence-based approaches to the drug treatment of diseases. It is the most widely used and comprehensive pharmacotherapy textbook/reference avaialable for pharmacists and prescribers. Now in a new full-color format. PPN1109
Pharmacy Practice News • November 2009
COMPLIANCE continued from page 76
for their entire shifts. But in most hospitals, which are under 200 beds, people are running in and out.” “Telling people you can have a clean room that will maintain an ISO 5 environment is the wrong message for most hospitals, unless they have the gowning, gloving and sterility procedures in place to support it,” Mr. Van Hassel added. That’s exactly what Mr. Kvancz and Dr. Yaniv at Cleveland Clinic have done with their clean-room operations. For example, clean-room staff members wear disposable jumpsuits instead of lab coats; active air-sampling tests for bacteria, molds, and fungus and monthly fingertip tests reveal unwanted growth. They also are looking into automating the preparation of syringes and minibags. “You can have the cleanest environment in the world; it won’t prevent a problem if personnel aren’t well trained and disciplined in their own practices,” said Dr. Yaniv.
Periodic Testing For Contaminants Urged Similarly, UPMC Braddock has cleanroom staff periodically imprint their gloved hands into a petri dish, and
‘Telling people you can have a clean room that will maintain an ISO 5 environment is the wrong message for most hospitals, unless they have the gowning, gloving and sterility procedures in place to support it.’
—Tom Van Hassel, RPh, MPA
Typical Clean-Room Characteristics • ISO 7 buffer zones • ISO 5 compounding zones, achieved with HEPA filters over stainless steel tables • Sterile, washable, nonshedding PVC wall laminate
blot their gowns into another petri dish. The samples are sent off to incubate for 48 hours. “Any kind of colony growth we find would be bad,” said Mr. Schonder. The facility also tests the air for particles and bacterial growth, surface-tests countertops and doorknobs, performs annual competency testing for admixture staff and attends to a daily cleaning regimen. Such diligence will be key to their success, added Mr. Van Hassel. “Big Pharma tries to limit contamination by preparing one product per room, and it is still difficult for them to do. It’s much harder in a hospital setting with multiple people preparing multiple items.” The output at Yuma Regional averages between 200 and 250 IV admixtures per day, mostly individual doses for individual patients; that includes about 50 chemotherapy admixtures per month. This is enough to warrant equipping
his pending clean room with hoods, for which he says he will engage “HWI or someone like them.” Yet Mr. Van Hassel contended that many hospitals are not able to justify the investment in a clean room, either because they lack the volume of IV admixtures, the space to dedicate or the budget to spend. Have one, and it necessitates new policies and procedures, staff training and environmental maintenance, he noted. Nevertheless, other sources said the open-architecture clean-room concept appeals to them because the resulting open workspaces enable high visibility between supervising pharmacists and the technicians preparing most of the IV admixtures. And clean rooms have the added benefit of less ambient noise (no hood motors running) and more comfortable temperatures (no heat from the hoods).
USP Chapter <797> ‘Vague’
Resources and Tips Know who’s out there. A partial list of clean-room vendors, from a consultancy, can be seen at http://usp797.org/Vendors.htm. The American Society of Health-System Pharmacists USP797 Guide, a 23-page PDF file, can be accessed at http://www.ashp.org/s_ashp/docs/files/DiscGuide797-2008.pdf. Do a needs assessment. Determine if your IV admixture volume, work flow, budget and staff composition make a clean room or barrier isolator hoods, or both together, appropriate for your facility. Calculate all of the costs. Let hospital administrators know there’s a cost to meeting USP <797> standards—and a potentially greater cost if you don’t. If sued for any reason, chances are good your facility will be held to the stringent USP Chapter <797> standards rather than any less-demanding standards of a state pharmacy board or state health department. Understand the risks. Don’t underestimate the operator risk associated with handling hazardous medications such as cephalosporins and cytotoxic drugs such as chemotherapy. Don’t skimp. Design the clean room to exceed current standards, because the USP updates the air-quality requirements every two to three years, and the rules could become more stringent. Consider a consultant. Use a consultant who knows both USP Chapter <797> and the capabilities of different vendors in the marketplace. Have the consultant oversee construction of the project. (“It is hard for pharmacy directors to know the ins and outs of design options, work flow, heating-ventilation-air conditioning issues and the USP regulations,” Mr. Kvancz said.) Consider a consultant who is based in a design-and-build firm, who knows the USP standards and can advise on your dealings with architects, engineers and other specialists. Verify. It is OK to use the same clean-room vendor for ongoing maintenance, but definitely use an independent organization to certify air quality during the twice-a-year inspections. Contracting tips. Use a clean-room contractor from start to finish, so the company is fully accountable and delivers better quality. Also, determine your optimal work flow and communicate that to the contractor before designing the room; making changes after-the-fact can be costly. To limit cost overruns, contract the room on an “open-book” basis with an approved budget. —A.H. Sources: American Society of Health-System Pharmacists, HWI Clean Rooms, Containment Technologies Group, Cleveland Clinic, University of Pittsburgh Medical Center Braddock Hospital, Yuma Regional, USP797.org.
Deric Haddad, the chief executive and chief operating officer of HWI, which also built clean rooms for Duke University in Durham, N.C., Shands at the University of Florida in Gainesville and Mount Sinai Medical Center in New York City, said the “vague” language in USP Chapter <797> has resulted in some confusion regarding compliance. “Pharmacy directors aren’t clear on what they need to do,” Mr. Haddad said. “Many go to architects who get engineers who know conventional construction. They have great intentions, but lack expertise in USP <797> [requirements] and the ergonomic work flow that’s unique to each pharmacy. To properly budget the jobs also requires the aseptic detail and monitoring accessories that will control the room environment.” He said clean rooms generally start at $50,000 and can surpass $1 million. To add very localized 1 cubic feet per minute particle monitors, which validate full-time that the room complies with standards, starts at $20,000. “Pharmacy directors want monitoring in their clean rooms, but often lack the budget. To spend one-third of their money on particle monitoring is tough in this economy. We offer it as an option that can be retrofitted in later,” said Mr. Haddad. In contrast, installed prices for barrier isolator hoods run between $15,000 and $35,000 apiece, depending on their function, size and complexity, said Hank
• ISO 8 anteroom with gloves, gowns, head/shoe covers, handwashing facilities • Biological safety cabinet • Higher air exchange rates • Positive pressure, as in an operating room, so air blows out of the clean room into the anteroom • Ongoing particle monitoring option
Rahe, BSIM, MSE, technical and regulatory director for Containment Technology Group (CTG), Indianapolis. “Hoods usually cost less than 70% of the cost of a properly designed clean room with smooth, easy-to-clean, hard wall surfaces and a defined pressure differential with the outside environment,” he noted. But up-front costs are only part of the metrics to be considered, Mr. Rahe noted. “The [ongoing] cost of operating a barrier isolator is less than 20% of the cost of a clean-room operation,” he said, and may include the cost of energy and the cost of disposables such as gowns, gloves, masks and shoe covers. “Then you need to account for the lost productivity time of operators gowning and gloving every time they go in,” he noted. Mr. Rahe contends that the exposure risk to pharmacists and technicians, and the patient safety risk due to potential contamination, is greater in clean rooms because of “procedural violations by staff.” For instance, the airflow that protects users of biological safety cabinets in clean rooms “depends on people moving very slowly, with arm movements [reaching in and out] of less than three miles per hour. That doesn’t happen in real life,” he said. Another issue “starting to come to light in Europe is the micro-contamination of the outside of vials and IV bags, and the instruments and accessories used in preparations. The content inside might be sterile, but the outside surfaces are handled as they’re transported by trucks and in warehouses. Europeans are beginning to automate the decontamination of all of these surfaces. In the United States, decontamination is done manually, and it’s not reliable,” said Mr. Rahe, noting that CTG has just introduced an automated system in the United States to decontaminate these surfaces. —Al Heller
T H E B A K E R C O M PA N Y
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I S O L AT O R S
did you know? healthcare industry experts have identified the use of commercially available ready-to-use iv products as a priority safe iv medication practice. 1
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a partner in the know. Partner with Baxter Healthcare Corporation, and we can help you achieve your medication error reduction goals and enhance productivity. Throughout our 78-year history, we’ve pioneered products that work together to drive efﬁciency, value, and a safer healthcare environment. We were the ﬁrst company to introduce needleless access systems and ﬂexible, closed systems for the delivery of intravenous (IV) medications, as well as the ﬁrst and only infusion pump to offer automatic tube loading. We have created innovative products that can help reduce errors throughout the medication management process, by advancing technology and improving the interface between technology and clinicians.
Baxter’s Frozen Premix Product line is just one example of how our comprehensive approach to healthcare continues to lead the industry. • GALAXY Frozen Premix Product line celebrated its 20th anniversary in 2009 • Baxter Frozen Premix Products are the only premix drug delivery systems available for unstable medications Ready-to-use medications can help reduce medication errors related to compounding, save pharmacy staff time with reduced number of steps, and produce less waste from unused or improperly mixed medications.2,3 Advance your institution through enhanced safety, convenience, and cost-efﬁciency with a partner in the know.
References: 1. Proceedings of a summit on preventing patient harm and death from i.v. medication errors. Am J Health-Syst Pharm. 2008;65:2367-2379. 2. Sanborn MD, Moody ML, Harder KA, et al. Second Consensus Development Conference on the Safety of Intravenous Drug Delivery Systems--2008. Am J Health-Syst Pharm. 2009;66:185-192. 3. van der Linden P, Douchamps J, Schmitt C, Forget D. Ready-to-use injection preparations versus conventional reconstituted admixtures: economic evaluation in a real-life setting. Pharmacoeconomics. 2002;20:529-536. Baxter, Committed to a Safer Healthcare Environment and Galaxy are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111197 11/09
The November 2009 Digital Edition of Pharmacy Practice News