Su m m Co er e v m e iew M ee vi si art tin tu ic l g s a e,
The Pharmacist’s News Source Hematology/Oncology Pharmacy Edition
Volume 38 • Number 5 • May 2011
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Psychiatric Medication in this issue Error Rates Slashed Via Clinical Hem/Onc Pharmacy e-Prescribing Initiative Japan nuclear crisis shakes U.S. drug supply.
omputerized prescribing and error reporting systems combined to reduce the rate of medication mistakes in the psychiatric unit at an inner-city Baltimore hospital by more than 80%, report Johns Hopkins researchers. The findings, published in the March issue of the Journal of Psychiatric Practice, represent the largest study to date evaluating such an intervention in the field and extend evidence of the benefit of electronic prescribing in reducing drug errors across all areas of medicine (J Psychiatr Pract 2011;17:81-88). “Whenever there is a human interface with medication, there is a possibility of error,” said Geetha Jayaram, MD, MBA, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, in Baltimore. Everything from indecipherable handwriting and inaccurate transcriptions, to miscalculations and administration mistakes, even
see DRUG ERRORS, page 71
Critical Care Statins in the ICU: ready for prime time?
Pain Medicine Pain contracts: are they really worth the hassle?
n advanced e-learning program offers pharmacists the opportunity to build the skills needed to be tomorrow’s clinical and management leaders, while also earning advanced credit toward master’s degree programs. The program is the result of an alliance between the ASHP Foundation’s Center for Health-System Pharmacy Leadership and GlobalHealth Education, an online educational services firm based in West Palm Beach, Fla. The initiative is an extension of efforts that began in 2008, when the center enrolled its first Pharmacy Leadership Academy (PLA) class. That first class came about in response to research that suggested a dramatic crisis in leadership within health-system pharmacy. “The world has only gotten more complicated
see ACADEMY, page 64
Helping Cancer Patients Quit Smoking Pays Off
Operations & Mgmt
Leadership in Action It shouldn’t be lonely at the top.
Telepharmacy Rural health-system reaps benefits of round-the-clock drug order review.
Online Academy Prepares Future Pharmacy Leaders
A call to action for the profession
Finally, a new drug for melanoma approved.
Drug Interactions in Post-Kidney Transplant Patients See page
Optimizing Warfarin Therapy Insert after page
Quality-of-Life Implications for Patients With Hereditary Angioedema Who SelfAdminister C1 Inhibitor
Salt Lake City—Smokers who develop cancer may think it is too late to improve their health by kicking the habit. That is a dangerous misconception that caregivers need to correct, according to Jane Pruemer, PharmD, BCOP, professor of clinical pharmacy practice at the James L. Winkle College of Pharmacy, University of Cincinnati Barrett Cancer Center, in Ohio. “You really need to stress that if they continue to smoke, they are at a greater risk for developing a second
maligancy, worse outcomes in general and poorer quality of life [QoL] than patients who manage to quit.” But merely highlighting those risks is not enough. Pharmacists who encounter such patients “should consider it their duty to also help them quit,” Dr. Pruemer said at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). In fact, quitting smoking can be one of the single most effective strategies to improve outcomes in
see QUIT SMOKING, page 9
In ER-positive breast cancer …
Presurgical Endocrine Therapy May Be Clue to Tumor Resistance Salt Lake City—The way a tumor responds to a short course of endocrine therapy given before scheduled surgery in women with estrogen receptor (ER)–positive breast cancer may predict how the malignancy will respond to long-term adjuvant
antiestrogen treatment, according to new research presented at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). Just two weeks of treatment with letrozole in presurgical ER-positive
see BIOMARKERS, page 23
See page 32
New Product Watson to Launch NulecitTM, a generic version of Ferrlecit
SEVENTH ANNUAL CONFERENCE
More Coverage: ✜M TM program a boon to cancer patients
✜T ips for enhancing rituximab safety, efficacy
✜N avigating cancer pain and drug dependency
11 12 22
Iss ue 6
PHARMACEUTICAL WASTE. Is your facility at risk?
Hospital pharmacies throughout the United States purchase well over 4 billion hazardous materials each year, generating more than 84,000 tons of hazardous pharmaceutical waste.1 The EPA has stepped up enforcements to ensure that pharmaceutical waste is managed safely from the moment it is generated and finally disposed.2 Pharmacists are responsible for the “cradle to grave” management of pharmaceuticals. CareFusion now offers Pyxis EcoStation™ system, a proprietary, automated waste management system that helps hospitals identify, classify, sort and segregate pharmaceutical waste, while providing pharmaceutical waste records to facilitate tracking and regulatory controls of more than 180,000 National Drug Codes.
Join us at the ASHP Summer Meeting, booth #912, to learn how CareFusion can help your hospital measurably improve pharmaceutical waste management, or visit carefusion.com/rxwastemanagement.
1 Fein, Adam J. Pembroke Consulting, Inc. 2010-11 Economic Report on Retail and Specialty Pharmacies, December 2010. 2 Accessed from http://www.epa.gov/oecaerth/civil/rcra/rcraenfstatreq.html. © 2011 CareFusion Corporation or one of its subsidiaries. All rights reserved. EcoStation and Pyxis are trademarks or registered trademarks of CareFusion Corporation or one of its subsidiaries. DI2726 (0511)
Pharmacy Practice News • May 2011
Up Front 3
Capsules CDC Releases New Guidelines To Prevent CRBSIs
The five most-viewed articles last month on pharmacypracticenews.com: 1. Not Keeping Patients at Home Looms as Big Cost Factor 2. The Power of Checklists Applied to Medication Storage 3. Glucose Management in Critically Ill Patients Still a Problem 4. ASHP Clinical Pearls 5. Hot Topics in Anticoagulant Therapy Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.
heard here first
‘We are drug managers and drug experts and [MTM programs are] a coming opportunity for us to be on the front line [of cancer care].’
See article, page 11
—David G. Frame, PharmD
To Scan 2-D Bar Codes in PPN: 1. Download the FREE Microsoft Tag Reader application through your smartphone browser. 2. Open the Tag Reader and let it focus on the bar-code image to instantly access related materials and/or Web sites.
he Centers for Disease Control and Prevention (CDC) and the Healthcare Infection Control Practices Advisory Committee have released updated guidelines for the prevention of intravascular catheterrelated bloodstream infections (CRBSIs). The new guidelines, which replace the recommendations published in 2002, place a heavy emphasis on the education and training of health care personnel, using chlorhexidine scrubs for skin antisepsis, ensuring a maximal sterile barrier for catheter insertions and avoiding the routine replacement of central venous catheters as an infection prevention strategy. Scan to access new “The updated CDC guidelines are rich with new recommendations that CRBSI guidelines are based on additional scientific research that has emerged since the prior version was published,” noted Russell N. Olmsted, MPH, 2011 president of the Association for Professionals in Infection Control and Epidemiology, in a press release. “This is an important resource to support efforts toward the elimination of CRBSIs.” Central line–associated bloodstream infections (CLABSIs), the most common type of nosocomial bloodstream infection, carry an estimated mortality rate of 12% to 15%. The treatment of these infections costs U.S. hospitals an estimated $29,000 per patient and $2.3 billion annually. These types of bloodstream infections, however, are considered highly preventable when proper precautions are taken.
Evidence-based Prevention The updated guidelines include recommendations based on a five-step checklist that has been shown to be effective in preventing central-line catheter infections. The checklist stresses hand hygiene, full-barrier precautions during catheter insertions, chlorhexidine antisepsis at the insertion site, avoiding veins in the arm or leg, checking catheter lines each day, and removing them when they are no longer needed. A study of 103 Michigan-area hospital ICUs (N Engl J Med 2006;355:2725-2732) found that the use of the checklist led to a 66% reduction in CLABSIs after 18 months. Earlier this year, the CDC issued a report on the number of CLABSIs in the ICUs of U.S. hospitals in 2001 and 2009 to gauge the impact of evidence-based prevention programs (MMWR Morb Mortal Wkly Rep 2011;60:243-248). The investigation found an estimated 58% reduction in CLABSIs between 2001 and 2009 (43,000 vs. 18,000 cases, respectively). This reduction represents an estimated 3,000 to 6,000 fewer mortalities and an estimated cost savings of $414 million for the U.S. health care system. After the realization that these infections could be prevented, the Department of Health and Human Services set a national goal for a 50% reduction in CLABSIs by 2013. This call to action urges health care facilities to adhere to proven central-line insertion practices. In 2008, the Centers for Medicare & Medicaid Services designated CLABSIs as a “never event,” meaning hospitals will not receive additional reimbursements for treating the infections. Several commercial insurers have adopted this practice. To view the complete “Guidelines for the Prevention of Intravascular Catheter–Related Infections, 2011,” visit http://www.cdc.gov/hicpac/pdf/guidelines/bsi-guidelines-2011.pdf. —Seth Kandel
Michele McMahon Velle, MAX Graphics/Creative Director
Robert Adamson, PharmD, Livingston, NJ
Frank Tagarello, Senior Art Director/Managing Director, MAX Graphics
Ernest R. Anderson Jr., MS, RPh, Boston, MA
Volume 38 • Number 5 • May 2011 • pharmacypracticenews.com
Anesthesiology/Pain Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY David S. Craig, PharmD, BCPS, Tampa, FL Biotechnology Indu Lew, PharmD, Livingston, NJ Cardiology C. Michael White, PharmD, Storrs, CT
Internal Medicine Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP, Des Moines, IA
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NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM
Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Kate O’Rourke, Contributing Editors
Oncology Robert T. Dorr, PhD, RPh, Tucson, AZ
James Prudden, Group Editorial Director
Robert Ignoffo, PharmD, San Francisco, CA
Robin B. Weisberg, Manager, Editorial Services
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Charles F. Caley, PharmD, Storrs, CT
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Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA
Ali McBride, PharmD, MS, BCPS, St. Louis, MO
Larry Ereshefsky, PharmD, San Antonio, TX Complementary and Alternative Medicine Cathy Rosenbaum, PharmD, Cincinnati, OH Critical Care Judi Jacobi, PharmD, FCCM, Indianapolis, IN
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Where does your thrombin come from?
Graphics are for illustrative purposes only. Not intended to depict actual manufacturing process or application method. Thrombin products are for topical use only.
RECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical.
References: 1. RECOTHROM [package insert]. Seattle, WA: ZymoGenetics, Inc. 2. Evithrom [package insert]. Somerville, NJ: Ethicon, Inc. 3. Thrombin-JMI [package insert]. Bristol, TN: King Pharmaceuticals, Inc. RECOTHROM is a registered trademark of ZymoGenetics, Inc. ©2011 ZymoGenetics, Inc. All rights reserved. RT396-00, January 2011
IMPORTANT SAFETY INFORMATION FOR RECOTHROM
Contraindications • Topical use only – DO NOT INJECT directly into the circulatory system • Do not use for the treatment of massive or brisk arterial bleeding or in patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins Warnings and Precautions • Potential risk of thrombosis if absorbed systemically • In patients with known hypersensitivity to snake proteins, there may be potential for allergic reaction
RECOTHROM is recombinant human thrombin RECOTHROM is human thrombin produced via recombinant DNA technology using a genetically modied Chinese hamster ovary (CHO) cell line1 Other thrombins are derived from human or bovine plasma2,3 – In a phase 3 study comparing RECOTHROM to bovine thrombin, the overall incidence of adverse events was similar between treatment groups – RECOTHROM has not been compared to human plasma-derived thrombin in clinical trials
Know your thrombin inside and out Visit RECOTHROM.com
Adverse Reactions • The serious adverse event that occurred in ≥1% (n=6/583) of patients exposed to RECOTHROM in completed clinical trials was atrial brillation. The most common adverse events reported in these trials (N=583) were incision site pain (51%), procedural pain (30%), and nausea (28%). Adverse events reported in these trials were consistent with those commonly observed in surgical patients
Please see Brief Summary of full Prescribing Information on following page.
6 Up Front
Pharmacy Practice News • May 2011
Events At ASHP Summer Meeting …
Elevate Your Practice in the Mile High City B ‘If a department really wants to be accountable, it should
reathtaking mountain views out the convention center’s floor-to-ceiling windows may be enough to inspire the 2,000 or so pharmacists expected to converge in Denver for the American Society of Health-System Pharmacists (ASHP) Summer Meeting, June 11-15. If not, a host of workshops, networking opportunities, high-profile speakers,
make certain that its pharmacists know what the expected outcome is every time a drug is prescribed and how to ensure that the outcome is achieved.’
—Max Ray, PharmD
educational activities and more than 100 exhibitors in the Mile High City should do the trick, suggested ASHP President Diane B. Ginsburg, MS, RPh, clinical professor and assistant dean at The University of Texas at Austin College of Pharmacy. “There are significant changes this year,” Ms. Ginsburg said. “Pretty much every facet of the meeting has been elevated.” Attendees can expect opportunities for intensive skill building in areas such as leadership, medication safety, clinical practice, precepting and informatics, with nearly double the continuing education credits offered compared with last year. Those who attend the weekend workshops can earn up to 32 credits over the course of the meeting.
Optimizing the Practice Model This summer’s theme of “elevate” also reflects the momentum built at the Pharmacy Practice Model Initiative (PPMI) Summit, which met in Irving, Texas in November. The 100-plus leaders in attendance agreed on a series of overarching principles and core elements for a new practice model. Their recommendations will be published in the June 15 issue of the American Journal of Health-System Pharmacy. Many of the discussions in Denver will center around these proposed changes, including the message from this summer’s keynote speaker, Jay Kaplan, MD, a physician who has helped emergency room physicians successfully transform their practices. Conference organizers hope that he will do the same for the pharmacy world. “Now is the time to make that move,” said Michelle Abalos, PharmD, director of educational programs at ASHP. “We’re pushing for pharmacists to be closer to the bedside even more so now than ever before, as well as to take on leadership positions.” Max Ray, PharmD, professor of pharmaceutical sciences at the University of Tennessee College of Pharmacy, in Memphis, is organizing a two-hour session on methods a department can use to determine where to redirect its practice model and how individual pharmacists can achieve a permanent paradigm shift. This might involve new policies, procedures, metrics and training programs. “If a department really wants to be accountable, it should make certain that its pharmacists know what the expected outcome is every time a drug is prescribed and how to ensure that the outcome is achieved,” Dr. Ray told Pharmacy Practice News.
Pharmacy Practice News • May 2011
Up Front 7
Events Adapting Leadership
tion and optimize patient outcomes, as well as how to elevate the role of the medication safety officer and address concerns that are unique to pediatric medication errors.
“We have 14 pages of recommendations from the PPMI Summit,” said Sharon Murphy Enright, president of EnvisionChange LLC in Richmond, Va., and coordinator of the Leadership Learning Community. “But what do we do with it?” For the fifth summer in a row, presentations, assignments, video-based scenarios and interactive group discussions will teach a key prerequisite for change: strong leadership. “Adaptive Leadership in the Permanent Whitewater” builds on the previous years’ lessons and the PPMI. “Today’s health care environment is turbulent, like navigating whitewater rafting,” said Dr. Abalos. “What you need to move the practice forward is innovative vision, skillful decision-making and the determination to lead even when things are chaotic.” The five sessions are designed to develop these traits, while encouraging pharmacists to collaborate with medical staff and administration. A CEO who also is a pharmacist will share tips on enhancing a pharmacist’s authority within an organization, and 16 different departments will discuss a real-life situation—whether an informatics issue or clinical conundrum—that they have successfully resolved.
Scan for scheduleat-a-glance. Instructions, page 3.
Tweeting, Friending And Bar Coding “You can’t talk about leadership or medication safety without focused learning on informatics,” said Dr. Abalos. Six sessions will touch on topics including meaningful use, computerized prescriber
see ASHP MEETING, page 8
Safety First For the first time, a full lineup of programming at this summer’s meeting will target medication safety issues. The first of the six sessions aims to put a face on medication errors. Michael Cohen, president of the Institute for Safe Medication Practices, will moderate as a range of speakers personalize the issue. Speakers will include James Padilla, president of Consumers Advancing Patient Safety, whose child suffered a fatal medical error. Robert Webber, a senior director of pharmacy services at the Ohio State University and a cancer survivor, will discuss how experiencing treatment errors influenced changes in his own practice. “We are all human and we have the capacity to make errors. I think people often forget about that,” said Joanne Kowiatek, RPh, MPH, pharmacy manager of medication safety at the University of Pittsburgh Medical Center, and organizer of the session. “Our goal is to better understand what leads to those errors and implement safeguards to prevent them.” Other speakers will offer suggestions for this “mistake proofing” of pharmacy practice, such as the use of oral syringes that cannot be connected to IV tubing. Participants also can expect advice on how to apply models that reveal process weaknesses, improve communica-
*Betamethasone 6 mg/mL as 3 mg/mL Betamethasone Sodium Phosphate and 3 mg/mL Betamethasone Acetate † Celestone® and Soluspan® are registered trademarks of Schering Corp. The intra-articular or soft tissue administration of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. Important Safety Information: As with any potent corticosteroid, adverse events have been associated with Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP, including fluid and electrolyte disturbances, as well as adverse reactions involving the following systems: allergic reactions, cardiovascular, dermatologic, endocrine, gastrointestinal, metabolic, musculoskeletal, neurological/psychiatric, and ophthalmic. Corticosteroids may also affect immune response. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP should not be administered intravenously or used in systemic fungal infections. Vaccination administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infections. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles and to seek medical advice without delay if exposed. Please see next page for brief summary of full prescribing information BB014, Iss. 3/2011
ONE LUITPOLD DRIVE | PO BOX 9001 | SHIRLEY, NY 11967 | 800-645-1706 | WWW.AMERICANREGENT.COM
8 Up Front
Pharmacy Practice News • May 2011
ASHP MEETING continued from page 7
order entry, order sets, informatics credentialing, mobile devices and about 20 different social media tools such as Facebook and Twitter. “A lot of people have implemented a large number of technologies,” said Christopher R. Fortier, PharmD, pharmacy manager at the Medical University of South Carolina, in Charleston, who coordinated three of the sessions. “But how do we take things to the next
level to optimize our current system?” Dr. Fortier will moderate and present on the PPMI Summit technology recommendations. He plans to highlight hospitals using innovative technologies such as IV intraoperability, pharmacy distribution bar coding and tracking and software that generates real-time triggers for clinical pharmacists. Other presenters will share specific examples of how hospitals and pharmacists enlist social media in their practice, even selecting a few lucky audience members to go through the
process of establishing the tools for their future use. To get everyone actively involved, a second screen in the informatics conference room will display a Twitter feed. People can tweet comments and questions (or answers) throughout the session. “We’re trying to push people to sign up for Twitter accounts before the meeting if they don’t already have them,” said Dr. Fortier. For those not yet on the bandwagon, Dr. Fortier urges opening an account, downloading a Twitter app, signing in and then going
to http://bit.ly/dG2HT9 and clicking “Follow this list.”
Something for Everyone There will be plenty of other opportunities to network and learn in Denver. An eight-part clinical program will cover topics such as antimicrobial stewardship and current treatment guidelines in chronic kidney disease, and will introduce new drugs and products unveiled over the past year. Additional sessions will bring attendees up to date on what is happening inside the Beltway, including Sen. Amy Klobuchar’s (D-Minn.) proposed Senate Bill 296 and other efforts to confront ongoing drug shortages, as well as impacts on pharmacy practice from the Patient Protection and Affordable Care Act, the Joint Commission’s new medication reconciliation requirements (to go into effect in July), United States Pharmacopeia Chapter <797> guidelines and the 340B Drug Pricing Program. If they arrive early, participants can attend Saturday and Sunday workshops, which focus on starting residency programs, implementing the best preceptor practices and employing evidence-based decision making. Of course, lighter discussions will abound around food and music at the Grand Opening Reception on Sunday evening and Tuesday’s Harvey A. K. Whitney Lecture Award Reception and Dinner. “Whether you’re a leader, informaticist, medication safety officer or frontline clinician,” said Dr. Abalos, “there’s something for everybody at the summer meeting.” —Lynne Peeples
Come see us at Booth #519 at ASHP Summer Meeting Be sure to pick up one of our Special Projects and Publications
Hem/Onc Pharmacy 9
Pharmacy Practice News • May 2011
QUIT SMOKING continued from page 1
‘The time has come now for oncology pharmacists as health care providers to take a more active role in helping people actually quit smoking.’
—Jane Pruemer, PharmD
with small-cell lung cancer, the relative risk for recurrence was 11 in patients who quit smoking at the time of diagnosis versus 32 in those who continued to smoke (J Natl Cancer Inst 1997;89:1745-1747) (Figure). Those results were not without precedent, according to Dr. Pruemer. “There were reports back in the early 1980s that patients diagnosed with small cell lung cancer who continued to smoke were about 40 times more likely to develop a second non-small cell lung cancer than their age-matched controls
who were not smokers.” Breast cancer patients often receive radiation therapy, and in those who smoke there is an increased risk for developing lung cancer after radiation exposure. Kaufman et al found that persistent smoking in breast cancer patients was associated with a 38% increased risk for developing lung cancer (J Clin Oncol 2008;26:4044-4045). Additionally, patients with head and neck cancer who break their smoking habit are less likely to develop a second head and neck tumor
‘We know that patients who hear the quit-smoking message from multiple types of clinicians are more likely to succeed in quitting, so the more providers telling them to stop, the more likely they are to succeed.’
—Karen Hudmon, DrPH
Risk for second cancers Quality of life (based on Lung Cancer Symptom Scale Score; higher scores mean lower QoL)
30 20 10 0
cancer patients; it has both immediate a n d l o n g - t e r m benefits for all types of cancers, Dr. Pruemer stressed. “ K n o w i n g t h i s , we as health care providers are being inconsistent if we say we’re here to help and provide care, but then do not speak up about a continued major health risk that we know our patients have.” There are compelling reasons for helping cancer patients to quit smoking, Dr. Pruemer noted. Continued smoking has been associated with increased mortality and increased risks for second malignancies in cancer patients. It also has a negative effect on many cancer therapies. Examples of adverse effects include impaired wound healing and increased risk for infection after surgery, increased epithelial damage to irradiated tissue after radiation therapy and increased risk for mucositis in patients on longterm chemotherapy. Additionally, the hydrocarbons in cigarette smoke and nicotine can interfere with the action of certain cancer drugs, such as erlotinib (Tarceva, Genentech). Studies have shown increased mortality among cancer patients who smoke. In a retrospective study by Aksoy et al that studied the effect of smoking on survival in 240 consecutive female patients with breast cancer between 1990 and 2000, the mean disease-free survival was 41.8±4.4 months in smokers (95% confidence interval [CI], 33.2-50.4) compared with 92.4±10.7 months in nonsmokers, and the mean overall survival was 42.5±4.2 months (95% CI, 34.2-50.9) in the women who smoked, compared with 110.3±11.7 months (95% CI, 87.2133.4) in the nonsmokers (P=0.0069) (Breast J 2007;13:431-432). Similar results have been seen in patients with other cancers, including cervical, kidney and prostate cancer, as well as hematologic malignancies. Smokers with kidney cancer have a 31% increased mortality rate over that of nonsmokers who receive the same treatment (Int J Urol 2008;15:304-308). Prostate cancer patients who quit smoking at the time of diagnosis boost their chances of survival by 30% (Can Med Assoc J 1982;127:727-729), and the same is true for patients with bladder cancer. In a study by Talamini et al (Int J Cancer 2008;122;1624-1629), patients who smoked 20 cigarettes or more per day had a significantly higher risk for death (hazard ratio, 1.70; 95% CI, 1.062.73) and poorer five-year survival (60% and 46%, respectively) than nonsmokers. Second malignancies also are a significant concern. In patients with lung cancer, continued smoking will significantly increase the risk for developing a second lung cancer. In one study of 55 patients
Quit at time of cancer diagnosis
Continue to smoke
Adapted from: J Natl Cancer Inst 1997;89:1745-1747.
Adapted from: Chest 2004;126:1717-1728.
Figure. Impact of smoking status on cancer patients.
(Am J Clin Oncol 2007;30:531-539). Even with hematologic malignancies such as Hodgkin’s disease and non-Hodgkin’s lymphoma, there is an increased risk for the development of a second malignancy in patients who continue to smoke. A study concluded that 50 to 150 per 1,000 patients would go on to develop lung cancer 10 to 20 years after treatment if they continued to smoke (Lancet Oncol 2005;6:773-779). Smoking also affects QoL in physical functioning. Using the Lung Cancer Symptom Scale (LCSS), in which higher scores correspond to a lower QoL, Garces et al found that the score for never smokers was 17.6 (standard deviation [SD], 4.02) and the score was 28.7 (SD, 5.09) for persistent smokers (Chest 2004;126:17171728) (Figure). Additionally, patients with head and neck cancer who continue to smoke have been shown to have decreased physical functioning (Gen Hosp Psychiatry 2002;24:140-147). “This should be enough evidence to convince you of the importance of helping your patients to quit smoking, even though they may think there is no point since they already have cancer,” Dr. Pruemer said.
Refer Patients to a Smoking Cessation Program When a clinician gets involved in helping a patient to quit, the odds of success are doubled, Dr. Pruemer noted, citing data from a government report (Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service; May 2008). Pharmacists should ask all patients about their use of tobacco, but they also should be aware that many patients lie about the extent of this use. “We should encourage them to be honest about it, and motivate them to consider quitting by educating them regarding the link between [smoking and] their current illness, the proper use of cessation medications and the benefits of behavioral counseling,” Dr. Pruemer said. “Above all, refer the patient to a formal cessation program.” As far as whether health systems should develop smoking cessation programs in-house, she said, “I wouldn’t hold everybody to [that goal]. But at least refer your patients to a program that you know about; they are out there. And be sure that the treatment addresses the physiologic aspects of nicotine addiction as well as the behavioral aspects.” Pharmacotherapy plays an important role in helping patients to quit. Nicotine replacement therapy (NRT) alleviates withdrawal symptoms and gives patients the chance to break the habit without the notorious withdrawal side effects, Dr. Pruemer noted. “I
see QUIT SMOKING, page 10
Pharmacy Practice News • May 2011
QUIT SMOKING continued from page 9
believe nicotine patches are effective and am less supportive of the intermittent use of nicotine products, such as gum or lozenges.” Higher doses of nicotine replacement also may be required, especially for cancer patients who are heavy smokers. In these cases, treatment should be under the supervision of a physician, and also may involve other drugs, such as bupropion sustained release or varenicline (Chantix, Pfizer). Furthermore, a longer course of treatment may be required. NRT should be used with caution in patients who have underlying cardiovascular disease, including a myocardial infarction within two weeks of starting NRT; life-threatening arrhythmias; severe or worsening angina; and active temporomandibular joint disease (for nicotine gum only). Bupropion may increase dopamine levels in the central nervous system and should not be used in patients with a history of seizures or a current or prior diagnosis of bulimia or anorexia nervosa; patients who have used a monoamine oxidase inhibitor within the past 14 days; and patients who are abruptly discontinuing the use of alcohol or sedatives, including benzodiazepines. As for varenicline, it works by preventing nicotine from binding to the a4b2 nicotinic acetylcholine receptors, thereby decreasing nicotine withdrawal symptoms as well as cravings. Varenicline’s
most troubling side effects are nausea and vomiting. Additionally, it and bupropion are contraindicated in patients who may have suicidal tendencies. “The time has come now for oncology pharmacists as health care providers to take a more active role in helping people actually quit smoking,” Dr. Pruemer told Pharmacy Practice News. “We’re not there just to recommend that they quit. We should be there to help them do it, because we know that there are data showing that those who continue to smoke have poorer outcomes to treatment as well as poorer quality of life. If we can help them quit, we should see those improved outcomes.”
Pharmacists Can Help Patients Quit Smoking Karen Hudmon, DrPH, associate professor of pharmacy practice at Purdue University, West Lafayette, Ind., echoed Dr. Pruemer’s message about the importance of helping cancer patients give up their smoking habit. “There are so many reasons people with cancer should quit, because every type of cancer treatment—be it surgery, radiation and chemotherapy—is affected by smoking,” she said. Ideally, helping patients quit should be a team effort that involves the patient and multiple providers. “We know that patients who hear the quit-
Web at http://rxforchange.ucsf. smoking message edu/ccp. For quick access to this from multiple types site, scan the 2-D bar code at left. of clinicians are more likely to sucMore Data Support ceed in quitting, so Pharmacists As Cessation the more providers Counselors telling them to stop, Larry Dent, PharmD, associthe more likely they Scan to visit free CE program on are to succeed,” she smoking cessation. ate professor, pharmacy practice, Skaggs School of Pharmacy at the said. Instructions, p. 3 University of Montana, Missoula, Pharmacists are better equipped than caregivers in said he agreed with Dr. Pruemer that most disciplines to counsel can- tobacco cessation is an important responcer patients to stop smoking, Dr. sibility for pharmacists—especially pharHudmon noted. “Many medica- macists who interact with cancer patients tions interact with smoking. Drug who continue to smoke. “In addition to levels can change as a result of starting, being ideally situated to help smokers stopping and even changing one’s level quit, pharmacists are effective tobacco of smoking. Having a pharmacist on the cessation providers,” Dr. Dent said. In a randomized controlled trial team can be very helpful for this reason.” Dr. Hudmon also stressed the impor- assessing the effectiveness of a phartance of combination approaches to macist-delivered program for smoking smoking cessation for patients who have cessation, pharmacist time and attention not been successful with single approach- were the most important predictors of es. “There is evidence that supports the success, he said, citing a study that he led use of combination therapy using, for (Ann Pharmacother 2009;43:194-201). Of example, the long-acting nicotine patch 14 biologically confirmed quitters in the with an intermittent nicotine replace- treatment group, all but one (93%) comment therapy like lozenges, gum, inhalers pleted all three counseling sessions of or nasal spray to address the situational the pharmacist-delivered program, Dr. Dent noted. Of participants who attendcravings,” she said. For pharmacists and other health care ed all three sessions, 46% (13 of 28) were professionals who wish to learn more able to maintain continuous abstinence, about treating tobacco dependence in compared with only 5% (one of 22) of patients with cancer, Dr. Hudmon sug- those attending two or fewer sessions. gested participation in an online con—Fran Lowry tinuing education program. She recommended a two-hour free program offered by the Walther Cancer Institute Drs. Pruemer, Hudmon and Dent reported no relevant conflicts of interest. Foundation, which can be found on the
Study: Smoking Worsens Pain in Cancer Patients
eople diagnosed with cancer who continue to smoke report more severe pain and interference with activities of daily living due to pain than their counterparts who have never smoked or have quit, according to an analysis published in Pain (2011;152:60-65). The new study contributes to a growing and clinically meaningful body of evidence demonstrating an association between pain and smoking in patients with cancer, noted Michael Hooten, MD, who conducted a similar study on cancer pain in smokers. However, there might be other factors mediating the pain–smoking relationship, notably depression. “In a study I recently led, which examined the same relationship, we found that after controlling for depression, there was no significant difference in pain scores between smokers and nonsmokers with noncancer chronic pain” (Pain 2011;152:223-229), said Dr. Hooten, assistant professor in the Department of Anesthesiology at Mayo Clinic, in Rochester, Minn. Thus, depression may contribute to
the development of painful symptoms observed in smokers. In the current study, the investiga-
‘There may be a potentially reciprocal relationship between pain and smoking that acts as a positive feedback loop…’ —Joseph Ditre, PhD tors compared pain measures in 224 patients with more than a dozen types of cancer. Thirty-six of the patients were smokers, 108 had quit and 80 never smoked. Patients averaged 56 years of age and had not received IV chemotherapy two months prior to the study. To measure the patients’ pain severity, the extent pain interfered with daily living and pain-related distress, the investigators administered the six-point Likert
Medical Outcomes Survey 36-item Short Form (SF-36) Bodily Pain subscale over a one-week period. They also conducted multivariable analyses to control for age, gender, cancer diagnosis, disease stage, surgery status and education—all factors correlated with pain severity. The investigators found current cigarette smokers scored an average 3.04 on the SF-36, compared with nonsmokers who scored 2.28, on average (P<0.01). Smokers also had significantly more severe interference due to pain than both former and neversmokers, the team reported, with the three groups having mean scores of 2.46, 1.84 and 1.79, respectively, on the pain interference subscale of the SF-36 (P<0.01 for smokers vs. former and neversmokers). The investigators also found a positive and statistically significant correlation between lower pain scores and longer time since quitting among former smokers. The data suggest that continued smoking despite a cancer diagnosis is associated with greater pain severity and greater interference with activities
of daily living from pain. The study’s lead investigator, Joseph Ditre, PhD, called for more research to help unravel the complex interaction between pain and smoking. “There are two questions that need to be addressed,” said Dr. Ditre, assistant professor in the Department of Psychology at Texas A&M University, College Station. “The first is why smoking might lead to the development of painful conditions in the first place and how it might worsen existing pain. The second is how pain influences smoking behavior. There may be a potentially reciprocal relationship between pain and smoking that acts as a positive feedback loop wherein smokers motivated to smoke in response to pain may unwittingly be aggravating their pain by increasing their cigarette consumption, engendering a vicious cycle that could lead to greater nicotine dependence and worse pain.” —David Wild Drs. Hooten and Ditre reported no relevant conflicts of interest.
For your convenience
Enhancing our commitment to you
• Liquid • Room temperature storage 2-25° C (36-77° F) for the entire 2-year shelf life • Three presentations: 5, 10 and 20 gram vials
• Every vial is laser etched with its own unique identifier number*, which helps to deter tampering and counterfeiting • PediGri® On Line, unique to Grifols, offers full traceability from donation to the final product at www.pedigri.grifols.com * Laser etched identifier number may at times be covered by the label.
Important Safety Information Flebogamma® 10% DIF is a human immune globulin intravenous (IGIV) that is indicated for the treatment of primary immune deficiency (PI), including the humoral immune defect in common variable immunodeficiency, x-linked agammaglobulinemia, severe combined immunodeficiency, and Wiskott - Aldrich syndrome.
WARNING: ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE • Use of immune globulin intravenous (IGIV) products, particularly those containing sucrose, has 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 those receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Flebogamma® 10% DIF does not contain sucrose. • For patients at risk of renal dysfunction or failure, administer Flebogamma® 10% DIF at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]). Flebogamma® 10% DIF is contraindicated in patients who have had a history of anaphylactic or severe systemic reactions to the administration of human immune globulin and in IgA deficient patients with antibodies to IgA and a history of hypersensitivity. In case of hypersensitivity, discontinue Flebogamma® 10% DIF infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. In patients at risk for developing acute renal failure, monitor renal function, including blood urea nitrogen, serum creatinine, and urine output. Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Flebogamma® 10% DIF therapy. Thrombotic events may occur during or following treatment with Flebogamma® 10% DIF. Monitor patients at risk for thrombotic events, including those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and known or suspected hyperviscosity. Aseptic meningitis syndrome (AMS) may occur infrequently with Flebogamma® 10% DIF treatment. AMS may occur more frequently following high doses and/or rapid infusion of IGIV.
Flebogamma® 10% DIF 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 hemolysis. Non-cardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] may occur in patients following Flebogamma® 10% DIF treatment.
If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient serum. All patients, but especially individuals receiving Flebogamma® 10% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at a higher risk for the development of fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations regarding dosage and administration may reduce the risk of these types of events. Because Flebogamma® 10% DIF is made from human plasma, it may carry a risk of transmitting infectious agents, e.g. viruses, and theoretically, the Creutzfeldt-Jakob (CJD) agent. No cases of transmission of viral diseases or CJD have ever been identified for Flebogamma® 10% DIF. The most common adverse reactions (reported in ≥ 5% of clinical trial subjects) occurring during or within 72 hours of the end of an infusion were 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. The most serious adverse reactions observed with Flebogamma® 10% DIF were back pain, chest discomfort, and headache (2 patients); and chest pain, maculopathy, rigors, tachycardia, bacterial pneumonia, and vasovagal syncope (1 patient). Please refer to enclosed Flebogamma® 10% DIF full prescribing information for full prescribing details, including comprehensive adverse event profile and black box warning.
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Flebogamma 10%DIF ®
Immune Globulin Intravenous (Human)
Shaping the future Highly purified IGIV
Broad pathogen safety margin
• Trace amounts of IgA: <0.006 mg/mL 1 (specification value: <0.1 mg/mL) • Very low sodium content • Sorbitol stabilized
• Seven validated pathogen elimination steps including: - 20 nm nanofiltration - Dual specific inactivation: pasteurization and solvent detergent • Highly effective process: - 15.0 log reduction of PPV (PVB19 model) - ≥ 13.3 log reduction of EMCV (HAV model) - ≥ 6.2 log reduction through 4% PEG precipitation and ≥ 5.5 log reduction through 20 nm nanofiltration of an experimental agent considered a model for the vCJD and CJD agents 3
Demonstrated benefits in replacement therapy • In the pre-approval clinical trial: 2 - 0.025 serious bacterial infections/patient/year - Well tolerated: Does not put patients at increased risk for any adverse events other than those that could be reasonably expected in primary immune deficiency patients who are receiving an infusion of intravenous immune globulin
Please see reverse for Important Safety Information and Black Box Warning. (1) Data on file, Instituto Grifols, S. A. (2) Berger M. et al. Efficacy, Pharmacokinetics, Safety and Tolerability of Flebogamma® 10% DIF, a high purity human intravenous immunoglobulin in primary immunodeficiency. J Clin Immunol 2010; 30 (2): 321-9. (3) Diez JM, et al. Capacity of the manufacturing process of Flebogamma® DIF, a new human high purity intravenous immunoglobulin, to remove a TSE model-agent. Biologicals (2010), doi:10.1016/j.biologicals.2010.08.003.
Immune Globulin Intravenous (Human)
Monitor patients for clinical signs and symptoms of hemolysis. If signs and/or symptoms of hemolysis are present after Flebogamma® 10% DIF infusion, perform appropriate confirmatory laboratory testing (see Patient Counseling Information ).
For intravenous use only RX only
Transfusion-Related Acute Lung Injury (TRALI) Non-cardiogenic pulmonary edema may occur in patients following Flebogamma® 10% DIF 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.
BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
Monitor patients for pulmonary adverse reactions (see Patient Counseling Information ). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.
INDICATIONS AND USAGE Flebogamma® 10% DIF is a human immune globulin intravenous (IGIV) that is indicated for the treatment of primary immune deficiency (PI), including the humoral immune defect in common variable immunodeficiency, x-linked agammaglobulinemia, severe combined immunodeficiency, and Wiskott - Aldrich syndrome.
Infusion Reactions All patients, but especially individuals receiving Flebogamma® 10% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at a higher risk for the development of fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations regarding dosage and administration may reduce the risk of these types of events (see Dosage and Administration [2.3]).
Flebogamma® 10% DIF
DOSAGE AND ADMINISTRATION The recommended dose of Flebogamma® 10% DIF for patients with PI is 300 to 600 mg/kg body weight (3.0 to 6.0 mL/ kg), administered every 3 to 4 weeks. The infusion of Flebogamma® 10% DIF should be initiated at a rate of 0.01 mL/kg body weight/minute (1.0 mg/kg/ minute). If there are no adverse drug reactions, the infusion rate for subsequent infusions can be slowly increased to the maximum rate of 0.08 mL/kg/minute (8 mg/kg/minute). Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal dysfunction or thrombotic events, administer Flebogamma® 10% DIF at the minimum infusion rate practicable, and consider discontinuation of administration if renal function deteriorates. CONTRAINDICATIONS Flebogamma® 10% DIF is contraindicated in patients who have had a history of anaphylactic or severe systemic reactions to the administration of human immune globulin and in IgA deficient patients with antibodies to IgA and a history of hypersensitivity. WARNINGS AND PRECAUTIONS
WARNING: ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE • Use of immune globulin intravenous (IGIV) products, particularly those containing sucrose, has 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 those receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Flebogamma® 10% DIF does not contain sucrose. • For patients at risk of renal dysfunction or failure, administer Flebogamma® 10% DIF at the tminimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]).
Transmissible Infectious Agents Because Flebogamma® 10% DIF is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob (CJD) agent. No cases of transmission of viral diseases or CJD have ever been identified for Flebogamma 10% DIF. All infections suspected 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 1-888474-3657. Before prescribing or administering Flebogamma® 10% DIF, the physician should discuss the risks and benefits of its use with the patient (see Patient Counseling Information ). 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 BUN and serum creatinine, before the initial infusion of Flebogamma® 10% DIF and at appropriate intervals thereafter. • 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, because of the potentially increased risk of thrombosis. • If signs and/or symptoms of hemolysis are present after an infusion of Flebogamma® 10% DIF, perform appropriate laboratory testing for confirmation. • If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient’s serum. 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.
• Weigh the potential risks and benefits of Flebogamma® 10% DIF against those of alternative therapies in all patients for whom Flebogamma® 10% DIF is being considered. • Before prescribing Flebogamma® 10% DIF, the physician should discuss risks and benefits of its use with patients.
Adverse Reactions The most common adverse reactions (reported in ≥ 5% of clinical trial subjects) occurring during or within 72 hours of the end of an infusion were 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. The most serious adverse reactions observed with Flebogamma® 10% DIF were back pain, chest discomfort, and headache (2 patients); and chest pain, maculopathy, rigors, tachycardia, bacterial pneumonia, and vasovagal syncope (1 patient).
Hypersensitivity Severe hypersensitivity reactions may occur. In case of hypersensitivity, discontinue Flebogamma® 10% DIF infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Renal Dysfunction/Failure 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 Flebogamma® 10% DIF and at appropriate intervals thereafter. If renal function deteriorates, consider discontinue use of Flebogamma® 10% DIF.
In a multicenter, open-label, non-randomized, historically controlled clinical study, 46 individuals with primary humoral immunodeficiency received infusion doses of Flebogamma 10% DIF at 300 to 600 mg/kg body weight every 3 weeks (mean dose 469 mg/kg) or 4 weeks (mean dose 457 mg/kg) for up to 12 months (see Clinical Studies [14.1]). Routine pre-medication was not allowed. Of the 601 infusions administered, 130 infusions (22%) in 21 (47%) subjects were given pre-medications (antipyretic, antihistamine, or antiemetic agent) because of experience with consecutive infusionrelated adverse reactions.
In patients who are at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure, administer Flebogamma® 10% DIF at the minimum rate of infusion practicable. Hyperproteinemia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Flebogamma® 10% DIF therapy. It is clinically critical to distinguish true hyponatremia from a pseudo-hyponatremia that is temporally or causally related to hyperproteinemia with concomitant decreased calculated serum osmolarity 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 higher risk of thrombotic events. Thrombotic events may occur during or following treatment with Flebogamma® 10% DIF. Monitor patients at risk for thrombotic events, including those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and known or 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 Flebogamma® 10% DIF at the minimum rate of infusion practicable (see Dosage and Administration [2.3]). Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently with Flebogamma® 10% DIF treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae (3-4).
One subject experienced four serious adverse events (AEs, bacterial pneumonia, subcutaneous abscess and two episodes of cellulitis) and withdrew from the study. Two other subjects who participated in the study discontinued prematurely due to AEs (back pain/chest pain/headache; and chills/tachycardia). Three subjects experienced four serious non-related AEs (drug abuse/depression; hernia; and sinusitis). Forty-five (98%) subjects experienced at least 1 AE irrespective of the relationship with the product, and these subjects reported a total of 723 AEs. Thirty-eight subjects (83%) had an adverse reaction at some time during the study that was considered product-related. Of the 21 subjects receiving pre-medications, 12 (57%) subjects reported adverse reactions during or within 72 hours after the infusion in 48 of the 130 pre-medicated infusions (37%). Table 2. Treatment-related Adverse Events Occurring in ≥ 5% of Subjects with PI during a Flebogamma® 10% DIF Infusion or within 72 Hours after the End of an infusion Adverse Event
Subjects (%) [N=46]
Infusions (%) [N=601]
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 frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination to patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis.
Body temperature increased
AMS may occur more frequently following high doses (2 g/kg) and/or rapid infusion of IGIV.
Infusion site reaction
Pain in extremity
Hemolysis Flebogamma® 10% DIF 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 hemolysis (5-6). Delayed hemolytic anemia may develop subsequent to Flebogamma® 10% DIF therapy due to enhanced RBC sequestration (7), and acute hemolysis, consistent with intravascular hemolysis, has been reported.
The total number of adverse events occurring during or within 72 hours after the end of an infusion, irrespective of causality, was 359, excluding non-serious infections. Table 3 lists the AEs that occurred in greater than 5% of subjects during a Flebogamma® 10% DIF infusion or within 72 hours after the end of an infusion, irrespective of causality. Table 3. Adverse Events Occurring in ≥ 5% of Subjects with PI during a Flebogamma® 10% DIF Infusion or within 72 Hours after the End of an infusion, Irrespective of Causality Adverse Event
Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, dermatitis (e.g., 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
Subjects (%) [N=46]
Infusions (%) [N=601]
Cough or Productive cough
Infusion site reaction
Urinary tract infection
Pain in extremity
Body temperature increased
Keep Flebogamma® 10% DIF in its original carton to protect it from light.
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)
Gastroesophageal reflux disease
Respiratory tract congestion
In this study, the upper bound of the 1-sided 95% confidence interval for the proportion of Flebogamma® 10% DIF infusions associated with one or more AEs was 37.8% (total infusions: 208; actual proportions: 34.6%). The average percent of infusions with AEs during or within 72 hours after the end of an infusion for each individual subject was 36.7% and the upper bound of the 1-sided 95% confidence interval was 43.9%. AE reporting was based upon a clinical protocol precluding pre-medication against AEs. Pre-medication could be utilized only after the first 2 infusions only in those patients that exhibited adverse events. Forty-three of the 46 subjects enrolled in this study had a negative Coombs test at baseline. Of these 43 subjects, 10 (23.3%) developed a positive Coombs test at some time during the study. However, no subjects showed evidence of hemolytic anemia. Post-marketing Experience Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse reactions have been identified during post approval use of intravenous immune globulins, including Flebogamma 5% (see References ). Infusion reactions
Renal Respiratory Cardiovascular
Hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure Acute renal dysfunction/failure, osmotic nephropathy Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiac arrest, thromboembolism, vascular collapse, hypotension
DRUG INTERACTIONS Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as measles, mumps, and rubella. Inform the immunizing physician of recent therapy with Flebogama® 10% DIF so that appropriate measures may be taken (see Patient Counseling Information ). USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Animal reproduction studies have not been performed with Flebogamma® 10% DIF. It is also not known whether Flebogamma® 10% DIF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Flebogamma® 10% DIF should be given to a pregnant woman only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. Nursing Mothers Use of Flebogamma® 10% DIF has not been evaluated in nursing mothers. Pediatric Use Three (3) pediatric patients with primary humoral immunodeficiency (two between the ages of 6 and 10, and one 16 year old) were included in the clinical evaluation of Flebogamma® 10% DIF. This number of subjects is too small to establish safety and efficacy in the pediatric population (see Clinical Studies ). Geriatric Use Use caution when administering Flebogamma® 10% DIF to patients over 65 years of age who are judged to be at increased risk for developing certain adverse reactions such as thromboembolic events and acute renal failure (see Boxed Warning, Warnings and Precautions [5.2]). Do not exceed the recommended dose, and infuse Flebogamma® 10% DIF at the minimum infusion rate practicable. One (1) patient with primary humoral immunodeficiency at or over the age of 65 was included within the clinical evaluation of Flebogamma® 10% DIF. This number of geriatric patients was too small for separate evaluation from the younger patients for safety or efficacy (see Clinical Studies ). HOW SUPPLIED/STORAGE AND HANDLING Flebogamma® 10% DIF is supplied in single-use, individually laser etched vials containing the labeled amount of functionally active IgG. The following presentations of Flebogamma® 10% DIF are available:
Each vial has an integral suspension band and a label with two peel-off strips showing the product name and lot number. DO NOT FREEZE. When stored at room temperature (up to 25 ºC [77 ºF]), Flebogamma® 10% DIF is stable for up to 24 months, as indicated by the expiration date printed on the outer carton and container label.
Hem/Onc Pharmacy 11
Pharmacy Practice News • May 2011
A Helping Hand for Complex Drug Regimens
SEVENTH ANNUAL CONFERENCE
Pharmacists boost compliance with oral drugs, other treatment challenges Salt Lake City—A medication therapy management (MTM) clinic, where a pharmacist and a nurse practitioner develop individualized medication plans for patients newly diagnosed with cancer and coach them on how best to manage increasingly complex regimens, positively impacts safety and adherence. The practice model is particularly needed in the case of oral antineoplastic therapy, which is very complex and poses numerous barriers to adherence, according to Pragna Patel, PharmD, clinical-investigational oncology pharmacy manager at Montefiore Medical Center, New York City. Those barriers include the high cost of the medications, the occurrence of adverse events and the number of drugs that patients are required to take, Dr. Patel noted during a poster presentation at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). “Oral chemotherapy is often longterm, and research has shown that adherence rates with long-term therapies go down to 40% to 50%, adversely affecting disease outcome,” Dr. Patel said, citing, as an example, a review study by Partridge et al (J Natl Cancer Inst 2002;94:652-661). Even with short-term therapy, compliance can be a problem, according to the review study. In one trial cited in the review—of 108 patients taking selfadministered oral allopurinol for newly diagnosed malignancies—only 16.8% of patients were found to have minimum therapeutic serum levels of the drug over a six-month period of observation. Patients also were asked to self-report their adherence, and those reports overestimated adherence by a factor of 2, pointing to yet another challenge: “You really can’t trust many patients when they tell you they’re taking their medications,” Dr. Patel noted. And yet with selfadministered oral agents, “that’s often all you have to go by, at least initially.”
More Sobering Data Other studies underscore the problem, Dr. Patel noted. “A National Council on Patient Information and Education 2006 survey found that 49% of patients forgot to take their medication, 31% did not fill their prescription, 29% stopped altogether and 24% took less meds than they were supposed to take,” she told HOPA attendees. “We have found that these patients are confused and very much in need of guidance on how to take their medications.” To help provide that type of patient assistance, in January 2009, Dr. Patel and Una Hopkins, RN, FNP, started the
MTM clinic at the Montefiore Oncology Outpatient Center as a joint venture between pharmacy and nursing. Physicians referred their patients to the clinic for an appointment and the patients were instructed to bring all their medications, including prescription and nonprescription drugs, as well as herbals and vitamins, to their first visit. “We wanted them to bring the bot-
the clinic, resulting in 53 billable visits. “Technically, the pharmacist doesn’t get paid for the service because we are in New York state, and New York does not have a Collaborative Drug Therapy Management bill passed yet; it is still in the Senate,” Dr. Patel told Pharmacy Practice News. “However, since our program is a joint venture between the nurse practitioner and the pharmacy,
New medication Dose adjustment Drug discontinuation Drug–drug interactions Vaccination Drug procurement Herbals
‘When [patients] hear their diagnosis of cancer, they stop hearing anything else, so it is very important to bring them in separately just to talk about their medications.’ —Pragna Patel, PharmD
Figure. Type of pharmacist interventions.
tles of medications, not just the medication list,” Dr. Patel said. “The goal was to make sure they had a clear understanding of all of the medications they were taking.” The clinic hours were every Thursday afternoon between 3 and 5 p.m. Typically, a patient’s first visit lasted 40 to 60 minutes. Patients were seen as often as necessary. Only patients at greatest risk for nonadherence and safety issues were referred to the MTM clinic, but this was largely because of time and resource limitations, Dr. Patel said. “We considered at-risk patients to be those taking oral chemotherapeutics, [or] long-term hormone therapy, those taking more than five concomitant medications and those with multiple comorbid conditions. But almost every cancer patient falls into this high-risk category.” All relevant patient information was put on a one-page medication card that was given to the patient at the end of the clinic visit. The card, which could be folded to fit in the patient’s wallet, contained explicit information about the start date, drug name and strength, dose, formulation (e.g., pills, units, puffs or drops) and when and how to take each medication, as well as emergency contact numbers, the name of the patient’s primary care provider, pharmacies, dates of most recent adult immunizations and allergies. During 2009, 63 patients were seen at
the first visit to the clinic is designated as a follow-up visit for the nurse practitioner, and that is how we have been able to get some reimbursement.” Since the MTM clinic has been in operation, Dr. Patel has found that the main problems identified include drug–drug interactions, adherence issues with the prescribed oncology regimen, outdated immunizations and cost or insurance challenges in obtaining prescribed medications (Figure). Patients have been overwhelmingly enthusiastic about the clinic, giving it a 99% positive rating. “They are very grateful that someone has taken the time to talk to them about their treatment. When they hear their diagnosis of cancer, they stop hearing anything else, so it’s very important to bring them in separately just to talk about their medications,” Dr. Patel said. “The doctors like it, too: They tell me that after patients have been to the MTM clinic, it’s a totally different scenario. The patients are more relaxed and have a better understanding of what they are supposed to do, and this makes it easier for everybody, including the doctor.” Seeing cancer patients on a one-onone basis and counseling them about the correct way to use their medications has allowed Dr. Patel to uncover and correct problems. The hope is that this will not only improve safety but outcomes as well. “One patient literally had tears in her
eyes. She told me that nobody had time to talk to her and help her understand what to do. I have other patients who were on IV chemo and were also supposed to take oral chemo; I found out that they either did not get the oral chemo or they did not understand how to take it. For others, it was a matter of being unable to afford to pay the copay, so they didn’t even pick up the drug. And meanwhile, we are thinking that these patients are taking the whole treatment, when in fact they are not.”
Kudos on a Proactive Approach “This is probably one of the hottest topics in oncology pharmacy right now,” said David G. Frame, PharmD, assistant professor of pharmacy at the University of Michigan, Ann Arbor. “Compliance and a basic understanding of issues can be the source of major complications when we are dealing with chemotherapy that, overall, still has a fairly narrow therapeutic range.” Dr. Frame suggested that counseling patients who are on oral chemotherapy should begin as promptly as possible. “I feel very strongly that pharmacists should see these patients right up front, as they actually hand them their prescription. We are drug managers and drug experts, and this represents a coming opportunity for us to be on the front line,” he said. “I am glad to see that so many of us here at HOPA think it is important to start these types of clinics.” —Fran Lowry Drs. Patel and Frame reported no relevant conflicts of interest.
Pharmacy Practice News • May 2011
In Focus SEVENTH ANNUAL CONFERENCE
Follicular lymphoma patients require vigilance
New Rituximab Indication: Keep an Eye on Side Effects Salt Lake City—Adverse events (AEs) including hypogammaglobulinemia and infections can occur in patients with follicular lymphoma treated with rituximab, and they are likely to be even more common now that the drug has been approved as maintenance therapy. Pharmacists should be aware of these AEs and monitor their patients closely, said Mandy Gatesman, PharmD, in a presentation at the annual meeting of the Hematology/Oncology Pharmacy Association. Rituximab (Rituxan, Genentech) was granted approval by the FDA in January for maintenance therapy to prevent or delay relapse of follicular lymphoma in patients who responded to initial treatment with rituximab plus chemotherapy, based on the results of the PRIMA (Primary Rituximab in Maintenance) study (Lancet 2011;377:42-51). The duration of maintenance is still up in the air, but for now, it should be two years, according to data from the PRIMA study, said Dr. Gatesman, clinical pharmacy specialist in hematology and oncology at Virginia Commonwealth University Medical Center, in Richmond. More specifically, the approved dosing regimen for rituximab is 375 mg/m2 every eight weeks for two years. This means that patients now will have to visit the clinic every two months for two years, and this may be burdensome for many patients, she noted. Dr. Gatesman acknowledged that when the PRIMA study looked at quality of life, there was no difference between the observation and maintenance rituximab arms, indicating that the necessity of making so many trips for treatment did not appear to affect patients. However, she predicted that in clinical practice, it may have a negative impact. “I think that it is still a significant burden placed on patients and their caregivers to receive therapy at that schedule for that long a time.”
Be Vigilant for Hypogammaglobulinemia Beyond the potential inconvenience, the risk for hypogammaglobulinemia is very real in these patients. A singlecenter retrospective review evaluating immunoglobulin levels in patients receiving rituximab found that 33% of patients (44 of 134) receiving rituximab induction developed hypogammaglobulinemia compared with 55% of patients (27 of 49) receiving the more frequent maintenance rituximab regimen (P=0.006) (J Clin Oncol 2010;28: abstract 8088). Additionally, 20% of those receiving rituximab as mainte-
nance had to receive IV The FDA’s adverse-events immunoglobulin (IVIG) comsite, MedWatch, also reported pared with 10% of those who that of these 183 cases, 58.4% received rituximab induction had a fatal outcome. Because only (P=0.05). The PRIMA of this, the American Society study also found that 55% of Clinical Oncology (ASCO) of patients developed hypoissued a Clinical Opinion statgammaglobulinemia, regarding that screening of patients Scan for details of PRIMA study. less of whether they received should be considered “if highly rituximab as initial treatment Instructions, p. 3 immunosuppressive therapy is or as maintenance therapy. planned, including but not limited to Furthermore, infections are a problem regimens including rituximab” (J Clin with rituximab that seems to worsen Oncol 2010;28:3199-3202). with maintenance. In the PRIMA study, “If our patients are receiving 12 doses in there was a 15% increase in grade 2 the maintenance phase as well as potento 4 infections in the rituximab main- tially four to six doses prior to that, that’s tenance patients compared with those a lot of rituximab that they are receiving on observation. Additionally, a meta- and potentially increasing their risk for analysis by Vidal et al (J Natl Cancer hepatitis B reactivation,” Dr. Gatesman Inst 2009;101:248-255) found a nearly told Pharmacy Practice News. “At our twofold greater risk for developing an institution, we recommend looking at infection (relative risk [RR], 1.99; 95% hepatitis B status in all patients receiving confidence interval [CI], 1.21-3.27), and a rituximab. We would not delay starting nearly threefold greater risk for develop- rituximab therapy while awaiting the
‘Will there ultimately be a statistically significant overall survival benefit from rituximab maintenance [therapy]? Is maintenance safe to continue after two years?’
—Larry W. Buie, PharmD
ing a grade 3 or 4 infection (RR, 2.90; 95% CI, 1.24-6.76) in patients who received maintenance rituximab compared with those who did not. Reactivation of hepatitis B, possibly leading to liver failure, also is a concern with rituximab. A meta-analysis by Evens et al, covering 1997 to 2009, found 183 rituximab-associated cases of hepatitis B reactivation (Ann Oncol 2010; doi:10.1093/ annonc/mdq583). They found a significantly increased risk for hepatitis B reactivation in rituximab-treated patients compared with those not given rituximab (odds ratio, 5.73; 95% CI, 2.01-16.33; P=0.0009). The authors noted that the median number of rituximab doses prior to reactivation was six.
hepatitis B status because the data show that we have to give a few doses for the reactivation to occur, but if they do test positive as a hepatitis B chronic carrier, we initiate antiviral therapy.” She added that, because the rates of infection appear to be so high, looking at patients’ immunoglobulin (Ig) levels while they are on therapy is a good strategy. “Potentially, we could give them IVIG if necessary.”
IVIG Caveats But before IVIG is administered, “it would be important to know what the patient’s IgG level is at baseline,” cautioned Jerry Siegel, PharmD, FASHP, clinical associate professor at the Ohio
State University College of Pharmacy, in Columbus. “If the IgG level is below 600 mg/dL, then treat them as if they were a primary immunodeficiency patient. The dose could be adjusted to maintain a level above 800 mg/dL to provide protection from infection. Keep in mind that both rituximab and IVIG are used for ITP [idiopathic thrombocytopenic purpura]; therefore, a platelet count at baseline and 24 hours after therapy may be beneficial to prevent hyperthrombocytosis and a potentially hypercoagulable state.” Additionally, he pointed out that “IVIG itself adds additional side effects, such as fever and chills, that may confound the diagnosis of infection.” Trials are enrolling patients to see if a longer duration of rituximab maintenance—as long as four years—might be a better strategy. There also is a Phase III trial of R-CVP (rituximab, cyclophosphamide, prednisolone and vincristine) versus R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone) followed by maintenance rituximab, “so we can potentially answer the question about whether frontline induction chemotherapy really does matter for these patients.” Larry W. Buie, PharmD, BCPS, BCOP, hematology/oncology clinical specialist at the University of North Carolina at Chapel Hill, told Pharmacy Practice News that rituximab has been a very important addition to the treatment armamentarium for follicular lymphoma. “Multiple studies have shown that when rituximab is added to chemotherapy, there are significant improvements in failure-free and overall survival. The question has been with regard to rituximab maintenance: which patients and for how long?” he said. In spite of the PRIMA trial, which showed that in the group receiving rituximab maintenance progression-free survival was longer and the risk for progression was decreased by 45% after 36 months of follow-up, questions remain, Dr. Buie said. “Will there ultimately be a statistically significant overall survival benefit from rituximab maintenance? Is maintenance safe to continue after two years? What are the risks of prolonged maintenance—increased infections? Resistance? As Dr. Gatesman said, all patients should be screened for hepatitis B prior to rituximab therapy.” —Fran Lowry Drs. Gatesman and Buie reported no relevant conflicts of interest. Dr Siegel reported a consulting agreement with CSL Behring.
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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.
Pharmacy Practice News • May 2011
Japan’s Nuclear Crisis Reaches US Pharmacies Soo Kang, PharmD PGY1 Pharmacy Resident Clara Maass Medical Center Belleville, New Jersey
Elena Beyzarov, PharmD Director of Medical Communications Livingston Services
Shilpa Amara, PharmD Medical Communications Specialist Livingston Services Saint Barnabas Health Care System West Orange, New Jersey
ow that the threat of meltdown at Japan’s earthquake- and tsunamistricken nuclear power complex has eased, at least one question remains: How vulnerable is our nation’s supply of radiation sickness medications, given the panic buying and subsequent depletion of potassium iodide (KI) stocks that occurred in the days and weeks following the disaster? Much of the panic buying was triggered by reports that potentially cancercausing radioactive plumes were crossing the Atlantic. In the days that followed those reports, alarmed US residents visited various Internet sites to purchase KI, which was being touted as a panacea for radiation sickness. As a result of the surge in demand, the price of KI skyrocketed. According to some reports, a package of 14 tablets that normally costs about $10 soared to $540 in some ebay.com listings—a shocking 5,300% increase. Although some manufacturers struggled to meet demands for KI in a suddenly lucrative market, others simply gave up, temporarily ceasing production.1-4 During the crisis, authorities continued to stress the unlikelihood of clinically significant radiation from Japan reaching US shores. But with the media fueling the fire by dubbing the disaster a “second Chernobyl,” suppliers were left scrambling to meet demands for 3 different versions of FDA-approved KI and local pharmacies were being flooded with questions related to radiation exposure. Even on the East Coast, far removed from even a hint of significant radiation exposure, people were looking to stock up on KI. Contacted at the height of the panic, Javier Rodriguez, RPh, pharmacist-in-charge at a Target Pharmacy in NJ, said, “We get a handful of calls on a daily basis from people requesting [the tablets]. We can’t even order KI from the wholesaler, and although it can be compounded the old-fashioned way, we’re not exactly advertising it right now, since it’s not an emergency and I don’t want to add to the hysteria.” Indeed, the surging demand for KI impacted compounding pharmacies,
placing those facilities under sudden pressure to compound tablets faster than they could secure raw materials. Bruce Ruck, PharmD, director of drug information and professional education at the New Jersey Poison Information and Education System, has been warning the public against buying, stockpiling, and prophylactically ingesting KI—especially because KI overdose, which has been reported at several poison control centers,5 may cause serious reactions (eg, tachycardia, dizziness, and vomiting). Additionally, administration of KI for longer than 2 weeks may lead to severe hypothyroidism.
But there’s another downside to mass purchasing of KI that goes well beyond an effect on any one individual: The hoarding may deplete national supplies, which are typically reserved for potential incident-related radiation exposure among US citizens residing near nuclear plants. In New Jersey, for example, a 1-day supply of KI (for use during potential radiation contamination) is distributed to all residents and workers in counties located within 10 miles of nuclear power plants.6 “We need to have adequate supplies of KI so that we can replace expired product on a regular basis,” Dr. Ruck pointed out. Hoarding of KI has another potential downside: It may obscure the fact that there are several other treatments that should be on hand in cases of radiation exposure, including Prussian blue, diethylenetriaminepentaacetate (DTPA) and granulocyte growth factors. However, none of those agents are useful in protecting against the exposure itself; rather, they can be effective in minimizing damage if such exposure occurs. Prussian blue, the blue dye from the 1960s, may be used to treat patients internally contaminated with radioactive cesium (mainly Cs-137) and nonradioactive thallium (once an ingredient in rat poison).7,8 Working through an ion exchange to trap these radioactive substances in the intestines and prevent reabsorption, Prussian blue reduces the half-life of cesium and thallium from 110 to 30 days and from 8 to 3 days, respectively. The dye, which is relatively safe in most patients (including pregnant
women), is started immediately once radiation exposure is suspected, but is still effective if treatment is delayed.8 Common side effects include GI upset, constipation, and discolored stool.7 In the interest of preventing dye-related poisonings, patients should be warned against desperately ingesting Prussian blue artist’s dye as a substitute for in this setting requires more formal investigation.11
The Fear Factor? There is another question raised by Japan’s nuclear disaster: Is the level of concern it triggered in the US over radiation exposure warranted? Although exposure to small amounts of radiation from natural sources (eg, soil, sun) and medical equipment is a predictable part of everyday life, inadvertent exposure to larger-than-expected
‘I caution people not to just go out and buy stuff that says radiation remedy or prevention, because they don’t know what they’re buying.’ —Bruce Ruck, PharmD pharmaceutical-grade Prussian blue. DTPA, available since the 1960s, is a chelating substance used to treat internal contamination from a variety of transuranic radioactive elements such as americium, plutonium, californium, curium, and berkelium. Currently, DTPA, available as calcium trisodium (Ca-DTPA) and zinc trisodium (ZnDTPA) injections, is approved for chelation of only plutonium, americium, and curium.9 When given within the first day after internal contamination, Ca-DTPA is about 10 times more effective at chelation than Zn-DTPA; however, after 24 hours, both products are equally effective. Although chelating agents generally work best to remove radioactive material when given shortly after contamination, DTPA may still be somewhat effective if treatment is delayed several days or even weeks. The agent may be given for extended durations (depending on total exposure) and response to therapy may be measured by the amount of metal excreted in urine.10 Based on their supportive role in aiding neutrophil recovery among patients receiving chemotherapy, granulocyte growth factors (eg, filgrastim, pegfilgrastim) have been evaluated as a potential treatment for bone marrow injury caused by radiation; however, their clinical utility
quantities is what experts fear. Unfortunately, “we don’t know exactly what the radiation threshold is,” said Douglas Cipkala, MD, hematologist-oncologist at Saint Peters University Hospital, in New Brunswick, NJ. Obviously, “the more radiation you’re exposed to, the greater the risk for adverse health consequences.” But how much is too much remains unknown, because for some susceptible individuals, even one computed tomography scan may be enough to increase their risk for developing a malignancy, Dr. Cipkala noted. (That increased risk, he explained, is based on studies of survivors of the Hiroshima and Nagasaki atomic bombs that have been used to model cancer rates over time.) According to the CDC, acute radiation syndrome—which may affect bone marrow, as well as the gastrointestinal (GI), cardiovascular, and central nervous systems—develops after exposure to a relatively high radiation dose (eg, >0.7 Gy or 70 rads); however, mild symptoms may be observed with doses as low as 0.3 Gy or 30 rads.12 In situations where internal radiation contamination is suspected, the initial concern is inhalation of radioactive iodine, which is readily absorbed by the thyroid gland, leading to thyroid
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Pharmacy Practice News • May 2011
Cancer Patients Can Be Drug Abusers Too
SEVENTH ANNUAL CONFERENCE
Drug seeking, diversion among hurdles to overcome Salt Lake City—Managing cancer pain in the outpatient setting can be very challenging, particularly if a patient is at high risk for drug abuse. “Cancer patients can be drug abusers too,” said David Craig, PharmD, director of the Pain and Palliative Care Pharmacist Residency Program at H. Lee Moffitt Cancer Center and Research Institute
in Tampa, Fla. “Just because they have a cancer diagnosis does not mean that they will not abuse the drugs we give them to treat their pain.” Assessing their degree of risk for drug abuse is the first step in managing these patients, Dr. Craig said at the annual meeting of the Hematology/Oncology Pharmacy Association.
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As an example of this type of patient, Dr. Craig presented the case of a 37-year-old man with a history of squamous cell carcinoma of the glottis who had received radiation and chemotherapy followed by a total laryngectomy and a gastric feeding tube. This patient had a history of heroin addiction and had completed a rehabilitation program with methadone. The decision was made to treat the patient’s pain with methadone and oxycodone, with adjuvant pregabalin (Lyrica, Pfizer). The methadone caused a prolongation of his QT interval but his other laboratory values remained within normal ranges.
Caveats for Methadone
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“Methadone can cause QT prolongation and it is important to monitor patients for this,” he added. “Also, if you are going to use intravenous methadone for an extended period of time, use the formulation that is free of preservatives, because the intravenous formulation can cause more QT prolongation.” Other methadone “pearls” include performing an electrocardiogram at baseline for high-risk patients, such as those at risk for torsades de pointes, patients using concomitant QT-prolonging drugs or other drugs that may have significant interactions with methadone, patients on oral doses exceeding 100 mg per day and patients with electrolyte abnormalities. Monitoring should be done more frequently if the patient’s current QTc is greater than 450 ms but less than 500 ms, and if the QTc is greater than 500 ms, “watch out!” Dr. Craig warned. The squamous cell cancer patient continued to report that his pain was at 9 out of 10, describing it as “sharp,” “stabbing,” “burning” and “constant,” despite the methadone, oxycodone and pregabalin regimen, and he requested oxycodone CR. “This patient was really challenging,” Dr. Craig noted. “Sometimes, despite what you do, patients will not respond. I could have jacked the dose of methadone up to 1,000 mg and probably nothing would have happened. Patients have perceptions about how they think
Hem/Onc Pharmacy 23
Pharmacy Practice News • May 2011
‘Some tumor cells are refractory to treatment, so finding out why they are resistant would allow us to develop targeted therapies and improve outcomes.’
continued from page 1
breast cancer patients produced changes in some of the tumors that indicated resistance to endocrine therapy, said presenter Justin M. Balko, PharmD, PhD, a research fellow under Carlos L. Arteaga, MD, at Vanderbilt-Ingram Cancer Center, Vanderbilt University, in Nashville, Tenn. “Approximately 70% of breast cancers express the estrogen receptor, and in general, ER positivity is considered to be a good prognostic factor,” Dr. Balko said. “Unfortunately, many ER-positive breast cancer patients will ultimately have a recurrence of their disease, despite surgical resection and five years of adjuvant endocrine therapy. Some tumor cells are refractory to treatment, so finding out why they are resistant would allow us to develop targeted therapies and improve outcomes.” The study was prompted by an earlier effort by British researchers—the IMPACT (IMmediate Preoperative Arimidex, tamoxifen or Combined with Tamoxifen) trial—that found a relationship between expression of the proliferation marker Ki67 in breast tumors after short-term treatment with antiestrogens and a better response to therapy (J Clin Oncol 2005;23:2477-2492). The latest study was designed and conducted by Dr. Arteaga and Ingrid Meszoely, MD, a surgical oncologist and director of the Breast Center at Vanderbilt. In collaboration with researchers from the they are doing that we, as health care professionals, cannot control. In this case, the patient did not feel that I was doing a good job. And if the patient doesn’t think you are doing a good job, you’re not.”
Assessing Risk for Abuse It is important to stratify patients’ risk for abusing drugs, Dr. Craig said. Clinicians have a choice of three assessment tools that can help: the Opioid Risk Tool (ORT), the Current Opioid Misuse Measure (COMM), and the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). The ORT is a five-question screening tool that can predict opioid-related aberrant behavior (Pain Med 2005;6:432442). It uses the following factors to gauge risk: 1. Family history of substance abuse 2. Personal history of substance abuse 3. Age (16-45 years) 4. History of preadolescent sexual abuse (women only) 5. Psychological illness “Younger age is more predictive of substance abuse potential. A history of preadolescent sexual abuse accounts for 4 points but only in females,” Dr. Craig
—Justin M. Balko, PharmD, PhD
University of Texas MD Anderson Cancer Center in Houston and Dana-Farber Cancer Institute in Boston, the study investigators sought to identify genomic and proteomic biomarkers related to Ki67 after letrozole treatment in the hope of gaining more insight into mechanisms of endocrine resistance. The hope was that they would uncover “mechanisms of endocrine resistance that ... might be targetable by additional therapeutics,” Dr. Balko noted. Twenty-three postmenopausal women with stage I and II ER-positive, HER2-negative breast cancer had a core needle biopsy two weeks before their scheduled surgery. They received 2.5 mg of letrozole daily for 14 days. The tumor specimen obtained at biopsy and the actual tumor removed at surgery were analyzed with a variety of techniques, including gene expression analysis, DNA sequencing for more than 400 known mutations and reverse-phase proteomic analysis. said. “A total score of 0 to 3 indicates low risk, 4 to 7 is moderate risk and greater than 8 is high risk.” The COMM assessment tool (http:// www.painedu.org) uses more subjective questions and is a 17-item, 5-point Likert scale questionnaire. The test is quick and easy to administer, has been validated in approximately
‘We have to treat their cancer pain, but we cannot give them a free ticket to all of the drugs they want, simply because they have cancer.’ —David Craig, PharmD 500 patients, and is ideal for documenting decisions about the level of monitoring planned for a particular patient or justifying referrals to a specialty pain clinic. The COMM evaluates behaviors in the past 30 days and is scored by adding the sum of responses of patients to questions,
As in the IMPACT trial, Ki67 expression was significantly reduced with letrozole treatment in most patients. Additionally, genes correlated with Ki67 were strongly correlated with phosphorER (ser 118), a target of the MAPK pathway. Proteomic analysis also identified additional activation patterns indicative of PI3K/mTOR activity. “A full analysis of the planned 140 patients will be reported once accrual is complete. Additional centers at the NSABP [National Surgical Adjuvant Breast and Bowel Project], Emory [University], and the INEN [National Institute of Neoplastic Diseases] in Lima, Peru, are collaborating with Vanderbilt to meet the targeted sample size,” Dr. Balko said.
Clues for Further Study “Our most interesting observation was that PI3-kinase (p110a) mutations, which have been suggested to potentially play a role in endocrine resistance, were found to be associated with a lower response to short-term letrozole compared with ER-positive tumors with wild-type p110a,” Dr. Balko noted. “That observation now supports the design of studies where we look for p110a mutawhere 0 equals “never” and 4 equals “very often.” A score of 9 or higher is considered a positive score. “The COMM is useful for screening and telling us how aggressive we have to be,” Dr. Craig said. The SOAPP-R (http://www.painedu. org) is similar to the COMM, but is more cumbersome to use. It consists of a 24-item questionnaire on a 5-point Likert scale, and a score of 18 or higher is considered high risk, a score between 10 and 21 is moderate risk and a score of less than 9 is low risk. “Patients with active substance abuse are very challenging to treat, and so are patients with psychiatric illnesses,” Dr. Craig told Pharmacy Practice News. “We have to treat their cancer pain, but we cannot give them a free ticket to all of the drugs they want, simply because they have cancer.” He added, “the health care system discriminates against patients with noncancer pain. If the patient has cancer pain, it’s ‘come right in, we’re going to treat you right away.’ There is a big disconnect and I see this a lot.”
Weighing Empathy Against Abuse Potential Lee Kral, PharmD, BCPS, adjunct
tions and then treat patients who have the mutation with a PI3-kinase inhibitor, along with endocrine therapy. This will allow us to determine whether the combination improves on the outcome of those patients compared with the current standards of care.” Commenting on the study, David G. Frame, PharmD, clinical hematology/ oncology specialist, University of Michigan Health System, in Ann Arbor, told Pharmacy Practice News, “I think it is absolutely fantastic to see a pharmacist presenting this kind of work. I often hear a lot of comments about this type of research being over our heads, but this is the wave of the future for us. If we don’t understand these underlying mechanisms of resistance, it will be very difficult for us to understand the rationale for using these therapies appropriately. If we can predict within two weeks who is going to potentially have the best response or the worst response to this type of therapy, that could really change outcomes for patients.” —Fran Lowry Drs. Balko and Frame reported no relevant conflicts of interest.
assistant professor at the University of Iowa Hospitals and Clinics Center for Pain Medicine, in Iowa City, said she would agree with all of Dr. Craig’s comments. “The reality is that even patients with a history of substance abuse or who are at risk for substance abuse do get cancer. Also, treatment of pain related to cancer may unmask an underlying addiction, and survivors who have pain from the treatment of their cancer may use opioids to help them cope with that pain,” she noted. Health care providers can feel caught between the empathy they have for the patient and the need to prevent abuse and diversion, she added. Dr. Kral admitted that she finds herself spending more time talking to oncologists about opioid screening tools, urine drug screens, and opioid consent and management agreements. “This is something most of them never thought they would have to deal with, but it is becoming ever more a part of their daily practice.” —Fran Lowry Drs. Craig and Kral reported no relevant conflicts of interest.
Pharmacy Practice News • May 2011
‘We’re not exactly advertising [compounded KI] right now, since it’s not an emergency and I don’t want to add to the hysteria.’
continued from page 14
injury/cancer, particularly in infants/ fetuses, children and patients with low iodine stores. KI is known to flood the thyroid gland with stable iodine, preventing the organ from absorbing radioactive iodine—but it can only go so far. Consumers should be told that KI only protects the thyroid (not other parts of the body) from radioactive iodine— it cannot reverse effects of radioactive iodine once damage to the thyroid has occurred—and it cannot protect the body from radioactive elements other than radioactive iodine.12 A dose of KI is recommended before or immediately following radiation exposure in all children and adults under the age of 40 years who are not allergic to iodine or shellfish, and if radiation still poses a threat 24 hours later, a repeat dose is administered (unless the patient is pregnant or breastfeeding, or is a newborn).9,10 Given the fact that KI is classified as a Pregnancy Category D agent (due to risk for inhibiting fetal thyroid function) and is excreted in breast milk, pregnant and breastfeeding women should especially be discouraged from panic-buying KI products. Interestingly, adults older than age 40 years are at low risk for thyroid injury, but are at an increased risk for allergic reactions to KI. As such, this age group should not take KI unless significant risk for exposure is present.13 Common adverse reactions associated with KI include GI upset, inflammation of salivary glands, allergic reactions, and rash. Patients with known sensitivity to iodine and individuals with rare dermatologic conditions (eg, dermatitis herpetiformis, hypocomplementemic vasculitis) should avoid use.2
A Warning Against Stockpiling Given all of these caveats, what do we tell panicked patients desperately seeking to stockpile any and all products used for radiation exposure? Reassurance always helps, so it is important to emphasize that the risk from Japan’s nuclear power emergency is continuously monitored by the Nuclear Regulatory Commission and, given the thousands of miles separating the 2 countries, US territories are not expected to experience harmful levels of radioactivity. “The main thing is that nobody should take anything unless directed to do so,” Dr. Ruck stressed. “I caution people not to just go out and buy stuff that says radiation remedy or prevention, because they don’t know what they’re buying.” In fact, they may be buying counterfeit products, Dr. Ruck noted. A wave of dubious manufacturers have started capitalizing on escalating public fear
—Javier Rodriguez, RPh
by flooding the market with fake KI products and other supposed “radia-
tion cures.” In response to this activity, the FDA has issued a statement alerting consumers to be wary of Internet sites and other retail outlets promoting products (eg, dietary supplements, devices, vaccines, food items) that
make false claims to prevent or treat effects of radiation.14 Those seeking more information on treatments relating to radiation exposure may call the New Jersey Poison Control Center at (800) 222-1222.
Step up to a range of insulin delivery options.
As part of Eli Lilly and Company’s ongoing commitment, we provide healthcare facilities with a choice of vial sizes. Humalog® (insulin lispro injection [rDNA origin]), Humulin® R U-100 (regular insulin human injection, USP [rDNA origin]), and Humulin® N (NPH human insulin [rDNA origin] isophane suspension) are available in a smaller vial size.* The smaller vials are designed to give healthcare facilities ﬂexibility when evaluating insulin storage and distribution (ﬂoor stock vs individual patient supply), in addition to the 10 mL vial and Humalog® KwikPen™. • Humalog Smaller Vial* NDC Number - 0002-7510-17 • Humulin R U-100 Smaller Vial* NDC Number - 0002-8215-17 • Humulin N Smaller Vial* NDC Number - 0002-8315-17 * Smaller vials contain 3 mL of insulin in a 5 mL vial.
Humalog Indication Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control of hyperglycemia. Humalog should be used with longeracting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.
0211 PRINTED IN USA
©2011, LILLY USA, LLC. ALL RIGHTS RESERVED.
Humalog Important Safety Information Contraindications Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients. Warnings Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of action. Therefore, when used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an insulin pump). Glucose monitoring is recommended for all patients with diabetes. The safety and effectiveness of Humalog in patients less than 3 years of age have not been established. There are no adequate and well-controlled clinical studies of the use of Humalog in pregnant or nursing women.
Hem/Onc Pharmacy 25
Pharmacy Practice News • May 2011
In Focus References 1. Pollack A. Anxiety over radiation drives a sales surge for a drug against thyroid cancer. The New York Times. March 15, 2011.http://www. nytimes.com. Accessed March 21, 2011. 2. Broadwater L. Irrational nuclear fears lead to potassium iodide shortages in U.S. The Baltimore Sun. March 18, 2011. http://www. baltimoresun.com. Accessed March 21, 2011. 3. Edwards J. Pharmacies see a surge in potassium iodide purchases. CBS Local News Online. March 17, 2011. http://www.cbs6albany. com/news/fallon-1283700-pills-iodide.html. Accessed March 21, 2011. 4. Lazaruk S. Radiation fear prompts run on
iodine pills in B.C. The Vancouver Sun. March 19, 2011. http://www.vancouversun.com/Radiat ion+fear+prompts+iodine+pills/4473503/story. htm. Accessed March 21, 2011. 5. Popping potassium iodide already? Really bad idea. Poison control centers hear early reports of sickness from preventive pills. http://www. msnbc.msn.com/id/42135438/ns/healthhealth_care/. Accessed March 20, 2011. 6. State unveils potassium iodide distribution plan. http://www.nj.gov/health/news/p20619a. htm. Accessed March 20, 2011. 7. Centers for Disease Control and Prevention. Emergency preparedness and response: Prussian blue fact sheet. http://www.bt.cdc. gov/radiation/prussianblue.asp. Accessed March 17, 2011.
8. Lexi-Comp OnlineTM. Hudson, OH: LexiComp, Inc.; March 18, 2011. 9. New York State Department of Health. Prophylactic use of potassium iodide (KI) in radiological emergencies. Information for physicians. http://www.health.state.ny.us/ environmental/radiological/potassium_iodide/ docs/information_for_physicians.pdf. Accessed March 16, 2011. 10. U.S. Department of Health and Human Services. Radiation Emergency Medical Department. Ca-DTPA/Zn-DTPA (Diethylentriamene pentaacetate). http://www.remm.nlm. gov/dtpa.htm. Accessed March 17, 2011. 11. Centers for Disease Control and Prevention. Emergency preparedness and response:
Humalog Important Safety Information, continued
Humalog Important Safety Information, continued
Warnings, continued Starting or changing insulin therapy should be done cautiously and only under medical supervision.
Other Side Effects, continued in action of Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those who are fasting, have autonomic neuropathy or renal impairment, are using potassiumlowering drugs, or taking drugs sensitive to serum potassium level).
Hypoglycemia Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia can happen suddenly, and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening. Other Side Effects Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and hypersensitivity. Systemic allergy is less common, but may be life-threatening. Because of the difference
Please see adjacent pages for Brief Summary of full Prescribing Information for Humalog. Please see full user manual that accompanies the pen. Humalog® and Humalog® KwikPen™ are registered trademarks of Eli Lilly and Company and are available by prescription only. Humulin® is a registered trademark of Eli Lilly and Company.
Neupogen fact sheet. http://www.bt.cdc.gov/ radiation/prussianblue.asp. Accessed March 24, 2011. 12. Centers for Disease Control and Prevention. Emergency preparedness and response: acute radiation syndrome fact sheet. http://www. bt.cdc.gov/radiation/ars.asp. Accessed March 17, 2011. 13. Centers for Disease Control and Prevention Emergency preparedness and response: Potassium iodide. http://www.bt.cdc.gov/ radiation/ars.asp. Accessed March 17, 2011. 14. The U.S. Food and Drug Administration. Radiation Safety. http://www.fda.gov/ NewsEvents/PublicHealthFocus/ucm247403. htm. Accessed March 25, 2011.
HUMALOG® INSULIN LISPRO INJECTION (rDNA ORIGIN) BRIEF SUMMARY: Consult package insert for complete prescribing information. INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used without a longer-acting insulin when used in combination therapy with sulfonylurea agents. Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients with type 2 diabetes. CONTRAINDICATIONS: Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or any of its excipients. WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an external insulin pump). External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin. Patients should carefully read and follow the external insulin pump manufacturer’s instructions and the “PATIENT INFORMATION” leaflet before using Humalog. Physicians should carefully evaluate information on external insulin pump use in the Humalog physician package insert and in the external insulin pump manufacturer’s instructions. If unexplained hyperglycemia or ketosis occurs during external insulin pump use, prompt identification and correction of the cause is necessary. The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION). Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using an external insulin pump. Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the need for a change in dosage. PRECAUTIONS: General—Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins. As with all insulin preparations, the time course of Humalog action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress. Hypoglycemia—As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control. Renal Impairment—The requirements for insulin may be reduced in patients with renal impairment. Hepatic Impairment—Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary. Allergy—Local Allergy—As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Systemic Allergy—Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life-
threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving Humulin R® (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053). Antibody Production—In large clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both Humulin R- and Humalogtreatment groups. As expected, the largest increase in the antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy. Usage of Humalog in External Insulin Pumps—The infusion set (reservoir syringe, tubing, and catheter), Disetronic® D-TRON®2,3 or D-TRONplus®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external insulin pump should not be exposed to temperatures above 37°C (98.6°F). In the D-TRON®2,3 or D-TRONplus®2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be selected every 48 hours or less. When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and Storage). Information for Patients—Patients should be informed of the potential risks and advantages of Humalog and alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia, and periodic assessment for diabetes complications. Patients should be advised to inform their physician if they are pregnant or intend to become pregnant. Refer patients to the “PATIENT INFORMATION” leaflet for timing of Humalog dosing (<_15 minutes before or immediately after a meal), storing insulin, and common adverse effects. For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the “PATIENT INFORMATION” leaflet that accompanies the drug product and the User Manual that accompanies the delivery device. They should also reread these materials each time the prescription is renewed. Patients should be instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose of needles. Patients should be advised not to share their Pens with others. For Patients Using External Insulin Pumps: Patients using an external infusion pump should be trained in intensive insulin therapy and in the function of their external insulin pump and pump accessories. Humalog was tested in the MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic®2 H-TRONplus® V100 insulin pump (with plastic 3.15 mL insulin reservoir), and the Disetronic D-TRON®2,3 and D-TRONplus®2,3 insulin pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. The infusion set (reservoir syringe, tubing, catheter), D-TRON ®2,3 or D-TRONplus®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced, and a new infusion site selected every 48 hours or less. Humalog in the external pump should not be exposed to temperatures above 37°C (98.6°F). A Humalog 3 mL cartridge used in the D-TRON®2,3 or D-TRONplus®2,3 pump should be discarded after 7 days, even if it still contains Humalog. Infusion sites that are erythematous, pruritic, or thickened should be reported to medical personnel, and a new site selected. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. Laboratory Tests—As with all insulins, the therapeutic response to Humalog should be monitored by periodic blood glucose tests. Periodic measurement of hemoglobin A1C is recommended for the monitoring of long-term glycemic control. Drug Interactions—Insulin requirements may be increased by medications with hyperglycemic activity, such as corticosteroids, isoniazid, certain lipid-lowering drugs (eg, niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy (see CLINICAL PHARMACOLOGY). Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (eg, octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients. Mixing of Insulins—Care should be taken when mixing all insulins as a change in peak action may occur. The American Diabetes Association warns in its Position Statement on Insulin Administration, “On mixing, physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological response to the insulin mixture may differ from that of the injection of the insulins separately.” Mixing Humalog with Humulin® N or Humulin® U does not decrease the absorption rate or the total bioavailability of Humalog.
Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect compared with regular human insulin. Pregnancy—Teratogenic Effects—Pregnancy Category B—Reproduction studies with insulin lispro have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to Humalog. There are, however, no adequate and wellcontrolled studies with Humalog in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted. Nursing Mothers—It is unknown whether Humalog is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both. Pediatric Use—In a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf life may be reduced (see DOSAGE AND ADMINISTRATION). Geriatric Use—Of the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were 65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed. ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a difference in frequency of adverse events between the 2 treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Whole—allergic reactions (see PRECAUTIONS). Skin and Appendages—injection site reaction, lipodystrophy, pruritus, rash. Other—hypoglycemia (see WARNINGS and PRECAUTIONS). OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent premeal hyperglycemia. When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longeracting insulin being given may need to be adjusted when using Humalog. The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or
femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin preparations, the time course of action of Humalog may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques. Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30, and Humulin® R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted Humalog may remain in patient use for 28 days when stored at 5°C (41°F) and for 14 days when stored at 30°C (86°F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump. Parenteral drug products should be inspected visually before use whenever the solution and the container permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be refilled with insulin. External Insulin Pumps—Humalog was tested in MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic®2 H-TRONplus® V100 insulin pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON®2,3 and D-TRONplus®2,3 pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. HOW SUPPLIED: Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each presentation containing 100 units insulin lispro per mL [U-100]): 10 mL vials NDC 0002-7510-01 (VL-7510) 3 mL vials NDC 0002-7510-17 (VL-7533) 5 x 3 mL cartridges3 NDC 0002-7516-59 (VL-7516) 5 x 3 mL prefilled insulin delivery devices (Pen) NDC 0002-8725-59 (HP-8725) 5 x 3 mL prefilled insulin delivery devices (Humalog® KwikPen™) NDC 0002-8799-59 (HP-8799) 1
MiniMed® and Polyfin® are registered trademarks of MiniMed, Inc. Disetronic®, H-TRONplus®, D-TRON®, and Rapid® are registered trademarks of Roche Diagnostics GMBH. 3 3 mL cartridge is for use in Eli Lilly and Company’s HumaPen ® MEMOIR™ and HumaPen ® LUXURA™ HD insulin delivery devices, Owen Mumford, Ltd.’s Autopen ® 3 mL insulin delivery device, and Disetronic D-TRON ® and D-TRONplus ® pumps. Autopen ® is a registered trademark of Owen Mumford, Ltd. HumaPen ®, HumaPen® MEMOIR™ and HumaPen® LUXURA™ HD are trademarks of Eli Lilly and Company. Other product and company names may be the trademarks of their respective owners. 2
Storage —Unopened Humalog should be stored in a refrigerator (2° to 8°C [36° to 46°F]), but not in the freezer. Do not use Humalog if it has been frozen. Unrefrigerated (below 30°C [86°F]) vials, cartridges, Pens, and KwikPens must be used within 28 days or be discarded, even if they still contain Humalog. Protect from direct heat and light. Use in an External Insulin Pump—A Humalog 3 mL cartridge used in the D-TRON®2,3 or D-TRONplus®2,3 should be discarded after 7 days, even if it still contains Humalog. Infusion sets, D-TRON®2,3 and D-TRONplus®2,3 cartridge adapters, and Humalog in the external insulin pump reservoir should be discarded every 48 hours or less. Literature revised December 7, 2009 KwikPens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA. Pens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France. Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Hospira, Inc., Lake Forest, IL 60045, USA or Lilly France, F-67640 Fegersheim, France. Cartridges manufactured by Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA. www.humalog.com Copyright © 1996, 2008, Eli Lilly and Company. All rights reserved.
Pharmacy Practice News • May 2011
San Diego—When it comes to the use of statins in the ICU, there is more evidence from clinical trials to suggest a benefit in patients undergoing cardiovascular interventions than there is in patients with sepsis, but potential mechanisms of benefit exist for both indications, experts said at the annual meeting of the Society of Critical Care Medicine. The putative benefits for statins in the immediate pre- and postoperative periods for patients having cardiac or vascular surgery are primarily related to their pleiotropic effects, said Judith Kristeller, PharmD, BCPS, associate professor of pharmacy practice, Wilkes University, in Wilkes-Barre, Pa. These include improved endothelial function likely due to a reduction in P-selectin, and increased nitric oxide bioavailability which promotes coronary vasodilation. Statins also have anti-inflammatory and anti-thrombotic effects, which can stabilize plaque and attenuate myocardial ischemia-reperfusion injury. Dr. Kristeller cited two randomized controlled trials of statins in patients undergoing percutaneous coronary intervention (PCI). The first trial, ARMYDA (Atorvastatin for Reduction of Myocardial Damage During Angioplasty), randomized 153 statin-naïve patients to 40 mg per day of atorvastatin or placebo one week before PCI. The investigators reported a reduction in myocardial injury (5% vs. 18%; P=0.025) in favor of atorvastatin, and a reduction in myocardial infarction (Circulation 2004;110:674-678). The NAPLES (Novel Approaches for Preventing or Limiting Events) II study evaluated an intensive dose of atorvastatin—80 mg—given within 24 hours of PCI versus placebo in 668 statin-naïve patients. Like ARMYDA, this study also showed a reduction in myocardial injury (9.5% from 16%; P=0.014) (JACC 2009;54:2157-2163). This benefit was more common in patients who had elevated C-reactive protein at baseline, Dr. Kristeller noted.
Boosting the Effect Evidence also suggests that giving a statin boost to patients already on statins can improve cardiovascular outcomes. A study investigating statin reload in 383 chronic statin users with stable angina or non–ST-elevated acute coronary syndrome (NSTEMI-ACS) undergoing PCI found that patients randomized to 80 mg atorvastatin 12 hours before the procedure, and an additional 40 mg of atorvastatin two hours before PCI, had a 3.7% incidence of major adverse coronary events (MACE) versus 9.4% in patients randomized to placebo (P=0.037) (JACC 2009;54:558-565). In a subgroup analysis, MACE was reduced only in patients
with acute coronary syndrome, and not in patients with stable angina. Statins also have several biochemical effects in cardiac surgery patients, Dr. Kristeller added. The drugs can decrease the systemic inflammatory response associated with cardiopulmonary bypass surgery, decrease the release of myocardial enzymes and prevent myocardial injury. Despite these promising results, caution still is warranted, according to Dr. Kristeller. “There are some limitations with these studies,” she told Pharmacy Practice News. “For instance, studies enrolling statin-naïve patients required extensive screening in order to find sufficient numbers of patients, and that really limits the application of [the findings] to the general population. We also need more studies involving chronic statin users. Placebo control trials in cardiac and vascular surgery patients are unlikely due to ethical restrictions, but we still need to evaluate doses, load-
reducing leukocyte migration and recruitment, reducing the inflammatory response, anticoagulant properties, and direct antibiotic and antifungal effects. A recent meta-analysis published by Janda et al found that 15 of 20 trials showed positive results, one study showed that statins might be associated with harm and four others showed no effect (J Crit Care 2010;25:656.e7-22). The pooled analysis showed that statins were associated with an approximate 40% reduction in mortality; however, there was also significant heterogeneity among the studies, making it difficult to come to a definite conclusion. Another meta-analysis of 15 studies of statins in bacterial infections (11 retrospective, three prospective and one matched cohort/case–control) found 12 that were positive and three that indicated no effect (PLoS One 2010;5:e10702). The overall effect was a very impressive reduction in mortality of almost 50% but, as in Janda’s
‘Unless we have some compelling reasons to change what we now do—which is to follow the package insert recommendations for holding [statins] during acute medical illness—I see no reason to change.’
—Zachariah Thomas, PharmD
ing regimens and timing of statins. We also need to evaluate drug combinations with ß-blockers and ACE [angiotensinconverting enzyme] inhibitors.” For now, the existing evidence suggests that statins can be used safely and effectively preoperatively, Dr. Kristeller concluded.
Statins for Patients With Sepsis As is true for cardiovascular disease, there are many potential reasons why statin therapy would be effective for sepsis, said Zachariah Thomas, PharmD, clinical assistant professor at Rutgers, the State University of New Jersey and surgical ICU pharmacist at Hackensack University Medical Center, in New Jersey. Unfortunately, most of the data that support a benefit are retrospective in nature. Although the results are promising, it is premature to conclude that statins are, in fact, of benefit. “To me, the whole story sounds similar to what we saw a few years ago regarding the beneficial effects of ß-blockers in noncardiac surgery. There were a lot of really well-done retrospective studies, but the positive results were not borne out in [subsequent] prospective trials,” Dr. Thomas said. Possible mechanisms for the way statins would work in sepsis include
meta-analysis, there was significant heterogeneity among the trials. “These are primarily retrospective studies and you can only get so much usable information from them,” Dr. Thomas noted. “These types of data make me cautious. Unless we have some compelling reasons to change what we now do—which is to follow the package insert recommendations for holding these agents during acute medical illness—I see no reason to change.”
Statins Show Exciting Promise C. Michael White, PharmD, professor of pharmacy at the University of Connecticut in Storrs, and director of UCONN/Hartford Hospital EvidenceBased Practice Center in Hartford, considers statins to have exciting potential in the ICU. “Statins are very promising in patients undergoing myocardial procedures such as cardiac surgery,” he said. “We have previously found in an observational study [Curr Med Res Opin 2007;23:1783-1790] that patients on higher-intensity statin therapy at the time of cardiac surgery have a lower risk of post-cardiac surgery atrial fibrillation than those on lower doses, even in the face of high background ß-blocker use.” The finding supports the data showing
Experts Ponder the Role of Statins in the ICU
8 6 4
Figure. Major coronary events in statin- and placebo-treated patients undergoing PCI. MACE, major adverse coronary events; PCI, percutaneous coronoray intervention
that high-intensity statin dosing, or reloading, would be an effective strategy, Dr. White continued. “What we need is a clinical trial that evalu- Scan for statins’ role ates high- ver- in combating ICU infections. sus low-intensity Instructions, page 3. statin therapy and shows additional benefits in the face of high baseline use of ß-blockers.” Because people at high risk for cardiac disease need to achieve low-density lipoprotein (LDL) levels of 60 to 70 mg/dL anyway, the use of highintensity therapy is needed in a majority of patients, he added. “Too often we start too low and never get people to their LDL goal, so if the need for a short-term anti-inflammatory and endothelial-dependent vasodilatory effect hastens that aggressive dose, I’m all for it.” With regard to the role of statins in sepsis and in bacteremia to prevent sepsis from occurring, Dr. White said that he was excited about the drugs’ potential. “The science is promising. Statins can attenuate bacterial cell replication by denying intrabacterial production of cholesterol and cholesterol cascade intermediaries, preventing excessive inflammation in response to bacteria,” he noted. But Dr. White emphasized, as did Dr. Thomas, that although exciting, the preliminary data are observational. “They cannot prove causality—just suggest an association. I look forward to the upcoming clinical trials. In the meantime, I also suggest supportive care with fluids and vasopressors, activated protein C and low-dose steroids in severe sepsis.” Drs. Kristeller, Thomas and White reported no relevant conflicts of interest.
Docetaxel Injection (10 mg/mL concentration)
Clarity of glass
Exclusive Onco-Tain™ packaging for safe handling
PVC reinforced bottom
WARNING: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid Retention See full prescribing information for complete boxed warning • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle • Should not be given if neutrophil counts are < 1500 cells/mm . Obtain frequent blood counts to monitor for neutropenia 3
Indications and Usage Docetaxel Injection is a microtubule inhibitor indicated for: Breast Cancer (BC): single agent for locally advanced metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC
1. Data on ﬁle at Hospira P11-3232A-10.5x13-Mar., 11
• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 • Severe ﬂuid retention may occur despite dexamethasone
Safety Information Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic prostate cancer
Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, ﬂuid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See brief Prescribing Information on reverse side.
Pharmacy Practice News • May 2011
Boosting Dexmedetomidine Dose May Not Enhance Sedation E
scalating doses of the drug dexmedetomidine may not offer greater sedation for critically ill patients, according to a retrospective review. When dexmedetomidine (Precedex, Hospira) received FDA approval in 1999, it was anticipated that the drug would provide an alternative to other agents such as benzodiazepines. In addition, because it does not cause respiratory depression, the agent was viewed
as a way to help liberate patients from mechanical ventilation. The FDA recommended an initiating dose of 1 mcg/kg of predicted body weight, followed by up to 0.7 mcg/kg per hour of continuous infusion for up to 24 hours. “Based on more recent literature, our hospital started allowing clinicians to dose dexmedetomidine up to 1.4 mcg/ kg per hour and we wanted to evaluate the impact of this change,” said Morgan
Jones, PharmD, critical care pharmacy resident at the Ohio State University Medical Center, in Columbus, and lead author of the study. The researchers presented their findings at the 2011 annual meeting of the Society of Critical Care Medicine in San Diego (abstract 759). Previous research had hinted at the safety and efficacy of higher doses, but failed to provide a direct comparison to doses within the FDA-approved label-
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.
Docetaxel Injection, For intravenous infusion only. Initial U.S. Approval: 1996
WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1) • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) • Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) • Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) • Severe fluid retention may occur despite dexamethasone (5.5) –––––––––––––––––––––––––––––––––––––––––––– CONTRAINDICATIONS ––––––––––––––––––––––––––––––––––––––– • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) ––––––––––––––––––––––––––––––––––––––––– WARNINGS AND PRECAUTIONS –––––––––––––––––––––––––––––––––– • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ––––––––––––––––––––––––––––––––––––––––––– ADVERSE REACTIONS –––––––––––––––––––––––––––––––––––––––– Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
ing, Dr. Jones noted. In the new study, he and his colleagues identified 133 patients in the ICU who received dexmedetomidine for continuous sedation. Patients were considered to be in the low-dose group if their maximum dose was less than or equal to 0.7 mcg/kg; a high dose was considered any dose exceeding 0.7 mcg/ kg. The researchers then evaluated which patients maintained a Richmond Agitation and Sedation Scale (RASS) score within the goal range of –1 to +1, the recommended sedation level at the researchers’ home institution. To the team’s surprise, the percentage of RASS scores maintained within the goal range was greater in the 90 patients receiving low doses than the 43 patients in the high-dose group: 60% versus 49%, respectively (P=0.03).
Signs of Undersedation Although the researchers found no difference in the rate of oversedation between the two groups, 19% of RASS scores for patients who received a high dexmedetomidine dose indicated undersedation, vs. 5% in the low-dose group (P=0.05). “If a patient hasn’t achieved adequate sedation within FDA-approval dose range, they may not achieve it with dose escalation,” Dr. Jones concluded. Approximately 38% of patients in both groups experienced hypotension, the most common adverse effect. The researchers hypothesized that genetic polymorphisms within the medication’s target, the central a2 receptor, could predispose some patients to not respond to dexmedetomidine. However, no evidence yet exists of such a link. Study limitations also could explain the surprising results, according to Keith Candiotti, MD, an anesthesiologist at the University of Miami, in Florida. “The spectrum of drug requirements for ICU sedation can be quite large,” Dr. Candiotti said. “Since the study was retrospective, the patients in the high-dose group may have had many reasons why they were harder to sedate. Additionally, the abstract doesn’t tell us the actual doses these patients received. “I will tell you from personal experience that if you increase dexmedetomidine high enough most patients will be sedated,” added Dr. Candiotti. —Lynne Peeples
Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA
Dr. Jones reported no relevant conflicts of interest. Dr. Candiotti has received research funding from, and has served as a consultant for, Hospira.
Pharmacy Practice News • May 2011
Smokers’ Lung Function Likely Mediated by Heavy Metals R
esults of a recent study may help guide the future treatment of patients with chronic obstructive pulmonary disease (COPD). Two analyses of a cross-section of more than 8,000 Americans presented at the 2011 annual meeting of the Society of Critical Care Medicine indicate that high levels of cadmium and cobalt in the urine and blood serum may significantly increase the risk for developing COPD (abstracts 44 and 48). “The findings are based on one of the largest databases around and add another piece of the puzzle [regarding] the effects of heavy metals on lung function,” said Brian Carlin, MD, assistant professor in the Department of Critical Care and Pulmonology at Drexel University College of Medicine, in Pittsburgh. Dr. Carlin was not involved in the study. “Interventions may ultimately target heavy metal concentrations, but at present all we can do to minimize the effects of these metals is reduce industrial exposure and emphasize the role these metals play in first- and secondhand smoke-related COPD.” Shikhar Agarwal, MD, a resident in the Department of Internal Medicine at the Cleveland Clinic, in Ohio, and a colleague, conducted the two analyses. They examined heavy metal concentrations in the urine of 612 patients with COPD and 7,570 subjects without COPD. The subjects were registered in the National Health and Nutrition Examination Survey database, representing a cross-section of the American population. The researchers looked for statistical associations between COPD and urine concentrations of more than a dozen heavy metals. They controlled for the presence of known COPD risk factors, including age, gender, race, hypertension, hyperlipidemia, diabetes, body mass index, C-reactive protein, cardiovascular disease and chronic kidney disease. The researchers found that for every 10-fold increase in the concentration of cadmium in the urine, the risk for COPD nearly tripled (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.8-3.9; P<0.05). The presence of a high level of cobalt also increased the odds of developing COPD, but to a lesser extent (OR, 1.5; 95% CI, 1.01-2.2; P<0.05). A high cadmium level was associated with an increased risk for both emphysema and chronic bronchitis, whereas cobalt was associated only with a higher incidence of chronic bronchitis. In a second analysis, Dr. Agarwal and his colleague examined lead and cadmium levels in serum for a possible correlation with COPD development in 5,709 active smokers (of whom 597 had been diagnosed with COPD), 6,833 former smokers (of whom 725 had COPD) and 13,657 never-smokers (of whom 638 had COPD). Similar to the first analy-
sis, known COPD risk factors were controlled, as well as the presence of high cadmium and lead levels. As expected, current smokers were 2.4 times more likely to have COPD than neversmokers (95% CI, 2.07-2.88; P<0.001). However, after controlling for high cadmium levels, they found the odds of developing COPD dropped to 1.72 times among smokers compared with neversmokers, which suggested
that the relationship between smoking and COPD was mediated by cadmium (95% CI, 1.34-2.19; P<0.001). It also was determined that cadmium concentrations above 0.5 mcg/L in serum increased the risk for emphysema and cadmium levels higher than 0.74 mcg/L in serum were associated with a higher risk for chronic bronchitis. Statistical adjustment for the presence of lead did not affect the risk for COPD.
Dr. Agarwal emphasized the study was not a controlled, interventional trial and the findings only generate hypotheses. “Future research may lead to the development of direct interventions, like antioxidant therapy, that may help reduce or mitigate the effects of heavy metals.” —David Wild Drs. Carlin and Agarwal reported no relevant conflicts of interest.
Donepezil HCl Tablets — another New Unit Dose product from AHP!
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Quality-of-Life Implications for Patients With Hereditary Angioedema Who Self-Administer C1 Inhibitor Timothy Fox, PharmD
Jefferson Home Infusion Service Thomas Jefferson University Hospital Philadelphia, Pennsylvania
Introduction Hereditary angioedema (HAE) is characterized by sudden episodes of brawny, nonpitting edema associated with significant discomfort and pain.1 HAE affects between 1 in 10,000 and 1 in 50,000 persons.2 Although it is a rare disorder, the European Dermatology Forum considers HAE to be a skin disease with significant public health implications.3 Commonly affected areas of the body include the extremities, genitalia, trunk, gastrointestinal (GI) tract, face, and larynx (Figure 1). Up to 30% of untreated patients who experience a laryngeal attack may asphyxiate.4 Approximately 50% of patients with HAE will be symptomatic by age 10 years,5 but diagnosis may lag for 10 to 22 years.6 Undiagnosed patients are at risk for frequent and severe attacks, resulting in 15,000 to 30,000 emergency department (ED) visits annually.7 Patients with the most frequent and severe symptoms can be disabled for 100 to 150 days per year.8 HAE is caused by mutations in the C1 inhibitor (C1INH) gene, which confer C1 esterase inhibitor deficiency.9 The disease is an inherited autosomal dominant disorder, placing 50% of children at risk when one parent is affected. However, 25% of cases are caused by spontaneous mutations. Type 1 HAE results in reduced C1INH protein in the blood and represents 85% of cases.9 Type 2 HAE causes expression of dysfunctional C1INH protein and represents 15% of cases.9 HAE with normal C1INH activity primarily affects women and is thought to be a separate disease entirely, possibly resulting from a factor XII mutation.6 The following discussion briefly reviews the differential diagnosis of HAE, its available therapies for prophylaxis, and methods of administration that may improve patient outcomes.
Pathophysiology of HAE Activation of the contact, complement, and fibrinolytic plasma cascades is
Pharmacy Practice NeWS • may 2011
implicated in HAE attacks. C1INH regulates plasma cascade activity. However, in people with HAE, C1INH levels are 5% to 30% of normal.4 Therefore, the ability to regulate cascade activity is variable in these patients, allowing massive production of vasoactive bradykinin in the contact pathway6 that results in unpredictable and sudden increases in vascular permeability. Excess bradykinin production is thought to be the primary cause of swelling in HAE.10 Inflammation and allergy are not implicated.10
Clinical Presentation One-third of patients with HAE will have erythema marginatum, a serpiginous, nonpruritic rash distinct from urticaria, on the trunk and appendages before or during an attack.6 A tingling sensation also may be felt in the area of an imminent attack.6 Mild attacks may worsen for 24 to 36 hours and resolve over the next 36 to 48 hours, but severe attacks may last for 3 to 5 days.11 Urogenital attacks are not life-threatening but may require treatment. These attacks result from any activity that places pressure on the genitals or pelvic area.9 Extremity attacks are frequent, affecting 96% of HAE patients.12 These attacks cause temporary disability but rarely require emergency treatment. Abdominal attacks can be mild to severe and are the second most frequently reported type of attack.4,12 Abdominal symptoms include pain, vomiting, constipation, diarrhea, and intestinal
obstruction, often suggesting an acute abdomen. Misdiagnosis in these cases may result in unnecessary surgery.4 Patients with abdominal symptoms and hypotension due to fluid loss to the abdomen are at risk for hypovolemic shock and should be treated as emergencies. Extreme swelling may occur during facial attacks. Patients with facial attacks are at high risk for life-threatening laryngeal swelling.4,13
Treatment Danazol, an attenuated androgen, is approved for long-term prophylaxis in adults.14 Danazol increases C1INH concentration in the blood via the liver. In a retrospective study, patients treated with oral danazol reported an 83.8% reduction in the number of attacks per year, with 14.4% of patients still having at least 11 attacks per year.15 However, nearly 80% of patients reported events, including weight gain, menstrual irregularities, female virilization, headache, myalgia, depression, and acne. Serious adverse events (AEs), including myocardial infarction, stroke, deep vein thrombosis, acute pancreatitis, and liver cell adenoma, also were reported infrequently.15 CINRYZE™ (C1 esterase inhibitor [human]) is indicated for routine prophylaxis in adults and adolescents and is administered by IV infusion of 1,000 U every 3 to 4 days.16 In a randomized, double-blind, placebo-controlled trial in patients with frequent attacks (≥2 per month), patients receiving C1INH
Figure 1. Facial and extremity swelling in patients with HAE. Images used with permission from HAEA.org.
reported half the number of attacks compared with placebo. Attacks in the group receiving C1INH were significantly less severe and significantly shorter in duration compared with the placebo group. AEs are uncommon and include upper respiratory infection, sinusitis, rash, and headache.16
Self-Administration of C1INH CINRYZE™ also is approved for patient self-administration and can be reconstituted via the Mix2Vial® transfer device. The Mix2Vial® allows for needleless reconstitution and may reduce waste and product loss due to reconstitution errors (Figure 2). For each 10-mL dose, 2 vials of CINRYZE™ must be prepared using a second Mix2Vial® transfer device. All candidates for self-administration will require training by a health care professional prior to beginning self-administration. Consensus recommendations for developing a home therapy program exist.17 Prior to its approval for self-administration, patients were dependent on physician and emergency services for C1INH administration, where they experience considerable inconvenience and delay in treatment. A study in Europe of C1INH self-administration for routine prophylaxis has shown reduced frequency of attacks and improved quality of life (QoL) after patients began self-administration.18 Many of the patients in one study had between 5 and 60 attacks per year with a median duration of 3 days per attack.18 For
the Science Behind PoSitive Patient outcomeS
100 80 60 40 20 0
Physical Role Function Physical
Mental Role Social Health Emotional Function
Figure 3. Improvement in Short-Form Health Survey quality-of-life scores following initiation of C1INH self-administration.18
therapy. Patients who have been studied after entry into a home therapy program had substantially improved QoL and were able to pursue more normal work and family lives.
Note. For each 10 mL dose, 2 vials of ciNryZeTM must be prepared using a second mix2Vial® transfer device.
those patients who experienced the most frequent attacks, the 3-day duration translates into 180 days of disability per year. Figure 3 illustrates the improvements in QoL scores captured by the Short-Form Health Survey after patients began self-administration of C1INH (P<0.05 for all physical and mental categories; Figure 3).18 The cost of C1INH therapy should be considered in the context of high patient disability, where frequent and severe attacks significantly reduce QoL and patient productivity.18,19 Self-administration of C1INH may increase usage of this medication in patients who were previously undertreated because of increased access to the medication. However, studies suggest that C1INH use in the home does not increase total C1INH usage over hospital-based treatment with C1INH.19,20 Normalization of patient life through convenient and appropriate C1INH
therapy also may reduce costs to health care systems by obviating the need for frequent clinic and ED visits and by reducing the number of episodes requiring hospitalization.
Summary HAE is caused by inherited C1INH deficiency that results in overproduction of bradykinin. Massive bradykinin release leads to attacks of swelling that may be life-threatening. Prophylaxis reduces the frequency and severity of these attacks. Each facial attack and each abdominal attack with hypotension potentially constitute an emergency and should be thoroughly evaluated. CINRYZE™ and danazol are FDA-approved for long-term prophylaxis. CINRYZE™ has an additional approval for patient self-administration and may be a safer alternative to long-term androgen
Financial Disclosure Statement Dr. Fox received an honorarium from ViroPharma Incorporated for his authorship of this manuscript.
8. Cicardi M, Zingale L. How do we treat patients with hereditary angioedema. Transfus Apher Sci. 2003;29(3):221-227. 9. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161(20):2417-2429. 10. Davis ae, 3rd. mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin North Am. 2006;26(4):633-651. 11. Zuraw BL. Hereditary angiodema: a current state-ofthe-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new? Ann Allergy Asthma Immunol. 2008; 100(1 suppl 2):S13-S18. 12. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med. 1976;84(5):580-593. 13. Bork K, Barnstedt SE. Laryngeal edema and death from asphyxiation after tooth extraction in four patients with hereditary angioedema. J Am Dent Assoc. 2003;134(8):1088-1094.
14. Danazol [package insert]. Philadelphia, Pa: Lannett; 2007.
1. Frank MM. Hereditary angioedema: the clinical syndrome and its management in the United States. Immunol Allergy Clin North Am. 2006;26(4):653-668.
15. Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol. 2008; 100(2):153-161.
2. Bowen T, Cicardi M, Bork K, et al. Hereditary angiodema: a current state-of-the-art review, VII: Canadian hungarian 2007 international consensus algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008;100(1 suppl 2):S30-S40. 3. Greaves MW. Skin diseases with high public health impact. Urticaria and angioedema. Eur J Dermatol. 2008;18(1):105-106. 4. Agostoni A, Aygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third c1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004;114(3 suppl):S51-S131. 5. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274. 6. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036.
16. CINRYZE [package insert]. Exton, PA: ViroPharma Biologics; 2010. 17. Gompels mm, Lock rJ, abinun m, et al. c1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005;139(3):379-394. 18. Bygum A, Andersen KE, Mikkelsen CS. Self-administration of intravenous c1-inhibitor therapy for hereditary angioedema and associated quality of life benefits. Eur J Dermatol. 2009;19(2):147-151. 19. Longhurst hJ, carr S, Khair K. c1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option. Clin Exp Immunol. 2007;147(1):11-17.
Figure 2. Reconstitution of CINRYZETM using the Mix2Vial® transfer device reduces sharps and reconstitution error.
Editorial support was provided by Clay Isbell and Innovative Strategic Communications LLC and was funded by ViroPharma Incorporated.
7. Moore GP, Hurley WT, Pace SA. Hereditary angioedema. Ann Emerg Med. 1988;17(10):1082-1086.
20. Longhurst H, O’Grady C. Home therapy for HAE: the Barts experience. J Allergy Clin Immunol. 2004;114:S99-S100.
Pharmacy Practice NeWS • may 2011
Pharmacy Practice News • May 2011
Circumventing Drug–Drug Interactions In Post–Kidney Transplant Recipients With Metabolic Syndrome Niki S. Mehdizadegan PharmD Candidate
Tuan Huynh PharmD Candidate
Charmaine D. Rochester, PharmD, BCPS, CDE Associate Professor, Department of Pharmacy Practice and Science University of Maryland School of Pharmacy Baltimore, Maryland
rug–drug interactions (DDIs) occur when one drug (the precipitant drug) alters the pharmacokinetics and/or pharmacodynamics of another drug (the object drug) when they are taken concurrently, leading to toxicity or
treatment failure.1 DDIs are of considerable concern for health care professionals
Scan for PDF of this review. Instructions, p. 3
because they are responsible for 2.8% of all hospital admissions,2 and, according to a survey by the American Society of Health-System Pharmacists, patients rank DDIs as one of their greatest concerns when they are in a hospital or health system.3
Significant DDIs can occur in post–kidney transplant patients who require immunosuppressive therapies to prevent organ rejection, including interleukin-2 receptor antagonists, calcineurin inhibitors, antiproliferatives, corticosteroids, mammalian target of rapamycin (mTOR) inhibitors, and monoclonal and polyclonal antibodies.4 Metabolic syndrome, a constellation of abnormalities including dyslipidemia, insulin resistance, high blood pressure, and obesity, affects one-fourth of all Americans and is a common finding in renal transplant recipients.5,6 Metabolic syndrome is considered an independent risk factor leading to chronic kidney disease (CKD) and ultimately renal transplantation, and it also can be exacerbated by immunosuppressive therapies.7,8 Therefore, it is not surprising that in addition to immunosuppressive agents, post– kidney transplant recipients often require antihypertensive agents, cholesterol-lowering drugs, and antihyperglycemic agents.9-12 Additionally,
the literature suggests that cardiovascular morbidity is the most common cause of death in post–kidney transplant patients.13 Health care professionals face significant challenges regarding DDIs, because many immunosuppressive therapies have clinically significant interactions with other medications in the post– kidney transplant recipient’s medication profile. This article aims to assist pharmacists in identifying clinically relevant DDIs and circumventing these interactions in post–kidney transplant patients who have metabolic syndrome. As part of a multidisciplinary team, pharmacists can use the information provided in the text, case presentation, and Tables 1 through 3, combined with diligent screening and monitoring, to help identify and circumvent DDIs and prevent negative outcomes in post–kidney transplant recipients who have metabolic syndrome. Text continues on page 42, tables on page 39
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Warfarin Therapy COURTNEY KRUEGER, PHARMD, BCPS Clinical Assistant Professor Drug Information Group University of Illinois at Chicago College of Pharmacy Chicago, Illinois
arfarin, a vitamin K antagonist, has been approved for use as an anticoagulant for nearly 60 years.1 It is not only the most commonly used oral anticoagulant in the United States, but
it also ranks among the top 40 most commonly used medications in adult patients who are not hospitalized.2,3 Although warfarin is frequently prescribed, it is not viewed favorably due to its complicated management.
In fact, a recent study showed that more than 10% of warfarin-treated patients discontinued therapy within 3 months and nearly 20% were not monitored during therapy.4 This is alarming considering that inappropriate use or insufficient monitoring of warfarin can result in serious thromboembolic or hemorrhagic events. The Institute for Safe Medication Practices has deemed warfarin a high-alert medication due to its risk for causing patient harm if it is used in error.5 This review discusses the complicated nature of warfarin therapy, including extensive monitoring requirements and significant adverse events (AEs), as well as emerging alternatives to warfarin.
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
Pharmacology and Pharmacokinetics Warfarin inhibits the γ-carboxylation of the vitamin K– dependent coagulation factors II, VII, IX, and X, as well as the anticoagulant proteins C and S.3,6,7 Although warfarin is absorbed rapidly after oral administration, the therapeutic effect of warfarin is delayed for a week or more due to the long half-lives of factors II, IX, and X.3,6,7 Compared with other vitamin K–dependent coagulation factors, such as factor II, which has a 50-hour half-life, factor VII has a much shorter half-life (approximately 6 hours), which results in elevation of the prothrombin time (PT) shortly after administration. Clinicians must use caution because this early elevation does not reflect a full
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anticoagulant effect. Additionally, protein C has a halflife of 8 hours; thus, hypercoagulability may result. Unfortunately, a number of pharmacokinetic drug interactions occur with warfarin because it is highly bound to plasma proteins and metabolized via the cytochrome P450 (CYP) enzyme system.6,7 Different CYP enzymes are responsible for the metabolism of the 2 warfarin enantiomers. The more potent S-enantiomer is metabolized by CYP2C9 and the R-enantiomer by CYP1A2, CYP2C19, and CYP3A4.
The anticoagulant properties of warfarin are useful in multiple clinical situations including primary and secondary prophylaxis of venous thromboembolism (VTE), prevention of systemic embolism and stroke in patients with prosthetic heart valves or atrial fibrillation (AF), and, in some patients, primary or secondary myocardial infarction (MI) prophylaxis.3 The American College of Chest Physicians (ACCP) 2008 Practice Guidelines on antithrombotic and thrombolytic therapy provide an indepth review of these indications as well as a chapter on the management of vitamin K antagonists.8
Patients with AF are at risk for systemic embolism and stroke.11,12 The risk for stroke in a patient with AF commonly is determined using the Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke (doubled) (CHADS2) score.13 This risk stratification tool assigns 2 points to patients with prior stroke or transient ischemic attack (TIA) and 1 point for each of the following: heart failure, hypertension, diabetes, and age older than 75 years. The 2006 American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) guidelines for AF recommend that patients with 1 moderate-risk factor receive either aspirin or warfarin and those with a high-risk factor or those with more than 1 moderate-risk factor receive warfarin (risk factors, Table 1).12 The ACCP guidelines have similar recommendations.11 Lifelong therapy is recommended unless the patient develops contraindications. Patients who are not candidates for warfarin therapy (eg, those at high risk for bleeding, those who cannot be appropriately monitored) may receive the combination of aspirin and clopidogrel.14,15
PRIMARY VTE PREVENTION
Primary prevention of VTE is most commonly required for hospitalized patients; however, therapy may be continued after discharge for some patients who are at risk for a VTE.9 Typically, heparin, a lowmolecular-weight heparin (LMWH), or the injectable factor Xa inhibitor fondaparinux (Arixtra, GlaxoSmithKline) are recommended. However, warfarin is a potential option for patients undergoing orthopedic surgery, according to the ACCP guidelines. Warfarin may be continued up to 35 days after such surgery. Low-dose (sometimes referred to as mini-dose) warfarin has been used to prevent clotting of central catheters in patients with cancer, but this is no longer recommended.
Aspirin therapy is typically recommended over warfarin therapy for most patients who have had an MI; however, some patients may benefit from warfarin and aspirin combined.16,17 The ACCP guidelines recommend that patients with another indication for warfarin (eg, AF or VTE), an intracardiac thrombus, severe heart failure, or those with a large anterior MI be given low-dose aspirin with warfarin for at least 3 months.16 Similarly, the ACCP guidelines recommend aspirin for the primary prevention of MI; however, they state that warfarin may be used for patients who are at high risk for MI based on Framingham score.
SECONDARY VTE PREVENTION Warfarin commonly is used for secondary prevention of VTE in patients who have a deep vein thrombosis (DVT) or pulmonary embolism (PE).10 The purpose of anticoagulation in this situation is 2-fold: minimizing expansion of the current embolus and reducing the risk for recurrent events. Warfarin should be initiated at the time of diagnosis and continued for a minimum of 3 months. Patients with VTE initially should receive treatment with concomitant heparin, LMWH, or fondaparinux and warfarin due to the delayed anticoagulant properties of warfarin. These agents should be overlapped for at least 5 days and until the international normalized ratio (INR) is at least 2.0 for 24 hours. Patients who have a reversible risk factor for VTE (eg, an extended period of immobilization) may discontinue therapy after 3 months, whereas patients without a known risk factor should be considered candidates for longer treatment duration.
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PROSTHETIC HEART VALVES Anticoagulant therapy is recommended for patients with prosthetic valves.18 In patients with newly placed valves, heparin or LMWH should be given with warfarin for at least 2 days. Anticoagulation also is recommended for some patients with mitral valve disease or in patients with mitral valve prolapse. An in-depth discussion of warfarin therapy in these patients is outside the scope of this review. Further information can be found in the ACCP guidelines in the section titled “Valvular and Structural Heart Disease.”18
Dosing and Monitoring INITIATION
Several factors complicate the initiation of warfarin therapy. First, consideration must be given to the fact that vitamin K–dependent clotting factors are not immediately depleted.7 Therefore, when an immediate anticoagulant effect is desired, therapy with heparin, LMWH, or fondaparinux must be overlapped with
warfarin.3 Additional consideration must be given to the fact that there is great interpatient and intrapatient variability in response to warfarin.19,20 Thus, no clear-cut initial dose is suitable for every patient. Much research effort has been directed at predicting dosing requirements for individual patients. Factors such as age, gender, body size, vitamin K intake, and concomitant medications or disease states affect warfarin requirements, and these should be taken into consideration when choosing an initial dose.3,21 Recently, pharmacogenomic studies have revealed that variant alleles of the genes for CYP2C9, which is responsible for the metabolism of the S-isomer of warfarin, and vitamin K epoxide reductase (VKOR), a target site for warfarin’s action, both lower warfarin dose requirements.22,23 Multiple studies have compared a 5-mg initial warfarin dose with a variety of other regimens, including a 2.5- or 10-mg initial dose or a dose calculated on patient-specific parameters such as age. A 2003 publication by Kovacs et al concluded that a 10-mg initial dose resulted in more rapid achievement of a therapeutic INR compared with a 5-mg dose.24 However, 2 early studies comparing 5- and 10-mg doses concluded that a 5-mg dose of warfarin more effectively achieved therapeutic INRs than a 10-mg dose,25-26 and a recent systematic review concluded that an initial dose of 10 mg has no benefit over 5 mg.19 The ACCP guidelines recommend initial warfarin doses between 5 and 10 mg for the first 1 or 2 days but suggest that lower initial doses can be considered in elderly individuals and in patients with heart failure, liver disease, poor nutritional status, and in those at high risk for bleeding.3 One cohort study revealed that older women require the lowest warfarin doses and that a 5-mg dose of warfarin will result in excessive anticoagulation in more than 80% of this population; thus, a lower initial dose should be chosen for patients in this group.27 Concomitant medications that may alter sensitivity to warfarin or increase the risk for bleeding also should be considered when choosing an initial dose.3 Wittkowsky et al found that more than 80% of patients prescribed warfarin were receiving concomitant therapy with a potentially interacting drug.28 This study was conducted with data from a pharmacy claims database and may underestimate the true potential for drug interactions because nonprescription medications, including herbal products and supplements, were not identified. Thus, a thorough medication history must be collected at therapy initiation. In 2007, the FDA recommended incorporation of pharmacogenetic information in the warfarin labeling.3,29 The prescribing information was updated again in 2010 with more specific dosing information for VKORC1 and CYP2C9 genotypes.3,30 However, pharmacogenetic testing is not required, and studies on the utility of pharmacogenetic dosing algorithms have been conflicting.31,32 Pharmacogenetic testing is not used frequently in clinical practice today; however, ongoing research in this area will better define its role.
Table 1. ACC/AHA/ESC Stroke Risk Factors for Patients With AF Moderate-risk Factors
• Age ≥75 y • Hypertension
• Previous stroke, TIA, or embolism
• Heart failure
• Mitral stenosis
• LVEF ≤35%
• Prosthetic valve
• Diabetes mellitus ACC, American College of Cardiology; AF, atrial fibrillation; AHA, American Heart Association; ESC, European Society of Cardiology; LVEF, left ventricular ejection fraction; TIA, transient ischemic attack Based on reference 12.
Monitoring of PT typically is used to determine the appropriate maintenance dose of warfarin for a specific patient.3,21 The PT level is a marker of the reduction in factors II, VII, and X. Because the PT is not standardized, it is converted to a standard measure and reported as the INR. Typically, an INR of 2.0 to 3.0 is considered appropriate for most indications. A higher INR goal of 2.5 to 3.5 is recommended for some patients with prosthetic heart valves and those who have had recurrent events at a lower INR level.3,18 Lower INR goals may be set if warfarin is being used for primary prophylaxis of MI or for patients with a VTE who have received 6 months of therapy.3 Monitoring should be initiated within the first few days of therapy (in hospitalized patients, the INR often is obtained daily after the second or third dose), and subsequent doses should be adjusted as needed.3 A 2008 consensus statement from The Anticoagulation Forum recommended monitoring 2 or 3 times weekly for the first 7 to 10 days or until a stable INR and dose are reached.21 Algorithms and computer programs are available to assist in adjusting maintenance doses to sustain an INR in the therapeutic range. Illness, medication changes, or alterations in diet may affect warfarin requirements, and clinicians should remain vigilant for circumstances necessitating more frequent monitoring or dosage adjustments. Patient adherence to the medication regimen also must be closely monitored. Individuals who achieve a stable INR still must be monitored at least every 4 weeks.3 Generally, the weekly warfarin dose may be adjusted by 5% to 20% to correct INR measurements outside of the therapeutic range. In some cases in which the INR is minimally outside of the desired range or a causative factor for the alteration is identified, it may be appropriate to merely increase the frequency of monitoring, with the assumption that the INR will return to the therapeutic range without a dosage adjustment.3,33 The ACCP recommendations for the management of elevated INRs in patients who do not have significant bleeding are summarized in Table 2.3
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Table 2. ACCP Recommendations for Warfarin Management In Patients With Elevated INRs Without Significant Bleeding INR
Above therapeutic range but <5.0
• Lower or omit dose • Increase monitoring frequency • Resume therapy at an appropriate dose when therapeutic INR is achieved For minimally elevated INRs: • No dose reduction may be required
≥5.0 but <9.0
• Omit 1 or 2 doses • Increase monitoring frequency • Resume therapy at an appropriate dose when therapeutic INR is achieved For patients at increased bleeding risk: • Omit dose • Administer 1 to 2.5 mg of oral vitamin Ka For patients in need of urgent surgery: • Administer 1 to 5 mg of oral vitamin K • If the INR remains elevated at 24 hours, a 1- to 2-mg oral vitamin K dose may be administered
• • • • •
Hold warfarin Administer 2.5 to 5 mg of oral vitamin K Increase monitoring frequency Administer additional vitamin K if necessary Resume therapy at an appropriate dose when therapeutic INR is achieved
For additional information on the use of vitamin K, see section on adverse effects.
ACCP, American College of Chest Physicians; INR, international normalized ratio Based on reference 3.
A recent randomized trial comparing the administration of 1.25 mg of vitamin K with placebo for patients with supratherapeutic INRs of 4.5 to 10 with no bleeding found no differences in bleeding or thromboembolism between groups.34 This study supports the recommendation that vitamin K often is unnecessary for patients with mild to moderate supratherapeutic INRs. Patients with an isolated subtherapeutic INR have a low risk for thromboembolism, and administration of a rapid-acting anticoagulant rarely is necessary.3,35 Warfarin monitoring can be conducted by the prescriber in his or her individual practice; however, evidence suggests that patients who receive warfarin monitoring at an anticoagulation clinic or through a designated anticoagulation monitoring service have better outcomes.3 A 2006 systematic review showed that patients managed in community practice spent 8.3% less time in therapeutic range than patients managed in an anticoagulation clinic. 36 Pharmacist-managed anticoagulation clinics also have been shown to improve outcomes. One study found that patients managed by a pharmacist-run anticoagulation clinic not only spent more time in therapeutic range than patients managed by their physician but also had fewer thromboembolic events and less bleeding.37
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PERIOPERATIVE MANAGEMENT Warfarin often is discontinued before a major surgical procedure to minimize the risk for bleeding.38 Unfortunately, it must be discontinued several days in advance of any surgical procedure to allow regeneration of coagulation factors. The ACCP guidelines suggest that warfarin should be discontinued 5 days prior to surgical intervention. Therapy may be resumed 12 to 24 hours after the procedure. Patients with elevated INRs at the time of the procedure may require vitamin K administration. Heparin or LMWH often is used to provide perioperative anticoagulation while warfarin therapy is held (a process called bridging).38 Bridging is recommended for patients with a history of VTE, AF, or mechanical valves, unless they are at low risk for thromboembolism. Lowrisk patients are defined in Table 3.38
Adverse Effects BLEEDING COMPLICATIONS Bleeding is the primary adverse effect associated with warfarin therapy. In clinical trials, the risk for major bleeding has been reported to increase by 0.3% to 0.5% per year in patients treated with warfarin compared with those not receiving anticoagulation therapy.39 Risk
factors for bleeding include use of concomitant medications affecting coagulation, patient characteristics (eg, age, concomitant disease states), and the intensity and duration of anticoagulation therapy.39,40 Vitamin K should be administered to all patients with clinically significant bleeding.3,41,42 Intravenous administration of vitamin K is recommended for patients with serious or life-threatening bleeding. The subcutaneous route is not recommended because of variable absorption, and the intramuscular route should be avoided because it is associated with hematoma at the administration site.41 The ACCP guidelines recommend a 10-mg initial dose of vitamin K.3 It can be readministered every 12 hours if the INR remains elevated. Vitamin K alone is insufficient for patients with serious or life-threatening bleeding. Options for additional therapy include fresh frozen plasma, prothrombin complex concentrates (PCCs), or recombinant factor VIIa.3 Fresh frozen plasma contains clotting factors that are necessary to replete those inhibited by warfarin; however, disadvantages of this treatment include a long infusion time and risk for fluid overload.3,41 The use of PCCs may be advantageous for some patients. PCCs (Bebulin VH, Baxter; Profilnine SD, Grifols) are derived from plasma and contain varying concentrations of factors II, VII, IX, and X. Individualized dosing of PCCs based on INR and body weight is recommended.41,42 Recombinant factor VIIa (NovoSeven, NovoSeven RT, NovoNordisk) is a recommended option in the 2008 ACCP guidelines; however, a 2008 review of the literature recommended against use of this agent because of a lack of quality evidence in favor of its use.43 A more recent retrospective study showed an improved time to therapeutic INR with the use of factor VIIa in patients receiving warfarin with a traumatic intracranial hemorrhage but did not show improved survival.44
OTHER ADVERSE EVENTS Warfarin is associated with AEs other than hemorrhage, the most significant of which are thrombotic complications that typically occur early after therapy initiation.3,45 Skin necrosis may occur as a result of hypercoagulability caused by a rapid decline in protein C levels. Patients typically present with thrombosis of capillaries and venules in subcutaneous tissue. If this situation develops, an alternative anticoagulant may be required; however, some patients may receive another trial of warfarin initiated at a very low dose.
Warfarin Alternatives Only recently have viable oral alternatives to warfarin emerged.46,47 These agents are direct inhibitors of either thrombin or factor Xa. They do not require INR monitoring and offer a faster onset and more predictable response than warfarin.45
DABIGATRAN ETEXILATE Dabigatran etexilate (Pradaxa, Boehringer Ingelheim) is a prodrug of dabigatran that directly inhibits thrombin (factor IIa).48 It has been FDA-approved to reduce
Table 3. Patients at Low Risk For Thromboembolism Condition
Patients Defined as Low Risk
Single event occurring >1 y ago with no current risk factor for VTE
Bi-leaflet aortic valve without AF and no additional risk factors for stroke
CHADS2 score â‰¤2 with no history of stroke or TIA
AF, atrial fibrillation; CHADS2, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke (doubled); TIA, transient ischemic attack; VTE, venous thromboembolism Based on reference 38.
the risk for stroke in patients with AF. Parenteral direct thrombin inhibitors such as bivalirudin (Angiomax, The Medicines Company) and argatroban (GlaxoSmithKline) have been available for some time, but dabigatran is the first oral agent available in the United States (ximelagatran did not reach the US market due to hepatotoxicity associated with its use). A Phase III open-label noninferiority trial known as RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) compared dabigatran at a dose of either 110 or 150 mg twice daily with warfarin adjusted to maintain an INR of 2.0 to 3.0 in patients with AF at risk for stroke.49 The primary efficacy outcome was occurrence of stroke or systemic embolism; major hemorrhage was the primary safety outcome. The rate of stroke or systemic embolism was 1.69% per year with warfarin compared with 1.53% and 1.11% per year with dabigatran 110 and 150 mg, respectively. Dabigatran was deemed noninferior to warfarin. Major bleeding was lower in patients receiving dabigatran 110 mg (2.71% per year), but the rates of major bleeding were similar for the 150-mg dose (3.11% per year) and warfarin (3.36% per year). Dyspepsia was the most common AE reported with dabigatran. Dabigatran also has shown noninferiority to warfarin in the treatment of VTE50; however, this use is not approved by the FDA. In February 2011, the ACC/AHA/Heart Rhythm Society (HRS) released an update to the AF guidelines, recommending dabigatran as a warfarin alternative.51 The recommendation is specific to patients with paroxysmal or permanent AF who have additional risk factors for stroke but do not have a prosthetic valve or hemodynamically unstable valve disease. Patients with severe renal or liver disease are not candidates for dabigatran, and the guideline cautions that patients who are well controlled on warfarin will receive little benefit from a switch to dabigatran therapy. The recommended dose of dabigatran for patients with AF is 150 mg twice daily for patients with normal renal function.48 The dose must be reduced in patients with renal dysfunction; the recommended dose is 75 mg
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twice daily in patients with a creatinine clearance of 15 to 30 mL per minute. The prescribing information for dabigatran provides detailed information on how to change from or to warfarin and from or to parenteral anticoagulants. Dabigatran etexilate is a substrate for P-glycoprotein.48 Therefore, concomitant administration with drugs known to induce this enzyme may result in lower serum concentrations of dabigatran (concomitant use generally should be avoided). P-glycoprotein inhibitors may cause increased dabigatran serum concentrations; however, pharmacokinetic studies with ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin revealed that no dose adjustments are necessary when dabigatran is used with these agents.
Rivaroxaban (Xarelto, Ortho) and apixaban (Pfizer) are oral factor Xa inhibitors that are being studied as anticoagulants but have not yet received FDA approval.52 Factor Xa inhibitors offer an obvious advantage to warfarin with respect to reduced monitoring, but they also may have advantages over thrombin inhibitors because they have been shown to cause less bleeding in animal studies and are not associated with rebound hypercoagulability.47,52 These 2 agents have very similar pharmacokinetic profiles, with high bioavailability, short half-lives, and CYP3A4 metabolism. Rivaroxaban may be dosed once or twice daily, whereas apixaban must be dosed twice daily. Rivaroxaban has been compared with warfarin for the treatment of VTE and was found to be noninferior for preventing recurrent VTE and to have similar bleeding rates.53 Preliminary results of Rocket AF (Randomized, Double-Blind Study Comparing Once Daily Oral Rivaroxaban With Adjusted-Dose Oral Warfarin for the Prevention of Stroke in Subjects With Non-Valvular Atrial Fibrillation) were released at the AHA meeting last fall.54 Rivaroxaban again performed favorably, with the study indicating noninferiority to warfarin for prevention of stroke or systemic embolism. Similar trials with apixaban are under way.47
OTHER INVESTIGATIONAL AGENTS A number of other oral factor Xa inhibitors are in Phase II or III trials, including betrixiban (Portola), darexaban (Astellas), edoxaban (Daiichi-Sankyo), and letaxaban (Takeda).55 Additionally, tecarfarin (Aryx Therapeutics), a medication that has the same mechanism of action as warfarin but is not metabolized through the CYP pathway, is under investigation. In theory, tecarfarin may result in anticoagulant therapy that is less cumbersome to manage.46 Although a small study in patients with AF showed improved time within the therapeutic range with tecarfarin, further study is necessary.56
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SAFETY CONCERNS WITH WARFARIN ALTERNATIVES Since the approval of dabigatran, some experts have expressed concern with the lack of required monitoring.57,58 Although clinical practice guidelines recommend at least monthly INR monitoring with warfarin, no such parameters exist for dabigatran because INR monitoring is unnecessary.3 Typically, warfarin monitoring sessions not only ensure therapeutic INR levels but also serve as opportunities to uncover potential drug interactions, as well as bleeding complications or symptoms of a thromboembolic event. Patients receiving dabigatran or other anticoagulants are still at risk for these complications; therefore, clinicians must provide appropriate follow-up and monitoring.
Conclusion Warfarin has been the mainstay in oral anticoagulation for decades, but its complicated dosing and frequent monitoring requirements make therapeutic management cumbersome for clinicians and patients alike. The recent approval of dabigatran, an oral direct thrombin inhibitor, provides an alternative option for patients with AF receiving warfarin. Future studies of dabigatran and other alternative agents may minimize the role of warfarin in clinical practice.
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Majerus PW, Tollefsen DM. Blood coagulation and anticoagulant, thrombolytic, and antiplatelet drugs. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilmanâ€™s the Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006:1467-1488.
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Evidence-Based Clinical Practice Guidelines (8th ed.). Chest. 2008;133(6 suppl):381S-453S. 10. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.). Chest. 2008;133(6 suppl):454S-545S. 11. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.).Chest. 2008;133(6 suppl):546S-592S.
predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther. 2010;87(4):459-464. 24. Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with lowmolecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med. 2003;138(9):714-719. 25. Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med. 1997;126(2):133-136.
12. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation— executive summary: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol. 2006;48(4):854-906.
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28. Wittkowsky AK, Boccuzzi SJ, Wogen J, Wygant G, Patel P, Hauch O. Frequency of concurrent use of warfarin with potentially interacting drugs. Pharmacotherapy. 2004;24(12):1668-1674.
14. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526):1903-1912.
29. Food and Drug Administration. MedWatch The FDA Safety Information and Adverse Event Reporting Program. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm152972.htm. Accessed April 4, 2011.
15. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;57(2):223-242. 16. Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.). Chest. 2008;133(6 suppl):776S-814S. 17. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary: a report of the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines on the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol. 2004;44(3):671-719. 18. Salem DN, O’Gara PT, Madias C, Pauker SG. Valvular and structural heart disease: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th ed.). Chest. 2008;133 (6 suppl):593S-629S. 19. Heneghan C, Tyndel S, Bankhead C, et al. Optimal loading dose for the initiation of warfarin: a systematic review. BMC Cardiovasc Disord. 2010;10:18. 20. Lazo-Langner A, Kovacs MJ. Predicting warfarin dose. Curr Opin Pulm Med. 2010;16(5):426-431. 21. Garcia DA, Witt DM, Hylek E, et al. Delivery of optimized anticoagulant therapy: consensus statement from the Anticoagulation Forum. Ann Pharmacother. 2008;42(7):979-988. 22. Schwarz UI, Ritchie MD, Bradford Y, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358(10):999-1008. 23. Cavallari LH, Langaee TY, Momary KM, et al. Genetic and clinical
27. Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest. 2005;127(6):2049-2056.
30. Food and Drug Administration. http://www.accessdata.fda.gov/ drugsatfda_docs/label/2010/009218s108lbl.pdf. Accessed April 4, 2011. 31. Kangelaris KN, Bent S, Nussbaum RL, Garcia DA, Tice JA. Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin. J Gen Intern Med. 2009;24(5):656-664. 32. The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360(8):753-764. 33. Schulman S, Melinyshyn A, Ennis D, Rudd-Scott L. Singledose adjustment versus no adjustment of warfarin in stably anticoagulated patients with an occasional international normalized ratio (INR) out of range. Thromb Res. 2010;125(5):393-397. 34. Crowther MA, Ageno W, Garcia D, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med. 2009;150(5):293-300. 35. Clark NP, Witt DM, Delate T, et al for the Warfarin-Associated Research Projects and Other Endeavors Consortium. Thromboembolic consequences of subtherapeutic anticoagulation in patients stabilized on warfarin therapy: the low INR study. Pharmacotherapy. 2008;28(8):960-967. 36. van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006;129(5):1155-1166. 37. Chiquette E, Amato MG, Bussey HI. Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and healthcare costs. Arch Intern Med. 1998;158(15):1641-1647. 38. Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.). Chest. 2008;133(6 suppl):299S-339S.
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39. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.). Chest. 2008;133(6 suppl):257S-298S. 40. Makris M, van Veen JJ, Maclean R. Warfarin anticoagulation reversal: management of the asymptomatic and bleeding patient. J Thromb Thrombolysis. 2010;29(2):171-181. 41. Levi M. Epidemiology and management of bleeding in patients using vitamin K antagonists. J Thromb Haemost. 2009;7 (suppl 1):103-106. 42. Bershad EM, Suarez JI. Prothrombin complex concentrates for oral anticoagulant therapy-related intracranial hemorrhage: a review of the literature. Neurocrit Care. 2010;12(3):403-413. 43. Rosovsky RP, Crowther MA. What is the evidence for the off-label use of recombinant factor VIIa (rFVIIa) in the acute reversal of warfarin? ASH evidence-based review 2008. Hematology Am Soc Hematol Educ Program. 2008:36-38. 44. Nishijima DK, Dager WE, Schrot RJ, Holmes JF. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med. 2010;17(3):244-251. 45. Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM. Warfarininduced skin necrosis. J Am Acad Dermatol. 2009;61(2):325-332. 46. Ansell J. Warfarin versus new agents: interpreting the data. Hematology Am Soc Hematol Educ Program. 2010;2010:221-228. 47. Ruff CT, Braunwald E. Review: Will warfarin ever be replaced? J Cardiovasc Pharmacol Ther. 2010;15(3):210-219. 48. Dabigatran etexilate [package insert]. Ridgefield, CT: Boehringer Ingelheim; 2010. 49. Connolly SJ, Ezekowitz MD, Yusuf S, et al, and the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
50. Schulman S, Kearon C, Kakkar AK, et al, for the RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. 51. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/ HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;57(11):1330-1337. 52. Benmira S, Banda ZK, Bhattacharya V. Old versus new anticoagulants: focus on pharmacology. Recent Pat Cardiovasc Drug Discov. 2010;5(2):120-137. 53. Bauersachs R, Berkowitz SD, Brenner B, et al, for the EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. 54. The heart.org. Off orbit? ROCKET AF: rivaroxaban noninferior to warfarin, but superiority analyses at odds. http://www.theheart. org/article/1148785.do. Accessed April 4, 2011. 55. Pharmaceutical Research and Manufacturers of America. Medicines in development for heart disease and stroke. http://www.phrma.org/research/new-medicines. Accessed February 15, 2011. 56. Ellis DJ, Usman MH, Milner PG, Canafax DM, Ezekowitz MD. The first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation. Circulation. 2009;120(12):1029-1035. 57. Lowry F. FDA heeds advisory panel, OKs Pradaxa for stroke in AF patients. http://www.pharmacypracticenews.com/ViewArticle. aspx?d=Policy&d_id=51&i=November%2b2010&i_id=683&a_ id=16223. Accessed April 4, 2011. 58. Wittkowsky AK. New oral anticoagulants: a practical guide for clinicians. J Thromb Thrombolysis. 2010;29(2):182-191.
Pharmacy Practice News â€˘ May 2011
Educational Review Ed review continued from page 36
Table 1. Drugâ€“Drug Interactions: Transplant Immunosuppressive Agents With Cholesterol-lowering, Antidiabetic, and Antihypertensive Agents
Colesevelam (Welchol, Sankyo)
Transplant Immunosuppressive Agents
Basiliximab (Simulect, Novartis)
Everolimus (Zortress, Novartis)
Rituximab (Rituxan, Genentech)
Sirolimus (Rapamune, Pfizer)
Chlolesterol-lowering Agents Bile Acid Sequestrants
Fibric Acids Fenofibrate (Lescol, Lescol XL, Novartis)
Statins Atorvastatin (Lipitor, Pfizer)
Rosuvastatin (Crestor, AstraZeneca)
Ezetimibe (Zetia, Merck/ Schering-Plough) Niacin Antidiabetic Agents Alpha-glucosidase agents Acarbose
Miglitol (Glyset, Pfizer)
DPP-4 Inhibitors Saxagliptin (Onglyza, BristolMyers Squibb)
Sitagliptin (Januvia, Merck)
Exenatide (Byetta, Amylin)
Liraglutide (Victoza, Novo Nordisk)
Glucagon-like peptide agonists
Repaglinide (Prandin, Novo Nordisk)
Table continues on page 40
Pharmacy Practice News • May 2011
Educational Review Table 1. Drug–Drug Interactions: Transplant Immunosuppressive Agents With Cholesterol-lowering, Antidiabetic, and Antihypertensive Agents
Sirolimus (Rapamune, TacroPfizer) limus
Rituximab (Rituxan, Genentech)
Basiliximab (Simulect, Novartis)
Transplant Immunosuppressive Agents
Everolimus (Zortress, Novartis)
Thiazolidinediones Pioglitazone (Actos, Takeda)
Rosiglitazone (Avandia, GlaxoSmithKline)
Other Insulin Metformin Pramlintide (Symlin, Amylin) Antihypertensive Agents Angiotensin-Converting Enzyme Inhibitors Benazepril
B/C B/C B/C B/C B/C B/C B/C
C C C C C C C
Angiotensin receptor blockers Candesartan (Atacand, AstraZeneca)
Irbesartan (Avapro, BristolMyers Squibb)
Olmesartan (Benicar, Sankyo) Valsartan (Diovan, Novartis)
Pharmacy Practice News • May 2011
Educational Review Table 1. Drug–Drug Interactions: Transplant Immunosuppressive Agents With Cholesterol-lowering, Antidiabetic, and Antihypertensive Agents Transplant Immunosuppressive Agents
Basiliximab (Simulect, Novartis)
Everolimus (Zortress, Novartis)
Rituximab (Rituxan, Genentech)
Sirolimus (Rapamune, TacroPfizer) limus
Calcium channel blockers Amlodipine
Aliskiren (Tekturna, Novartis)
Key A Mild drug–drug interaction
B Moderate drug–drug interaction
Consider therapy modification
C Severe/major drug–drug interaction
Footnotes 1. Concurrent use may result in myelosuppression. Monitor for increased azathioprine toxic effects (eg, neutropenia). 2. Concurrent use may result in hypoglycemia. Monitor for additive hypoglycemic effects. 3. Concurrent use may enhance the nephrotoxic effect of fibric acid derivatives and decrease the serum concentration of cyclosporine. Monitoring of renal function and cyclosporine concentrations will be required. Cyclosporine dose adjustment may be necessary. 4. Concurrent use may result in an increased risk for statin toxicity (myopathy or rhabdomyolysis); monitor for toxic effects (eg, increased serum creatine phosphokinase). 5. Concurrent use may result in increased ezetimibe and cyclosporine plasma concentrations. Monitor for increased effects/toxicity of cyclosporine and ezetimibe. Ezetimibe dose adjustment may be required. 6. Concurrent use may increase the serum concentration of DPP-4 inhibitors. Monitor blood glucose concentrations. 7. Concurrent use may result in increased meglitinide plasma concentrations. Monitor for increased effects of meglitinide. 8. Concurrent use may result in increased serum concentration of cyclosporine and an increased risk for cyclosporine toxicity (renal dysfunction, cholestasis, paresthesias). Closely monitor cyclosporine serum concentration. Cyclosporine dose reduction may be necessary. 9. Concurrent use may result in acute renal dysfunction. Monitor for increased signs and symptoms of nephrotoxicity and maintain adequate hydration to reduce the risk for harmful effects. 10. Concurrent use may result in increased valsartan exposure. 11. Concurrent use may decrease the metabolism of bisoprolol. Monitor for increased effects of bisoprolol. 12. Concurrent use may increase the serum concentration of cyclosporine (P-glycoprotein interaction). Closely monitor the cyclosporine serum concentration. Cyclosporine dose reduction may be necessary. 13. Concurrent use may result in an increased risk for dihydropyridine calcium channel blocker toxicity. Monitor for decreases in blood pressure. 14. Concurrent use may result in increased aliskiren exposure and plasma concentration. Avoid using together and consider alternative antihypertensive agents or immunosuppressants. 15. Concurrent use may increase the serum concentration of everolimus and risk for toxicity. Monitor everolimus trough concentrations and adjust dose as necessary.
18. Concurrent use may result in decreased corticosteroid absorption and effectiveness. Monitor for decreased serum concentrations and therapeutic effects of corticosteroids. Separating doses by 2 hours or longer may reduce the risk for interaction. 19. Concurrent use may increase the serum concentration of atorvastatin and hydrocortisone. Monitor for increased effects of atorvastatin and hydrocortisone. 20. Concurrent use may diminish the hypoglycemic effect of antidiabetic agents. Monitor blood glucose and adjust antidiabetic medication dosage as necessary. 21. Concurrent use may increase the serum concentration of hydrocortisone and carvedilol. Monitor for increased effects of hydrocortisone and carvedilol. 22. Concurrent use may increase the serum concentration of corticosteroid. Monitor for enhanced adrenal suppressant effects. 23. Concurrent use may increase the serum concentration of hydrocortisone and nicardipine. Monitor for increased effects of hydrocortisone and nicardipine. 24. Concurrent use may result in hypokalemia and subsequent cardiac arrhythmias. Monitor serum potassium. Addition of potassium-sparing diuretic and/or potassium supplementation may be necessary. 25. Concurrent use may result in reduced serum concentrations of leflunomide. Consider alternatives to bile acid sequestrants if possible. 26. Concurrent use may decrease metabolism of chlorpropramide, glimepiride, glipizide, glyburide, losartan, nateglinide, tolbutamide, or torsemide. Monitor for increased effects of these agents. 27. Concurrent use may increase the serum concentration of carvedilol. Monitor patients for signs and symptoms of excessive carvedilol effect (ie, hypotension, bradycardia, orthostasis, etc). 28. Concurrent use may result in reduced mycophenolic acid exposure. Avoid combination of mycophenolate and bile acid sequestrants. 29. Concurrent use may increase the serum concentration of mycophenolate. Monitor complete blood count with differential (eg, red blood cell count, hemoglobin, hematocrit) and mycophenolic acid serum levels. 30. Antihypertensive agents may enhance the hypotensive effect of rituximab. Consider withholding antihypertensive agents for 12 hours prior to rituximab infusion to avoid excessive hypotension. 31. Concurrent use may increase the serum concentration of atorvastatin or sirolimus. Monitor for increased effects of atorvastatin or sirolimus. 32. Concurrent use may increase the serum concentration of ß-blocker and sirolimus. Monitor for increased effects of ß-blocker and sirolimus. 33. Concurrent use may result in an increased risk for sirolimus toxicity (anemia, leukopenia, thrombocytopenia, hypokalemia, diarrhea). Monitor sirolimus levels and adjust sirolimus dose as necessary. 34. Concurrent use may increase the serum concentration of tacrolimus or carvedilol. Monitor for increased effects of tacrolimus or carvedilol. 35. Concurrent use may increase the serum concentration of and exposure to tacrolimus. Monitor serum tacrolimus concentrations.
16. Concurrent use may enhance the adverse/toxic effect of angiotensin-converting enzyme (ACE) inhibitor. Monitor for toxic effect of ACE inhibitor (eg, increased risk for angioedema). 17. Concurrent use may result in decreased plasma concentrations of everolimus. Avoid combination of nicardipine and everolimus.
Based on references 14 and 19.
Pharmacy Practice News • May 2011
Educational Review Text continued from page 36
The following case helps foster an understanding of the potential for DDIs among post-kidney transplant recipients with metabolic syndrome and provides recommendations to address some specific DDIs.
Case Presentation Chief Complaint: Headache, nausea, tremors, and diarrhea History of Present Illness: TJ is a 41-year-old Asian man, who presented with the above complaints at his primary care visit. Two weeks before the visit, the patient had been started on diltiazem to control his hypertension and omeprazole for newonset gastroesophageal reflux disease (GERD) symptoms. The patient denies any bleeding complications. Past Medical and Surgery History: 1995 and 2007: status post–live kidney transplant 2003: dyslipidemia 2003: hypertension 2004: type 2 diabetes 2005 and 2007: recurrent deep venous thrombosis 2009: GERD Social History: The patient lives with his wife and 2 children (aged 5 and 8 years). He denies alcohol, tobacco, and illegal drug use. Allergies: No known drug allergies Vital Signs: Body weight, 168 lb; height, 5 ft 5 in; blood pressure, 155/89 mm Hg; pulse, 95 beats per minute Laboratory Values: Hemoglobin A 1C (HbA 1C), 7.8%; fasting plasma glucose, 160 mg/dL; international normalized ratio (INR), 3.5 (2.1 in the previous 2 weeks; goal, 2-3); tacrolimus level, 10.8 ng/mL (7.6 ng/mL in the previous 2 weeks; goal, 5-8 ng/mL); blood urea nitrogen (BUN), 25 mg/dL Medications: See Tables 2 and 3.
Discussion Tacrolimus Toxicity Object drug: tacrolimus Precipitant drugs: diltiazem and omeprazole Explanation of interactions: The patient is experiencing tacrolimus toxicity, with headache, tremor,
nausea, and diarrhea. Tacrolimus is extensively metabolized by the hepatic cytochrome P 450 (CYP) 3A4 enzyme system. Diltiazem inhibits the CYP3A4 metabolism and thus can increase the serum concentration of, and exposure to, tacrolimus. Omeprazole primarily inhibits CYP2C19 and to a lesser extent, 3A4; however, in individuals who are 2C19-deficient, there is an increased risk for 3A4 inhibition. Asian and white individuals are more likely to have this underlying gene mutation. Recommendations: Discontinue omeprazole and use an alternative acid-suppression therapy, such as famotidine 20 mg twice daily, to manage the patient’s GERD. Discontinue diltiazem and increase the patient’s lisinopril 5 mg once daily to 20 mg once daily to control his hypertension. Continue to monitor the patient’s blood pressure (goal, <130/80 mm Hg). A second antihypertensive agent that does not clinically interact with the patient’s medications may be necessary for adjunctive management. Monitor the tacrolimus trough level, striving for a goal of 5 to 8 ng/mL, and continue to monitor renal and hepatic function and serum electrolytes.14-17
Five minutes before each meal
Once in the morning
Table 3. Patient Medications After Primary Care Visit
Warfarin Toxicity Object drug: warfarin Precipitant drugs: omeprazole and prednisone Explanation of interactions: The patient’s INR is elevated at 3.5. Warfarin is metabolized by several hepatic CYP isoenzymes, including 2C19, 2C9, and 3A4. Omeprazole inhibits both CYP2C19 and 3A4, and can enhance the anticoagulant effect of warfarin. Prednisone has pharmacodynamic interactions with anticoagulants and may enhance or diminish the effects of warfarin, by either decreasing vascular integrity or increasing blood hypercoagulability. Recommendations: Consider discontinuing omeprazole and instead using famotidine. It is appropriate to hold one dose of warfarin and then recheck INR in 1 week, with a goal of 2 to 3. Continue to monitor for signs of bleeding (eg, easy bruising, bloody or dark tarry stools, blood in the urine). If the patient’s INR continues to be elevated 1 to 2 weeks after the switch to famotidine, then a 5% to 15% reduction in the weekly warfarin dose may be necessary.14,18 The prednisone dosage should be continued because this most probably had minimal affect on the patient’s recently elevated INR. Mycophenolate Toxicity Object drug: mofetil (MMF)
Table 2. Patient Medications at Presentation
Five minutes before each meal
Once in the morning
Precipitant drug: omeprazole Explanation of Interaction: There is a serious DDI between omeprazole and MMF that increases the possible risk for acute rejection. Omeprazole decreases the hydrolysis and absorption of MMF to the active metabolite, mycophenolic acid, when gastric pH is increased. Recommendations: Consider using a less potent acid-suppressing agent that does not interact with MMF, such as an H2-blocker (eg, famotidine).14,19
Conclusion This case illustrates the critical function that clinical pharmacists perform in identifying and circumventing DDIs in post–kidney transplant patients who require immunosuppressive
therapy. Table 1 can help identify some of the common DDIs associated with these medications. As drug experts, pharmacists provide invaluable skills that help manage patients by optimizing medication therapies, reducing side effects, identifying and managing DDIs, improving adherence, and, ultimately, improving outcomes and survival.
References 1. Rang HP, Dale MM, Ritter JM, Flower R. Pharmacology. 6th ed. New York, NY: Churchill Livingstone; 2007. 2. Shapiro L, Knowles S, Shear N. Drug interactions of clinical significance for the dermatologist: recognition and avoidance. Am J Clin Dermatol. 2003;4(9):623-639. 3. American Society of Health-System Pharmacists. Survey reveals patient
Pharmacy Practice News • May 2011
Educational Review concerns about medication related issues. http://www.ashp.org/import/news/ pressreleases/pressrelease.aspx?id=183. Accessed April 5, 2011. 4. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(3):S1-S155. 5. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009;2(5-6):231-237. 6. Goldsmith D, Pietrangeli CE. The metabolic syndrome following kidney transplantation. Kidney Int Suppl. 2010;78(suppl 118):S8-S14. 7. Soveri I, Abedini S, Holdaas H, Jardine A, Eriksson N, Fellström B. Metabolic syndrome and cardiovascular risk in renal transplant recipients: effects of statin treatment. Clin Transplant. 2009:23(6):914-920.
11. Aakhus S, Dahl K, Wideroe TE. Hyperlipidaemia in renal transplant patients. J Intern Med. 1996;239(5):407-415. 12. Navaneethan SD, Perkovic V, Johnson DW, Nigwekar SU, Craig JC, Strippoli GF. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database Syst Rev. 2009;15(2):CD005019. 13. Gill JS, Rose C, Pereira BJ, Tonelli M. The importance of transitions between dialysis and transplantation in the care of endstage renal disease patients. Kidney Int. 2007;71(5):442-447. 14. Lexi-Comp Online™, Lexi-Interact™. Hudson, Ohio: Lexi-Comp, Inc.; 2010: December 12, 2010.
10. Premasathian NC, Muehrer R, Brazy PC, Pirsch JD, Becker BN. Blood pressure control in kidney transplantation: therapeutic implications. J Hum Hypertens. 2004;18(12):871-877.
New Product Advertisement NulecitTM Approved for the Treatment of Iron Deficiency Anemia
16. Irwin R, Rippe J. Intensive Care Medicine. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.
clinical practice guidelines. 8th ed. Chest. 2008;133(6 Suppl):160S-198S. 19. DRUG-REAX System. [Internet database]. Greenwood Village, CO: Thomson Reuters (Healthcare) Inc.; 2011.
17. Kidney Disease Outcomes Quality Initiative. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(suppl 1):S1-S290. 18. Ansell J, Hirsh J, Hylek E, et al. The pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based
Niki S. Mehdizadegan, Tuan Huynh, Charmaine Rochester, and their immediate families declare no actual or potential conflicts of interest or financial interests in any product or services discussed in the manuscript. The authors wish to thank Heather Hurley, PharmD, BCPS, clinical pharmacist, University of Maryland Medical Center, Baltimore, MD, for her review and input.
For the treatment of iron deﬁciency anemia in chronic hemodialysis patients undergoing epoetin therapy
8. Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs. 2009;69(16):2227-2243. 9. Cosio FG, Pesavento TE, Osei K, et al. Posttransplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int. 2001;59(2):732-737.
15. Burton M, Shaw L, Schentag J, Evans W. Principles of Therapeutic Drug Monitoring. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006.
Available in a Vial • Convenient administration of regular low doses of IV iron with 62.5-mg single-dose vials1
AB-Rated by the FDA2 • Nulecit™ is therapeutically equivalent to branded sodium ferric gluconate complex in sucrose injection3
Optimized ESA Usage and Hospital Spending • Sodium ferric gluconate complex in sucrose injection* showed a mean reduction in ESA requirements by up to 60.2%4 • Sodium ferric gluconate complex in sucrose injection* provided signiﬁcant cost savings when used with ESA therapy5† − $1390 net cost savings per g/dL Hb increase over 12 weeks compared to ESA alone5‡
Stability Data Available6
atson Pharmaceuticals announced plans to launch Nulecit (sodium ferric gluconate complex in sucrose injection), the first bioequivalent and therapeutically equivalent generic alternative to Ferrlecit® (Sanofi-aventis). Nulecit is approved for the treatment of iron deficiency anemia in adults and children age six years or older who are undergoing chronic hemodialysis and receiving supplemental epoetin therapy. In a press release, Watson noted that Nulecit will allow administration from a single-dose glass vial, minimizing the need for filter needles and test doses. Each 5 mL vial contains 62.5 mg of elemental iron for IV use. The company pointed out that the product is contraindicated in patients with anemia not related to iron deficiency, in patients hypersensitive to sodium ferric gluconate complex in sucrose or its inactive components, and in patients with evidence of iron overload.
• Data supports its stability in syringes and saline bags6 − Stability testing with syringes was conducted at room temperature for up to 2 days and at refrigerated conditions for up to 7 days − Stability testing with intravenous infusion bags containing 0.9% sodium chloride solution was conducted at room temperature for up to 1 day and at refrigerated conditions for up to 7 days
More Than 10 Years of Clinical Use7 • Sodium ferric gluconate complex in sucrose injection* is safe7 and effective8
Studies used Ferrlecit®. Nulecit™ is bioequivalent to Ferrlecit®. In anemic patients with high ferritin (500-1200 ng/mL), low TSAT (<25%), and receiving adequate ESA therapy. ‡ Economic model only included drugs and hospitalizations due to serious adverse events. In DRIVE (Dialysis Patients’ Response to IV Iron with Elevated Ferritin), patients were either given no iron (control group) or Ferrlecit® (sodium ferric gluconate in sucrose injection; 125 mg x 8); ESA dosage was raised 25% in each group at randomization with no further dose adjustments. DRIVE-II was a 6-week, observational extension of the DRIVE study designed to evaluate the sustained effects of IV iron administration on epoetin requirements, hemoglobin (Hb), and iron parameters under usual anemia clinical management. Investigators were not restricted in the type of iron product administered. *
For more information, please visit Nulecit.com. Important Safety Information • Sodium ferric gluconate complex in sucrose is contraindicated in non iron-deﬁcient anemias, in patients hypersensitive to sodium ferric gluconate complex in sucrose or its inactive components, or with evidence of iron overload • Hypersensitivity reactions have been reported with injectable iron products • Hypotension has been reported with rapid administration of IV iron • In a singledose, placebo-controlled safety study (n=1097), the most frequent adverse events occurring after sodium ferric gluconate complex in sucrose administration were hypotension, nausea, and vomiting and/or diarrhea • In multiple-dose studies (n=126), the most frequent adverse events, whether or not related to sodium ferric gluconate complex in sucrose administration were nausea, vomiting and/or diarrhea, injection site pain, hypotension, cramps, hypertension, dizziness, dyspnea, and chest pain Please see next page for references and brief summary of full Prescribing Information.
Ferrlecit® is a registered trademark of A. Nattermann & CIE. GmbH © 2011, Watson Pharma, Inc., Parsippany, NJ 07054. All rights reserved. 06662 4/11
Pharmacy Practice News • May 2011
After Boldt Retractions, Experts Ponder Fate Of Hetastarch A
nesthesiologists, critical care pharmacists and other clinicians in Europe and the United States are re-evaluating their use of hydroxyethyl starch for fluid management in surgery as investigators continue to probe the veracity of nearly 90 studies authored by now-disgraced German anesthesiologist Joachim Boldt, MD, PhD. On March 1, the Association of Surgeons of Great Britain and Ireland
announced that citations referring to six studies authored by Dr. Boldt, who was forced out of his position at the Klinikum Ludwigshafen late last year, had been withdrawn from the British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients. “The references by Boldt should not now be regarded as valid evidence pending their review,” a statement posted on the association’s Web site read. “We
shall undertake a thorough review of the recommendations of the guidelines to determine whether any adjustments to them are needed.” In Europe, changes in practice are evolving, said Jukka Takala, MD, director of intensive care medicine at University Hospital Bern, Switzerland. But “it’s clearly too early to evaluate this in any objective manner,” he said in an interview with Anesthesiology News, a sister publi-
References: 1. Nulecit™ full Prescribing Information, Watson Pharma, Inc. 2010. 2. US Department of Health & Human Services, US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (Database). Silver Spring, MD. http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=078215&Table1=OB_Rx. Accessed April 5, 2011. 3. US Department of Health and Human Services, Food and Drug Administration. Approved Drug Products with Therapeutic Equivalence Evaluations. 31st ed. 2011. 4. García Cortés MJ, Sánchez Perales MC, Borrego Utiel FJ, et al. Estudio de la eﬁcacia del hierro parenteral en pacientes en hemodiálisis tratados con eritropoyetina. Nefrologia. 1997;17:424-429. 5. Pizzi LT, Bunz TJ, Coyne DW, Goldfarb DS, Singh AK. Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney Int. 2008;74:1588-1595. 6. Data on ﬁle, Watson Laboratories, Inc. 7. Michael B, Coyne DW, Fishbane S, et al. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int. 2002;61:1830-1839. 8. Nissenson AR, Lindsay RM, Swan S, Seligman P, Strobos J. Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American clinical trial. Am J Kid Dis. 1999;33:471-482.
BRIEF SUMMARY See package insert for full Prescribing Information. INDICATIONS AND USAGE Nulecit™ (sodium ferric gluconate complex in sucrose injection) is indicated for treatment of iron deﬁciency anemia in adult patients and in pediatric patients age 6 years and older undergoing chronic hemodialysis who are receiving supplemental epoetin therapy. CONTRAINDICATIONS All anemias not associated with iron deﬁciency. Hypersensitivity to Nulecit™ or any of its inactive components. Evidence of iron overload. WARNINGS Hypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS. PRECAUTIONS General: Iron is not easily eliminated from the body and accumulation can be toxic. Unnecessary therapy with parenteral iron will cause excess storage of iron with consequent possibility of iatrogenic hemosiderosis. Iron overload is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias. Nulecit™ should not be administered to patients with iron overload. See OVERDOSAGE. Hypersensitivity Reactions: One case of a life-threatening hypersensitivity reaction was observed in 1,097 patients who received a single dose of sodium ferric gluconate complex in sucrose injection in a post-marketing safety study. In the post-marketing spontaneous reporting system, life-threatening hypersensitivity reactions have been reported rarely in patients receiving sodium ferric gluconate complex in sucrose injection. See ADVERSE REACTIONS. Hypotension: Hypotension associated with light-headedness, malaise, fatigue, weakness or severe pain in the chest, back, ﬂanks, or groin has been associated with administration of intravenous iron. These hypotensive reactions are not associated with signs of hypersensitivity and have usually resolved within one or two hours. Successful treatment may consist of observation or, if the hypotension causes symptoms, volume expansion. See ADVERSE REACTIONS. Carcinogenesis, mutagenesis, impairment of fertility: Long term carcinogenicity studies in animals were not performed. Studies to assess the effects of sodium ferric gluconate complex in sucrose injection on fertility were not conducted. Sodium ferric gluconate complex in sucrose injection was not mutagenic in the Ames test and the rat micronucleus test. It produced a clastogenic effect in an in vitro chromosomal aberration assay in Chinese hamster ovary cells. Pregnancy Category B: Sodium ferric gluconate complex in sucrose injection was not teratogenic at doses of elemental iron up to 100 mg/kg/day (300 mg/m2/day) in mice and 20 mg/kg/day (120 mg/m2/day) in rats. On a body surface area basis, these doses were 1.3 and 3.24 times the recommended human dose (125 mg/day or 92.5 mg/m2/day) for a person of 50 kg body weight, average height and body surface area of 1.46 m2. There were no adequate and wellcontrolled studies in pregnant women. Nulecit™ should be used during pregnancy only if the potential beneﬁt justiﬁes the potential risk to the fetus. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nulecit™ is administered to a nursing woman. Pediatric Use: Sodium ferric gluconate complex in sucrose injection was shown to be safe and effective in pediatric patients ages 6 to 15 years (refer to CLINICAL STUDIES section). Safety and effectiveness in pediatric patients younger than 6 years of age have not been established. Nulecit™ contains benzyl alcohol and therefore should not be used in neonates. Geriatric Use: Clinical studies of sodium ferric gluconate complex in sucrose injection did not include sufﬁcient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identiﬁed differences in responses between the elderly and younger patients. In particular, 51/159 hemodialysis patients in North American clinical studies were aged 65 years or older. Among these patients, no differences in safety or efﬁcacy as a result of age were identiﬁed. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reﬂecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Exposure to sodium ferric gluconate complex in sucrose injection has been documented in over 1,400 patients on hemodialysis. This population included 1,097 sodium ferric gluconate complex in sucrose injection-naïve patients who received a single-dose of sodium ferric gluconate complex in sucrose injection in a placebo-controlled, crossover, post-marketing safety study. Undiluted sodium ferric gluconate complex in sucrose injection was administered over ten minutes (125 mg of elemental iron at 12.5 mg/min). No test dose was used. From a total of 1,498 sodium ferric gluconate complex in sucrose injection-treated patients in medical reports, North American trials, and postmarketing studies, twelve patients (0.8%) experienced serious reactions which precluded further therapy with sodium ferric gluconate complex in sucrose injection. Hypersensitivity Reactions: See PRECAUTIONS. In the single-dose, post-marketing, safety study one patient experienced a life-threatening hypersensitivity reaction (diaphoresis, nausea, vomiting, severe lower back pain, dyspnea, and wheezing for 20 minutes) following sodium ferric gluconate complex in sucrose injection administration. Among 1,097 patients who received sodium ferric gluconate complex in sucrose injection in this study, there were 9 patients (0.8%) who had an adverse reaction that, in the view of the investigator, precluded further sodium ferric gluconate complex in sucrose injection administration (drug intolerance). These included one life-threatening reaction, six allergic reactions (pruritus x 2, facial ﬂushing, chills, dyspnea/chest pain, and rash), and two other reactions (hypotension and nausea). Another 2 patients experienced (0.2%) allergic reactions not deemed to represent drug intolerance (nausea/malaise and nausea/dizziness) following sodium ferric gluconate complex in sucrose injection administration. Seventy-two (7.0%) of the 1,034 patients who had prior iron dextran exposure had a sensitivity to at least one form of iron dextran (INFeD® or Dexferrum®). The patient who experienced a life-threatening adverse event following sodium ferric gluconate complex in sucrose injection administration during the study had a previous severe anaphylactic reaction to dextran in both forms (INFeD® and Dexferrum®). The incidences of both drug intolerance and suspected allergic events following ﬁrst dose sodium ferric gluconate complex in sucrose injection administration were 2.8% in patients with prior iron dextran sensitivity compared to 0.8% in patients without prior iron dextran sensitivity. In this study, 28% of the patients received concomitant angiotensin converting enzyme inhibitor (ACEi) therapy. The incidences of both drug intolerance or suspected allergic events following ﬁrst dose sodium ferric gluconate complex in sucrose injection administration were 1.6% in patients with concomitant ACEi use compared to 0.7% in patients without concomitant ACEi use. The patient with a life-threatening event was not on ACEi therapy. One patient had facial ﬂushing immediately on sodium ferric gluconate complex in sucrose injection exposure. No hypotension occurred and the event resolved rapidly and spontaneously without intervention other than drug withdrawal. In multiple dose Studies A and B, no fatal hypersensitivity reactions occurred among the 126 patients who received sodium ferric gluconate complex in sucrose injection. Sodium ferric gluconate complex in sucrose injection-associated hypersensitivity events in Study A resulting in premature study discontinuation occurred in three out of a total 88 (3.4%) sodium ferric gluconate complex in sucrose injection-treated patients. The ﬁrst patient withdrew after the development of pruritus and chest pain following the test dose of sodium ferric gluconate complex in sucrose injection. The second patient, in the high-dose group, experienced nausea, abdominal and ﬂank pain, fatigue and rash
following the ﬁrst dose of sodium ferric gluconate complex in sucrose injection. The third patient, in the low-dose group, experienced a “red blotchy rash” following the ﬁrst dose of sodium ferric gluconate complex in sucrose injection. Of the 38 patients exposed to sodium ferric gluconate complex in sucrose injection in Study B, none reported hypersensitivity reactions. Many chronic renal failure patients experience cramps, pain, nausea, rash, ﬂushing, and pruritus. In the postmarketing spontaneous reporting system, life-threatening hypersensitivity reactions have been reported rarely in patients receiving sodium ferric gluconate complex in sucrose injection. Hypotension: See PRECAUTIONS. In the single dose safety study, post-administration hypotensive events were observed in 22/1,097 patients (2%) following sodium ferric gluconate complex in sucrose injection administration. Hypotension has also been reported following administration of sodium ferric gluconate complex in sucrose injection in European case reports. Of the 226 renal dialysis patients exposed to sodium ferric gluconate complex in sucrose injection and reported in the literature, 3 (1.3%) patients experienced hypotensive events, which were accompanied by ﬂushing in two. All completely reversed after one hour without sequelae. Transient hypotension may occur during dialysis. Administration of Nulecit™ may augment hypotension caused by dialysis. Among the 126 patients who received sodium ferric gluconate complex in sucrose injection in Studies A and B, one patient experienced a transient decreased level of consciousness without hypotension. Another patient discontinued treatment prematurely because of dizziness, lightheadedness, diplopia, malaise, and weakness without hypotension that resulted in a 3 to 4 hour hospitalization for observation following drug administration. The syndrome resolved spontaneously. Adverse Laboratory Changes: No differences in laboratory ﬁndings associated with sodium ferric gluconate complex in sucrose injection were reported in North American clinical trials when normalized against a National Institute of Health database on laboratory ﬁndings in 1,100 hemodialysis patients. Most Frequent Adverse Reactions: In the single-dose, post-marketing safety study, 11% of patients who received sodium ferric gluconate complex in sucrose injection and 9.4% of patients who received placebo reported adverse reactions. The most frequent adverse reactions following sodium ferric gluconate complex in sucrose injection were: hypotension (2%), nausea, vomiting and/or diarrhea (2%), pain (0.7%), hypertension (0.6%), allergic reaction (0.5%), chest pain (0.5%), pruritus (0.5%), and back pain (0.4%). Similar adverse reactions were seen following placebo administration. However, because of the high baseline incidence of adverse events in the hemodialysis patient population, insufﬁcient number of exposed patients, and limitations inherent to the cross-over, single dose study design, no comparison of event rates between sodium ferric gluconate complex in sucrose injection and placebo treatments can be made. In multiple-dose Studies A and B, the most frequent adverse reactions following sodium ferric gluconate complex in sucrose injection were: Body as a Whole: injection site reaction (33%), chest pain (10%), pain (10%), asthenia (7%), headache (7%), abdominal pain (6%), fatigue (6%), fever (5%), malaise, infection, abscess, back pain, chills, rigors, arm pain, carcinoma, ﬂu-like syndrome, sepsis. Nervous System: cramps (25%), dizziness (13%), paresthesias (6%), agitation, somnolence. Respiratory System: dyspnea (11%), coughing (6%), upper respiratory infections (6%), rhinitis, pneumonia. Cardiovascular System: hypotension (29%), hypertension (13%), syncope (6%), tachycardia (5%), bradycardia, vasodilatation, angina pectoris, myocardial infarction, pulmonary edema. Gastrointestinal System: nausea, vomiting and/or diarrhea (35%), anorexia, rectal disorder, dyspepsia, eructation, ﬂatulence, gastrointestinal disorder, melena. Musculoskeletal System: leg cramps (10%), myalgia, arthralgia. Skin and Appendages: pruritus (6%), rash, increased sweating. Genitourinary System: urinary tract infection. Special Senses: conjunctivitis, abnormal vision, ear disorder. Metabolic and Nutritional Disorders: hyperkalemia (6%), generalized edema (5%), leg edema, peripheral edema, hypoglycemia, edema, hypervolemia, hypokalemia. Hematologic System: abnormal erythrocytes (11%), anemia, leukocytosis, lymphadenopathy. Other Adverse Reactions Observed During Clinical Trials: In the single-dose post-marketing safety study in 1,097 patients receiving sodium ferric gluconate complex in sucrose injection, the following additional events were reported in two or more patients: hypertonia, nervousness, dry mouth, and hemorrhage. Pediatric Patients: In a clinical trial of 66 iron-deﬁcient pediatric hemodialysis patients, 6 to 15 years of age, inclusive, who were receiving a stable erythropoietin dosing regimen, the most common adverse events, whether or not related to study drug, occurring in ≥ 5%, regardless of treatment group, were: hypotension (35%), headache (24%), hypertension (23%), tachycardia (17%), vomiting (11%), fever (9%), nausea (9%), abdominal pain (9%), pharyngitis (9%), diarrhea (8%), infection (8%), rhinitis (6%), and thrombosis (6%). More patients in the higher dose group (3.0 mg/ kg) than in the lower dose group (1.5 mg/kg) experienced the following adverse events: hypotension (41% vs. 28%), tachycardia (21% vs. 13%), fever (15% vs. 3%), headache (29% vs. 19%), abdominal pain (15% vs. 3%), nausea (12% vs. 6%), vomiting (12% vs. 9%), pharyngitis (12% vs. 6%), and rhinitis (9% vs. 3%). Postmarketing Surveillance: The following additional adverse reactions have been identiﬁed with the use of sodium ferric gluconate complex in sucrose injection from postmarketing spontaneous reports: dysgeusia, hypoesthesia, loss of consciousness, convulsion, skin discoloration, pallor, phlebitis, and shock. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. OVERDOSAGE Dosages in excess of iron needs may lead to accumulation of iron in iron storage sites and hemosiderosis. Periodic monitoring of laboratory parameters of iron storage may assist in recognition of iron accumulation. Nulecit™ should not be administered in patients with iron overload. Serum iron levels greater than 300 mcg/dL may indicate iron poisoning which is characterized by abdominal pain, diarrhea, or vomiting which progresses to pallor or cyanosis, lassitude, drowsiness, hyperventilation due to acidosis, and cardiovascular collapse. Caution should be exercised in interpreting serum iron levels in the 24 hours following the administration of Nulecit™ since many laboratory assays will falsely overestimate serum or transferrin bound iron by measuring iron still bound to the Nulecit™ complex. Additionally, in the assessment of iron overload, caution should be exercised in interpreting serum ferritin levels in the week following Nulecit™ administration since, in clinical studies, serum ferritin exhibited a non-speciﬁc rise which persisted for ﬁve days. The Nulecit™ iron complex in sucrose injection is not dialyzable. Sodium ferric gluconate complex in sucrose injection at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg caused deaths to mice, rats, rabbits, and dogs respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions. Individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events based on information from postmarketing spontaneous reports. These adverse events included hypotension, nausea, vomiting, abdominal pain, diarrhea, dizziness, dyspnea, urticaria, chest pain, paresthesta, and peripheral swelling. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Distributed by: Watson Pharma Inc. Corona, CA 92880 USA Manufactured by: Hikma Farmaceutica (Portugal), LDA Estrada Do Rio Da Mo, 8,8 AE 8B-Fervenca 2705-906 Terrugem SNT, Portugal January 2010 192147-1 PIN220-WAT/2
cation to Pharmacy Practice News. Tricia Meyer, PharmD, MS, director of pharmacy, Scott and White Healthcare, and an assistant professor of anesthesiology, Texas A&M College of Medicine, in Temple, Texas, voiced her concerns over the Boldt case when the research improprieties were initially reported (Pharmacy Practice News, January 2011). “As pharmacists, we utilize the literature on a daily basis to determine formulary status, dosing recommendations, appropriate indications, safety information and answers from physicians on individual patient medication needs,” she said. “The contaminated information may be disseminated when analyzed in systematic reviews or meta analysis. This further exacerbates the spread of false information.” As medication experts, Dr. Meyer added, “we risk conveying inaccurate information when data has been misrepresented. This can translate into patient errors and harm. Honesty and integrity are essentials for professionals and also patient safety.” Dr. Boldt, who has published nearly 350 articles, was a leading proponent of hetastarch (HES) as a volume expander for surgical and trauma patients. Many of his studies formed the basis of clinical guidelines for HES therapy worldwide. But other studies have documented adverse effects from HES, including increased risk for bleeding, heart and kidney failure and anaphylactic shock (Anesth Analg 2011:112:635-645). As a result, the debate over the efficacy and safety of colloid, crystalloid and even albumin solutions has been intense and long-standing. Dr. Boldt was thrust into the research and publishing scandal in October 2010, when the journal Anesthesia & Analgesia retracted a 2009 article of his over concerns of data manipulation and ethical lapses. Since then, investigators have been reviewing his research results. In March, a German medical board released a list of 88 articles for which it could not find evidence that Dr. Boldt had obtained proper approval from an institutional review board. An international group of 16 anesthesiology journals subsequently announced that it was retracting those papers. Dr. Boldt faces criminal charges for allegedly fabricating research results and forging the signatures of other scientists on submitted papers. Dr. Boldt has not responded to the allegations.
Broader Use in Europe HES is a synthetic colloid that has been used for fluid resuscitation since the 1960s. Practitioners in Europe and other countries have used HES more often and
Pharmacy Practice News • May 2011
Ethics solutions are used more sparingly here than they are abroad. “But the scandal may make it more difficult to broaden the label of existing colloidal solutions or bring new solutions into the U.S. market. “Because of the scrutiny from this scandal, I think the for a wider range of conditions than have practitioners in the United States. Several large clinical trials have found that HES does not improve clinical outcomes and impairs renal function and coagulation. Nevertheless, recent surveys of anesthesia and intensive care departments in Germany and Switzerland found that up to 80% of respondents believe HES does improve outcomes (Eur J Anaesthesiol 2006;23:206). “In Europe, there is a discrepancy between the narrow indication for which the [HES] products are labeled and where safety has been demonstrated, and the much broader clinical use, much of which has been supported by investigator trials, such as the now discredited work of Joachim Boldt,” said Steven L. Shafer, MD, professor of anesthesiology at Columbia University and editor-inchief of Anesthesia & Analgesia. Still, many European practitioners have shied away from HES over safety concerns. “We stopped using HES three years ago,” said Michael Bauer, MD, chief executive director of the Integrated Research and Treatment Center at the Center for Sepsis Control and Care, at Jena University Hospital in Germany. In this country, the FDA approved Voluven in 2007 as a plasma volume expander for use during high–blood loss surgeries. Manufactured by German drugmaker Fresenius Kabi AG and marketed in the United States by Hospira Inc., Voluven is a “third-generation” HES solution. It is considered to be an improved and safer version because of its lower molecular weight and lower degree of substitution compared with earlier HES solutions. “We have had some customer inquiries based on the current situation,” said Dan Rosenberg, a Hospira spokesman. “However, it’s important to note that the discredited scientist [Dr. Boldt] was not involved in the pivotal U.S. clinical trial that secured approval of Voluven in the United States.” Mr. Rosenberg declined to provide information about sales of the product before or after the controversy erupted. Dr. Shafer said he doubted the Boldt controversy would affect current clinical practice because newer colloidal
‘It’s important to note that the discredited scientist [Dr. Boldt] was not involved in the pivotal U.S. clinical trial that secured approval of Voluven in the United States.” —Dan Rosenberg
FDA may require a very broad demonstration of safety across the full spectrum of indications, not just acute volume replacement, before permitting broaden-
ing of existing labels or introducing new volume expanders into the U.S. market.” —Ted Agres
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Pharmacy Practice News • May 2011
Saint Barnabas Sets Up Anticoagulation Stewardship Program Ashley Acosta, PharmD, MPH
Shilpa Amara, PharmD
Daryl Schiller, PharmD, BCPS-ID
Pharmacy Practice Resident Saint Barnabas Behavioral Health Center
Medical Communications Specialist Livingston Services
Assistant Director of Clinical Pharmacy Services Saint Barnabas Medical Center
Robert T. Adamson, PharmD
Jennifer Costello, PharmD, BCPS
George Shehata, PharmD, CACP
Corporate Vice President of Clinical Pharmacy Service
Ambulatory Care Clinical Pharmacist Saint Barnabas Medical Center
tudies have shown that use of dosage and monitoring protocols can help to reduce the rates of major bleeding events associated with warfarin, a highly effective, yet often risky, medication. As a result, the Saint Barnabas Health Care System (SBHCS) implemented a pharmacy-operated anticoagulation stewardship program to monitor international normalized ratio (INR) values in all patients being treated with warfarin. This article describes the results of this initiative, as well as opportunities to expand and improve this program in the future. Established to help health care organizations address patient safety concerns, the Joint Commission’s National Patient Safety Goals (NPSGs) highlight strategies that can be used to improve patient care in various health care settings. One important NPSG, introduced in 2008, states that hospitals must reduce the likelihood of patient harm associated with the use of anticoagulant therapy. Although anticoagulants have an enviable library of evidence regarding their use in various clinical scenarios and patient populations, they also have the potential to cause harm due to complex dosing, insufficient monitoring, and inconsistent patient compliance.
Assistant Director/Clinical Coordinator Clara Maass Medical Center Saint Barnabas Health Care System Livingston, New Jersey
Warfarin in particular, with its proteinbinding tendencies, interaction potential, and narrow therapeutic index, can beget adverse patient outcomes even when managed by the most experienced clinicians. As a result, the Joint Commission has mandated that all patients undergoing warfarin therapy have their INR monitored on a regular basis.1 The NPSG and Joint Commission mandate have resulted in the expansion of anticoagulation management programs that have proven to be beneficial. Data indicate that use of institutional protocols for warfarin dosage and monitoring can increase facility adherence to evidence-based guidelines and improve clinical outcomes during anticoagulation management.2,3 A recent investigation conducted at Baylor University Medical Center found that patients treated in accordance with an institutional protocol experienced fewer bleeding events and fewer supratherapeutic INRs than those who received traditional therapy.2 Similarly, a randomized trial conducted at a university hospital in Cleveland, OH found that guideline-based management of warfarin dosing helped to reduce the rate of major bleeding events and increase the time during which INR levels were
within the desired therapeutic range.4 In light of these findings, and in anticipation of the enforcement of the Joint Commission’s NPSG, clinical pharmacists at SBHCS held a consensus meeting to discuss warfarin management and monitoring policies in October 2008. Based on the discussions, it was determined that the health-system pharmacists would review and record each patient’s INR before approving an order for warfarin in the future; if the INR was not already available, pharmacists would have the ability to request that this laboratory value be obtained. Current warfarin management guidelines, which are based on clinical studies that have demonstrated therapeutic success, recommend a target INR of 2 to 3 for the majority of patients being treated with warfarin,5 although certain cardiac patients with prosthetic heart valves have a slightly higher target of 2.5 to 3.5.6 Because INR values greater than 4 have been associated with an increased risk for intracranial hemorrhage,5 the pharmacists were instructed to consult the physician whenever warfarin was ordered in the face of a supratherapeutic INR. Following program implementation in 2009, an analysis was conducted to
Patients with INR >4, %
Figure. Percentage of patients with abnormal INR results. CMC, Community Medical Center; CMMC, Clara Maass Medical Center; INR, international normalized ratio; KMC, Kimball Medical Center; MMC, Monmouth Medical Center; NBI, Newark Beth Israel Medical Center; SBMC, Saint Barnabas Medical Center
Table. Abnormal INRs Before and After Stewardship Program Facility
Change in Patients With INR >4
CMC, Community Medical Center; CMMC, Clara Maass Medical Center; INR, international normalized ratio; KMC, Kimball Medical Center; MMC, Monmouth Medical Center; NBI, Newark Beth Israel Medical Center; SBMC, Saint Barnabas Medical Center
evaluate the impact of the anticoagulation stewardship on patients’ INR levels. The Trendstar billing database was used to identify all patients admitted to SBHCS who received a charge for warfarin between January 2008 and June 2010; patients admitted between January and December 2008 constituted the pre-implementation cohort, whereas those admitted between January 2009 and June 2010 comprised the postimplementation cohort. All patients with abnormal INR levels (ie, levels greater than 4) during these time periods were identified and stratified by facility. Patients who had an abnormal INR within the first 72 hours of admission were excluded from the study because this implied poor warfarin management prior to hospital entry. Following implementation of the anticoagulation stewardship program, the majority of SBHCS facilities experienced a reduction in the percentage of patients with abnormal INR levels (Table and Figure). One facility (CMC) did experience an increase in abnormal INRs following implementation of the stewardship program. That was likely due to the fact that some physicians at CMC were ordering multiple INRs on patients within the same day. For instance, a physician would receive an abnormal INR, and then repeat the test for a second or third time on the same day. This practice has since been fixed through education. The results of this analysis corroborate the value of establishing a pharmacy-run anticoagulation stewardship program in the health care setting. Implementation of this program largely increased INR monitoring within SBHCS; indeed, institution of the warfarin management program caused INR evaluation, which was among the top 15 clinical pharmacy
see HEALTH CARE, page 50
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Important Safety Information Privigen is indicated for the treatment of patients with primary immunodeﬁciency (PI) associated with defects in humoral immunity, including but not limited to common variable immunodeﬁciency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeﬁciencies. WARNING: Renal dysfunction, acute renal failure, osmotic nephrosis, and death may be associated with the administration of Immune Globulin Intravenous (Human) (IVIg) products in predisposed patients. Administer IVIg products at the minimum infusion rate possible. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIg products containing sucrose. Privigen does not contain sucrose. See full Prescribing Information for complete Boxed Warning.
In patients at risk for developing renal failure, monitor urine output and renal function, including blood urea nitrogen and serum creatinine. Thrombotic events have been reported with Privigen and other IVIg treatments. Monitor patients with risk factors for thrombotic events, including a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity. Aseptic meningitis syndrome (AMS) may occur infrequently with Privigen and other IVIg treatments; AMS may occur more frequently with high doses and/or rapid infusion of IVIg. Hemolysis, hemolytic anemia, and pulmonary adverse events have also been reported. There have been reports of noncardiogenic pulmonary edema in patients administered IVIg. If transfusion-related acute lung injury is suspected, test product and patient for antineutrophil antibodies.
Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin, in patients with hyperprolinemia, and in IgA-deﬁcient patients with antibodies to IgA and a history of hypersensitivity.
Privigen is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.
Privigen is manufactured by CSL Behring AG and distributed by CSL Behring LLC. Privigen is a registered trademark of CSL Behring AG.
Please see brief summary of full Prescribing Information on following pages.
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In clinical studies, the most common adverse reactions with Privigen were headache, pain, nausea, pyrexia/hyperthermia, fatigue, and chills.
Pharmacy Practice News • May 2011
Coagulation Therapy: Roundup of New Research Anaheim, Calif.—You could buy a new Lexus for what it costs to treat an average-sized adult male for bleeding episodes with NovoSeven, Novo Nordisk’s recombinant factor VIIa (fVIIa) product. A single milligram of the drug costs about $1,200; at the currently recommended dose of 90 mcg/kg, that’s about $10,000 per dose for a 200-pound man—and the labeling recommends additional doses every
two hours until bleeding stops. With cost containment on the agenda of every pharmacy department, two interventions to minimize the off-label use of NovoSeven, presented at the Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP), will be of particular interest. In both cases, investigators demonstrated that protocols aimed at reducing the unnecessary use of the
clotting factor could cut costs without decreasing safety or efficacy. Beginning in January 2009, a multidisciplinary committee at the University of Chicago Medical Center developed a stewardship program for the use of fVIIa. The drug was restricted to use by critical care, surgery and attending hematology specialists, and could be prescribed only in very specific circumstances: the FDA-approved uses, includ-
ing treatment or prophylaxis of bleeding in patients with hemophilia with inhibitors or patients with congenital factor VII deficiency, as well as certain surgical patients with significant exsanguination; intracranial and retroperitoneal hemorrhage; hemorrhage with refusal of blood products; and liver failure with a pending invasive procedure. Clear dosage guidelines also were implemented. “We had seen an increase in the
see HEALTH CARE, page 49
Pharmacy Practice News • May 2011
Cost Containment use of the drug for off-label indications, and other adjunctive therapies weren’t being maximized before initiating NovoSeven,” said Ishaq Lat, PharmD, BCPS, clinical coordinator for critical care. “There was also a heterogeneous approach to dosing practices. Our focus was to provide a more algorithm-based approach to the use of the drug, and hopefully as a side effect we’d decrease some of our consumption and expenditures.” The result was that during a 10-month period in 2009, 43 patients
‘These two studies document that there really aren’t any adverse outcomes in terms of efficacy, so safety can be maintained and costs can be cut by restricting the use of NovoSeven.’ —Mary Amato, PharmD, MPH, BCPS received fVIIa, with 14 documented interventions by pharmacists to limit the use of the drug, and this yielded a cost savings of approximately $70,000.
Approximately $176,000 in additional cost savings was estimated as a result of using a new dosing protocol instead of simply applying the standard 90 mcg/kg
dose for each indication. “Clinical outcomes, broadly speaking, were the same as they had been previously,” Dr. Lat said. Based on recent literature, including a paper in The New England Journal of Medicine (2010;363:1791-1800) that addressed thrombotic complications as a result of off-label use of fVIIa, the committee may further analyze some of the indications for which it allows the use of the agent.
Baptist Hospital Initiative A team at Baptist Hospital in Miami also conducted a retrospective review of patients receiving fVIIa, from January 2008 to October 2009. Based on their findings, a similar protocol was developed for appropriate use of the drug, which was first implemented in February 2010. The protocol recommended a rFVIIa dose of 1 mg for intracranial hemorrhage patients requiring surgical intervention and 40 mcg/kg for other indications. “Previously, NovoSeven had been used in its full dosage for brain bleeds. Now, we use a single milligram to quickly reverse coagulopathy prior to taking patients in for neurosurgery,” said Matthew Nguyen, PharmD, BCPS, the study’s lead author, now a clinical pharmacy specialist at Maricopa Medical Center in Phoenix. Other patients who meet the new protocol’s predefined criteria would receive 40 mcg/kg. “Before our protocol, there were no specific requirements for the use of NovoSeven,” Dr. Nguyen said. “Any physician could order it at any time, as long as they really wanted it. Our protocol recommended that they have hematology come by and assess the patient before doing anything else. Prior to the protocol, single doses may have been given up to 160 mcg/kg per dose, putting patients at an extreme risk for thromboembolic events. We have had just as much success
see COAGULATION, page 50
Pharmacy Practice News • May 2011
COAGULATION continued from page 49
with the 40 mcg/kg standard dose now in place, while reducing the risk for adverse events.” The institution’s average drug cost per patient decreased from $7,866 before the protocol to $4,560 two months after initiating the protocol. Interventions were made to enforce protocol dosing or deny inappropriate use, which ended up saving $20,520. Five patients had orders for fVIIa for a total of 38 mg. Using the protocol, however, the actual amount given was only 20 mg. In addition to cost savings, the team documented two pre-protocol incidents of ischemic stroke after high doses of fVIIa, in patients who would not have received the drug—or at least not a full dose—post-protocol. “One was a minor GI bleed and the other was a small subdural hematoma,” Dr. Nguyen said. “They both received a full dose, 90 mcg/kg, of the drug and ended up having a stroke.” “These agents are so expensive,” commented Mary Amato, PharmD, MPH, BCPS, associate professor of pharmacy practice at Massachusetts College of Pharmacy and Health Sciences, in Boston. “These two studies document that there really aren’t any adverse outcomes in terms of efficacy, so safety can be maintained and costs can be cut by
HEALTH CARE continued from page 46
activities in 2008, to rise to the top of this list in 2009. Increased INR monitoring, in turn, substantially reduced the number of patients experiencing supratherapeutic INR levels, thereby helping to optimize patient care. Although INR monitoring and evaluation have had a tremendous impact on anticoagulation management, additional opportunities exist for protocol improvement within the health care system. Although supratherapeutic INR values may lead to serious bleeding events, subtherapeutic values also have been shown to be detrimental; patients who spend time below their desired therapeutic range may be at increased risk for thromboembolism, particularly if they have mechanical heart valves.7 Thus, SBHCS plans to expand its definition of abnormal INRs to include values less than 2, which is expected to further enhance patient safety. Additionally, SBHCS will begin to evaluate IV anticoagulation therapy to expedite conversion to oral medication, thereby minimizing infection risk, reducing costs, and increasing convenience. Furthermore, eventually SBHCS will take additional measures to help assess the value of its anticoagulation stewardship program. To better evaluate the
In a separate presentation at the ASHP Midyear meeting, researchers focused on another aspect of coagulation: how renal insufficiency impacts drug therapy. An intervention aimed at prescribing unfractionated heparin rather than lowmolecular-weight heparin (LMWH) agents, such as enoxaparin (Lovenox, Sanofi-aventis), in such patients sig-
nificantly reduced the incidence of bleeding complications, according to a study presented by Khaled Elsaid, PharmD, PhD, assistant professor at the Massachusetts College of Pharmacy and Health Sciences, in Boston. “Enoxaparin and [other LMWHs] are excreted renally, and although the manufacturer [of enoxaparin] still has dosing information for patients with a creatinine clearance below 30—modifying it from twice daily to once daily—we decided that our patients with a history of chronic renal insufficiency should really not receive enoxaparin at all,” Dr. Elsaid said. “Research has shown that it tends to build up in the system in these patients, and when that happens, they are at a higher risk for bleeding complications.” The intervention did not eliminate the option of prescribing enoxaparin for patients with renal insufficiency, but new warning messages would appear in the electronic prescribing system, suggesting that the physician prescribe unfractionated heparin instead if a patient had a history of renal insufficiency or a creatinine clearance of less than 30. Before the intervention, 55.8% of
patients received unfractionated heparin and 44.2% of patients were prescribed enoxaparin, with an incidence of major bleeding of 10.3%. Overall, 70% of documented major bleeds were associated with the use of enoxaparin in patients with a creatinine clearance of less than 30. After the intervention, unfractionated heparin use rose to 86.3% and enoxaparin use dropped to 13.7%. Incidents of major bleeding decreased to 6.6%—a 36% risk reduction (P=0.05). None of the major bleeding episodes were associated with patients with renal insufficiency. Dr. Amato has seen similar protocols at other institutions for patients with reduced renal function with orders for LMWHs. Either the prescriber is prompted by computerized decision support to reduce the dose and/or alerts are sent to pharmacists, who contact the prescriber and recommend lowering the dose of LMWH or consideration of unfractionated heparin in patients with very poor renal function. “As far as I know,” she said, “there hasn’t been a randomized comparison of outcomes using preventive doses of unfractionated heparin versus a reduced dose of LMWH in these patients.” —Gina Shaw
impact of this initiative, SBHCS plans to analyze its effect on the average time to achieve a target INR, as well as the average time patients spend in the target range. Early stages of evaluation already have begun at SBMC, but will likely be assessed system-wide in the future. Finally, the reporting method will be redesigned to reflect the favorable outcomes of warfarin management; specifically, future analyses will focus on patients achieving target INR levels rather than those having abnormal INRs, to reinforce the positive effects of this initiative. Based on the encouraging findings of this intervention, SBHCS believes that creation or adoption of similar policies in other health care facilities would help to reduce warfarin-related adverse events and may considerably improve patient care. Furthermore, widespread implementation of anticoagulation stewardship programs would help to establish national benchmarks for target INR attainment goals. This analysis demonstrated that approximately 4% to 8% of patients within the health system have INR levels that fall outside of the target range, but it is difficult to assess the implications of these findings without comparative data from other institutions. Therefore, widespread implementation of anticoagulation stewardship initiatives would benefit both other
facilities and SBHCS. It may be challenging to gain hospitalwide acceptance for any pharmacy-related intervention, and a warfarin management protocol may be difficult to mandate, but the therapeutic benefits associated with such a protocol undoubtedly outweigh these obstacles. Thus, SBHCS strongly recommends that other facilities consider implementing anticoagulation monitoring policies. Institutions wishing to do so should keep in mind that system-wide consensus and education are vital components of the foundation for an effective anticoagulation stewardship program. Additionally, persistence is necessary to maintain awareness of the intervention among staff and to overcome setbacks or discouragement. Because staff education and acceptance are critical to facilitating implementation, periodic instruction may be necessary to ensure consistent adherence to the program. Implementation of an anticoagulation stewardship program has proven beneficial for SBHCS. Monitoring INR levels can improve warfarin management, thereby reducing the occurrence of adverse events and improving patient outcomes. Widespread application of anticoagulation initiatives can have a considerable impact on patient safety and undoubtedly would help to optimize drug therapy.
restricting the use of [fVIIa]. They document the importance of establishing protocols for the use of agents like this. Other expensive products with potential for overuse ... such as direct thrombin inhibitors, may also benefit from protocols promoting proper use to make sure they’re used appropriately and not wasted.” “Novo Nordisk does not recommend or promote use of NovoSeven outside of its labeled indication,” a company spokesperson said. “The company is committed to improving the lives of all patients with hemophilia with the aspiration to change possibilities in hemophilia by developing the next generation of treatments for patients with inhibitors.”
Reducing Bleeding In Renal Insufficiency
Drs. Lat, Nguyen and Amato reported no relevant conflicts of interest.
1. The Joint Commission. National Patient Safety Goals. http://www.jointcommission. org/NR/rdonlyres/868C9E07-037F-433D88580D5FAA4322F2/0/July2010NPSGs_Scoring_HAP2.pdf. Accessed November 15, 2010. 2. Damaske DL, Baird RW. Development and implementation of a pharmacist-managed inpatient warfarin protocol. Proc (Bayl Univ Med Cent). 2005;18(4):397-400. 3. Passman MA. Mandated quality measures and economic implications of venous thromboembolism prevention and management. Am J Surg. 2010;199(1 suppl):S21-S31. 4. Beyth RJ, Quinn L, Landefeld CS. A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin. Ann Intern Med. 2000;133(9):687-695. 5. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):160S-198S. 6. Salem DN, O’Gara PT, Madias C, Pauker SG. Valvular and structural heart disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):593S-629S. 7. Clark N, Witt D, Delate T, et al. The clinical consequence of subtherapeutic anticoagulation: the low INR study (LINeRS). J Thromb Thrombolysis. 2008;25(1):127-128.
The authors reported no relevant conflicts of interest.
Pharmacy Practice News • May 2011
Pain Medicine Part 2 of a Four-Part Series
Pain Contracts: Are They Really Worth the Hassle? C hris Herndon, PharmD, BCPS, has used opioid agreements for years and has over time worked to improve the agreements, making changes such as adding a requirement for pill counting at each clinic visit. But like most clinicians interviewed by Pharmacy Practice News, Dr. Herndon expressed some ambivalence about the agreements—sometimes called contracts—which have proliferated in recent years, driven by fears about patient abuse or diversion. The documents can inform patients about the risks associated with taking opioids, along with the potential consequences of poor behavior, such as missing appointments or losing prescriptions, said Dr. Herndon, assistant
of its stipulations, they complained Scan for more that they hadn’t on opioid contracts. been provided sufInstructions, p. 3 ficient time to read the paperwork. So he asked patients to instead return the paperwork at their follow-up visit, typically six to eight weeks later. Their response, if they failed a urine test at the follow-up: “I didn’t sign the contract.”
Although ABQ Health Partners uses pain contracts, Dr. Dole said that he has found talking to patients about opioid-related risks and expectations to be more productive.
professor in the Department of Pharmacy Practice at Southern Illinois University, in Edwardsville. However,
“there is no data to suggest that they do anything other than to make us (the clinicians) feel better,” said Dr. Herndon, who also works with chronic pain patients as part of a family medicine residency clinic. “I don’t think they change behavior in any way.” The agreements, which are migrating from pain clinics into broader medical practice, have morphed from an optional tool to standard medical practice in some treatment settings, according to Dr. Herndon and other pain specialists interviewed. Clinical policies and guidelines, including those issued by the Federation of State Medical Boards (FSMB), recommend that clinicians at least consider using the documents. The paperwork also can be strongly encouraged as part of state laws related to the prescribing of controlled substances. But some clinicians and ethicists continue to question what they describe as the inherently coercive nature of such agreements, given that patients seeking pain relief have little alternative other than to sign. A policy paper published 2010 in The American Journal of Bioethics (2010;10:5-12) advised against broad use of the agreements, recommending an informed consent process over a signed document. The paper, which emerged from a policy meeting held by the Center for Practical Bioethics in Kansas City, Mo., cited a number of other problems, including the potential for inadvertent discrimination or stigmatization of pain patients. Meanwhile, a 2010 review published in the Annals of Internal Medicine (152:712-720) highlighted the limited evidence about the agreements’ effectiveness. After sifting through nearly 4,700 abstracts, researchers reviewed 102 studies about opioid agreements or
‘For the most part … [a pain contract] tells us … that the patient is doing exactly what they are supposed to be doing. It gives us a measure of comfort.’
—Lee Kral, PharmD
urine drug testing and only found 11 that met the inclusion criteria. All 11 studies were observational in nature and were rated as poor to fair in quality. “We found a dearth of evidence of the impact of these tools on opioid misuse and no evidence that they impact hard clinical outcomes such as addiction or overdose,” said Joanna Starrels, MD, MS, author of the Annals paper, and assistant professor of medicine at the Albert Einstein College of Medicine and Montefiore Medical Center in New York City. “We don’t know yet how useful they are—it’s a problem of not enough evidence.”
Tool or Weapon? The FSMB, in its 2004 policy related to controlled substances, did not universally recommend written agreements, instead suggesting that they be considered if the patient is “at high risk for medication abuse or has a history of substance abuse.” Joint opioid treatment guidelines issued five years later by the American Pain Society and the American Academy of Pain Medicine adopted a similar stance. Clinicians “may consider” developing a written plan detailing both patient and clinician responsibilities and expectations, the authors wrote in 2009 in the Journal of Pain.
Peter Koo, PharmD, a pharmacist specialist in pain management at the University of California, San Francisco, describes the agreements as a way to build trust. “I promise to take care of them if they abide by the agreement,” said Dr. Koo, who oversees a medication therapeutic management clinic focused on chronic or postsurgical pain. “It’s just as much to protect the clinician as the patient. It’s not a one-way street because pain management is not a one-way street—pain management is a partnership.” Ernest Dole, PharmD, FASHP, CDE,
a pharmaceutical care coordinator in New Mexico, counts himself among the skeptics. Dr. Dole, a clinician who helps treat noncancer pain patients at ABQ Health Partners, a system of physician-owned clinics in Albuquerque, considers the signed documents well intentioned. But he said they can be counterproductive or even wielded against the clinician. “With a contract,
if somebody is going to lie to me, they are going to lie to me anyway,” he said. “I’ve also had some patients who were bright and savvy enough to be able to use the contract against me.” A case in point: Dr. Dole said that he used to ask patients taking opioid medications to review and sign the contract at their initial visit. But if they broke one
On the other hand, Lee Kral, PharmD, BCPS, a clinical pharmacy specialist at the Center for Pain Medicine, part of University of Iowa Hospitals and Clinics in Iowa City, said that formalizing the consent process with a signed document can help to some extent in reducing later misunderstandings. Its greatest payoff may be for the clinician’s peace of mind, she added. “For the most part, what it tells us is that the patient is doing exactly what they are supposed to be doing. It gives us a measure of comfort.” However, another recurring concern, one that needs to be researched, is whether the signed paperwork creates a false sense of security, Dr. Starrels said. “There is a possibility that [clinicians] might feel overly secure that the patient is not at risk because an agreement is in place,” she said.
Designing a Plan Some model agreements do exist. The 2009 opioid guidelines provide a sample document in the appendix (scan the 2-D bar code on this page to access). Individual providers also will revise and tweak their own paperwork depending on the types of patients they treat, or lessons learned over time. Dr. Koo said that the agreement he uses explicitly states that refills only can be handled on Mondays or Wednesdays. That step is taken to prevent patients from calling on Friday afternoons, in the hope of catching the on-call resident rather than their regular prescriber. Dr. Herndon, the pharmacist who counts his patients’ remaining pills, said that stipulation was added to his clinic’s agreement about a year ago. A few patients at the clinic, which primarily serves lower-income and under-insured patients, had been caught selling the medication to supplement their income. “More than catching the bad patients, it [the pill counting] enabled me to justify
see CONTRACTS, page 54
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Pharmacy Practice News • May 2011
CONTRACTS continued from page 52
and defend the use of these medications in the good patients.” Now the clinic, in consultation with attorneys, might add language that would allow clinicians to speak with the patient’s family, Dr. Herndon said. Several times in the prior six months, family members have conveyed worries about a patient’s opioid use, but clinicians were unable to talk further without a patient’s permission. “We kind of have our hands tied,” he said. Hospital pharmacists and other clinicians also report various approaches to handling urine checks, used to verify that the patient is taking the prescribed drug. Dr. Kral prefers a random rather than a regular timetable. “The randomness actually makes sure that people aren’t prepared.” She described one situation in which a patient on methadone who had been getting regularly scheduled urine screens was caught off guard by an unanticipated request. The spot check didn’t find any methadone but did identify cocaine. Dr. Kral realized that the woman had probably been taking the methadone immediately prior to each regular screen. Although it’s just speculation, she says, one possibility is that the woman was trading the methadone for cocaine. Dr. Starrels also prefers a random approach to screening—one with some minimum frequency—to reduce the likelihood of unintentionally discriminating against patients perceived to be a greater risk for opioid use or misuse, she said. To that end, she screens every patient at least once every six months to check that they are taking the prescribed drug and not selling or misusing it in some way.
A primary care practitioner who prescribes an opioid, however, may not be adopting such an aggressive risk reduction strategy, said Dr. Starrels, who helped author a related study that was published online February in the Journal of General Internal Medicine (doi: 10.1007/s11606-011-1648-2). The study, which assessed risk reduction strategies in 1,612 primary care patients taking opioids for noncancer pain, found that only 8% had undergone urine drug testing. The mean duration of opioid treatment in the retrospective study was 1.9 years. More worrisome, from Dr. Starrels’ perspective, was the frequency of medication refills. Nearly one in four patients, 23%, received more than one early opioid refill. That meant the prescription was refilled at least seven days before it should have run out, assuming the patient was taking the maximum dose. Additionally, patients with a current or past drug use disorder were significantly more likely to receive early refills than those patients without such a history. “This is concerning because it could mean that providers are unwittingly contributing to opioid misuse,” she said. While the study didn’t delve into underlying causes for the early refills, some possible scenarios include overuse or diversion, Dr. Starrels noted. Another possibility? “Clinicians may not be prescribing a sufficient opioid dose in the first place,” she said. Hospital pharmacists could help get at the root cause of early refills by alerting prescribers when they see the pattern emerging, Dr. Starrels pointed out. That type of support can be very helpful, she explained, because a doctor covering for the initial prescriber
Assessing Opioid Risk? THINK About Trying This Mnemonic Tool
hen assessing a patient taking an opioid, Ernest Dole, PharmD, recommends that clinicians rely less on signed agreements and more on an amalgam of factors to determine the potential risk for abuse or misuse. To assist, the New Mexico-based pharmaceutical care coordinator has developed a memory device—dubbed THINK—with Jennifer Strickland, PharmD, BCPS, a palliative care program development manager in Tampa, Fla.
T H I N K
: Take advantage of various resources, including state prescription drug monitoring programs and urine drug screens. :Have data in hand, such as the patient’s pain feedback based on visual analog scales and activity reports, along with imaging scan results.
: Don’t ignore your intuition, although this one is tricky. Dr. Dole cautioned clinicians to remain attuned to their own “subconscious biases.” :“No” is a valid answer. Don’t increase the dose, for example, if it’s not in the patient’s best interest.
: Know the panoply of related laws and regulations, including those from the state and the U.S. Drug Enforcement Administration. —C.H.
‘We don’t know yet how useful [pain contracts] are—it’s a problem of not enough evidence.’
—Joanna Starrels, MD, MS
may not yet have noticed the refill problem. Among other red flags worth pursuing, she said, are patients who get opioids from more than one prescriber and those who pay cash for the medication. If a patient is seeking opioids from a second prescriber, that could indicate abuse or diversion. Paying in cash also could raise questions about whether a patient is taking steps to hide his or her total opioid consumption, or for some reason wants to keep it off the insurance record, Dr. Starrels noted. At this point, “it appears that the opioid agreements are here to stay,” she
said, echoing a point made by other clinicians. “But their name and format continue to evolve.” Dr. Starrels’ preference: paperwork that’s more explanatory and less punitive in tone, such as a patient letter. That format, paired with patient counseling, might achieve the same goals for patients in pain and nervous clinicians alike, she said. “To me, the signature is not essential.” —Charlotte Huff Drs. Herndon, Starrels, Koo, Dole and Kral have reported no relevant conflicts of interest.
Study Validates Spinal Manipulation for Low Back Pain C hiropractic manipulation of the spine appears to be as effective as other commonly used approaches for treating chronic lower back pain (LBP), according to an evidence-based metaanalysis (Cochrane Database Syst Rev 2011;2:CD008112). “All of the modalities studied, including spinal manipulation, are effective in about two-thirds of patients with chronic low back pain,” reported Sidney Rubinstein, DC, PhD, a chiropractor and postdoctoral researcher at VU University Medical Center in Amsterdam, The Netherlands. “Spinal manipulation appears to be no better or no worse than other existing therapies for chronic low back pain ... [and] should be considered a valid choice for patients who suffer from this condition.” To determine the efficacy of spinal manipulation therapy for treating LBP,
Dr. Rubinstein’s team identified 26 studies (with 6,070 participants) that evaluated chronic LBP; nine of these studies met criteria for high quality. The authors compared trials evaluating spinal manipulation with those assessing other common treatment options, including yoga, exercise, acupuncture, massage, cognitive-behavioral therapy and analgesics. They found generally high-quality evidence that “spinal manipulation therapy has a small, statistically significant but not clinically relevant, shortterm effect on pain relief and functional status compared with other interventions.” Spinal manipulation therapy helped approximately 66% of patients with LBP, about the same success rate as was reported with other treatments. The authors found some evidence that spinal manipulation, when added to
another intervention, has a statistically significant short-term effect on pain relief and functional status. The review suggests that chiropractic spinal manipulation may be particularly helpful for patients with restricted back movement; patients free of psychological problems (e.g., anxiety and depression); and patients who have back pain with no involvement of the sciatic nerve. The results of the review were limited, however, because spinal manipulation was not compared with a “sham” procedure (i.e., placebo). The studies included in the review also had little or no data on recovery time, return to work after treatment, quality of life during and after treatment and costs. Bill McCarberg, MD, founder of the Chronic Pain Management Program at Kaiser-Permanente in San Diego, said
there were logical reasons why the review studies did not include sham therapy groups. “Just like in acupuncture studies, chiropractic techniques vary widely and sham therapy makes it impossible to have a true placebo control.” Despite these problems, the review study shows that chiropractic should be considered along with other treatments of a comprehensive pain management program, Dr. McCarberg pointed out. The number needed to treat suggests that chiropractic is a valid option in chronic pain management, and side effects were minimal in the high-quality studies. “Allopathic medicine should be embracing treatment options [that include chiropractic manipulation], if we believe in evidence-based care,” he said. —Alice Goodman
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Pharmacy Practice News • May 2011
Topiramate Increases Incidence of Cleft Palate, Lip
ew data suggest that the migraine headache drug topiramate increases the risk for the birth defects cleft lip and cleft palate in babies born to women who use the medication during pregnancy, according to a press release from the FDA. Topiramate (Topamax, Ortho-McNeil Janssen) is approved to prevent migraine headaches, but not to relieve the pain of migraines. “Health care professionals should carefully consider the benefits and risks of topiramate when prescribing it to women of childbearing age,” said Russell Katz, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Alternative medications that have a lower risk [for] birth defects should be considered.” Data from the North American Antiepileptic Drug (AED) Pregnancy Registry indicate an increased risk for oral clefts in infants exposed to topiramate during
the first trimester of pregnancy. Infants exposed to topiramate as a single therapy experienced a 1.4% prevalence of oral clefts, compared with a prevalence of 0.38% to 0.55% in infants exposed to other AEDs. Infants of mothers who did not have epilepsy and were not being treated with other AEDs had a prevalence of 0.07%. Similar data from the United Kingdom Epilepsy and Pregnancy Register supported the North American AED Pregnancy Registry data. Based on the data, topiramate will have a stronger warning in its prescribing information (PI). The pregnancy category will be changed to Pregnancy Category D. This means that there is positive evidence of
human fetal risk based on human data, but the potential benefits of the drug in pregnant women may outweigh the risks in certain situations. The FDA previously designated the drug as Pregnancy Category C because of the lack of human data. The patient medication guide and PI for Topamax and generic topiramate will be updated with the new information. Women who become pregnant while taking topiramate should talk to their health care professional about registering with the North American AED Pregnancy Registry, a group that collects information about outcomes in infants born to women treated with AEDs during pregnancy. —Staff
FDA Expands Zostavax Shingles Indication
he FDA has approved the use of Zostavax (zoster vaccine live, Merck), a live attenuated virus vaccine, for the prevention of shingles in individuals aged 50 to 59 years. Zostavax is already approved for use in individuals 60 years of age and older. Shingles is characterized by a rash of blisters, which generally develop in a band on one side of the body and can cause severe pain that may last for
weeks, and in some people, for months or years after the episode. The likelihood
of shingles increases with age. Approval was based on a multicenter study conducted in the United States and four other countries in approximately 22,000 people who were aged 50 to 59. Half of the subjects received Zostavax and half received a placebo. Study participants were then monitored for at least one year to see if they developed shingles. Compared with placebo, Zostavax reduced the
risk for developing shingles by approximately 70%. The most common side effects observed in the study were redness, pain and swelling at the site of injection, and headache. Zostavax was originally approved in 2006 for the prevention of shingles in individuals aged 60 years and older. —Staff
Study: Single-Dose Oral Mefenamic Acid Effective for Acute Post-op Pain
ral mefenamic acid 500 mg can effectively treat moderate to severe acute postoperative pain, according to a new study in the Cochrane Database of Systematic Reviews (2011;3:CD007553). Nearly 50% of patients with moderate to severe postoperative pain experienced a good level of relief after taking a single dose of mefenamic acid 500 mg. Mefenamic acid, a nonsteroidal antiinflammatory drug, most often is used for treating mild to moderate pain, including headache and postoperative and postpartum pain. To assess the efficacy and adverse events associated with a single dose of
oral mefenamic acid in acute postoperative pain cases, the investigators searched Cochrane Central, Medline, Embase and the Oxford Pain Relief Database for randomized double-blind, placebo-controlled studies through December 2010. The investigators found four studies (with 842 participants) that met the inclusion criteria; 126 participants were treated with mefenamic acid 500 mg, 67 with mefenamic acid 250 mg, 197
with placebo and 452 with lignocaine, aspirin, zomepirac or nimesulide. The researchers calculated the number needed to treat (NNT) for one participant to experience at least 50% pain relief four to six hours after taking mefenamic acid 500 mg compared with placebo. The investigators found the NNT to achieve at least 50% pain relief over six hours with a single dose of mefenamic acid 500 mg compared with placebo was 4, and the NNT to prevent
use of rescue medication over six hours was 6.5. Of the participants, 48% with moderate to severe postoperative pain experienced a good level of pain relief after receiving a single dose of mefenamic acid 500 mg, compared with about 20% who received placebo, and fewer patients on mefenamic acid 500 mg needed additional analgesia within six hours (47% vs. 62%, respectively). However, the efficacy of other doses of mefenamic acid and the drug’s safety and tolerability could not be assessed. The investigators noted that the results are preliminary. —Staff
More Than 10,000 Children Saved
travel. Your donation will help pay the cost of these medical expenses surrounding the surgery. By donating, you will bring a Gift of Life patient to the United States so they can receive desperately needed medical care. Your generosity will allow a child from a Third-World country to experience the kindness of others so that they may grow up to be a compassionate adult. Show the world you care about our youngest and most vulnerable citizens; allow them to become vocal ambassadors and inspirations around the world for the program, our country and our people.
The Gift of Life, Inc.: A Global Mission
fficially founded by Rotary District 7250 in 1975, The Gift of Life, Inc. is a dynamic international service program. Its purpose is to further the cause of world peace and understanding by facilitating free medical services, including lifesaving surgery to children suffering from congenital heart defects and other similar or allied illnesses, regardless of race, creed, gender, religion or national origin, and who would otherwise lack access to such medical care.
Gift of Life History In 1974, the Manhasset Rotary Club, located in Long Island, N.Y. responded to a request to bring a 5- year-old Ugandan girl to the United States for openheart surgery. At that time, surgery of this kind was not available in Uganda
In fall 2008, the Gift of Life performed its 10,000th lifesaving surgery. Although this was a significant milestone for the Rotarians, health care professionals and volunteers of this organization, the need for more help remains a constant struggle.
How You Can Help and without it the child would not survive. The little girl underwent a very successful four-hour open-heart surgical procedure to close a hole between the two lower chambers of her small heart. That single act of kindness 37 years ago has grown into a global movement that has treated children from 64 countries and six continents.
One of the most effective ways to help the Gift of Life, Inc. is to make a donation so that children around the world will continue to receive the medical care they desperately need. Although medical professionals donate their time and skills and the hospitals and medical centers greatly reduce their costs, money is still needed for medical supplies, recovery and
For more information, call (516) 504-0830, visit us online at www.giftoflifeinc.com or contact Jennifer Perri-Jayne, program director, at Giftoflife1@aol.com.
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For Intravenous Use Rx only
To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 1 1.1
INDICATIONS AND USAGE Intensive Care Unit Sedation Precedex® is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Precedex should be administered by continuous infusion not to exceed 24 hours. Precedex has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue Precedex prior to extubation. 1.2 Procedural Sedation Precedex is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Drug Administration Precedex should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Due to the known pharmacological effects of Precedex, patients should be continuously monitored while receiving Precedex. 5.2 Hypotension, Bradycardia, and Sinus Arrest Clinically significant episodes of bradycardia and sinus arrest have been reported with Precedex administration in young, healthy volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration. Reports of hypotension and bradycardia have been associated with Precedex infusion. If medical intervention is required, treatment may include decreasing or stopping the infusion of Precedex, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because Precedex has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of Precedex-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required. Caution should be exercised when administering Precedex to patients with advanced heart block and/or severe ventricular dysfunction. Because Precedex decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients. In clinical trials where other vasodilators or negative chronotropic agents were co-administered with Precedex an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with Precedex. 5.3 Transient Hypertension Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of Precedex. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable. 5.4 Arousability Some patients receiving Precedex have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms. 5.5 Withdrawal Intensive Care Unit Sedation With administration up to 7 days, regardless of dose, 12 (5%) Precedex subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) Precedex subjects experienced at least 1 event 24 to 48 hours after end of
study drug. The most common events were nausea, vomiting, and agitation. Tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of Precedex supportive therapy is indicated. Procedural Sedation Withdrawal symptoms were not seen after discontinuation of short term infusions of Precedex (<6 hours). 5.6 Tolerance and Tachyphylaxis Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions [see Adverse Reactions (6.1)]. 5.7 Hepatic Impairment Since Precedex clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2)]. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Use of Precedex has been associated with the following serious adverse reactions: • Hypotension, bradycardia and sinus arrest [see Warnings and Precautions (5.2)] • Transient hypertension [see Warnings and Precautions (5.3)] Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth. Intensive Care Unit Sedation Adverse reaction information is derived from the continuous infusion trials of Precedex for sedation in the Intensive Care Unit setting in which 1007 patients received Precedex. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 2. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)]. Table 2: Adverse Reactions With an Incidence >2%— Intensive Care Unit Sedation Population <24 hours*
Adverse Event Hypotension Hypertension Nausea Bradycardia Atrial fibrillation Pyrexia Dry mouth Vomiting Hypovolemia Atelectasis Pleural effusion Agitation Tachycardia Anemia Hyperthermia Chills Hyperglycemia Hypoxia Post-procedural hemorrhage Pulmonary edema Hypocalcemia Acidosis Urine output decreased Sinus tachycardia Ventricular tachycardia Wheezing Edema peripheral
All Randomized Precedex Precedex Placebo Propofol (N = 1007) (N = 798) (N = 400) (N = 188) (%) (%) (%) (%) 25% 12% 9% 5% 4% 4% 4% 3% 3% 3% 2% 2% 2% 2% 2% 2% 2% 2%
24% 13% 9% 5% 5% 4% 3% 3% 3% 3% 2% 2% 2% 2% 2% 2% 2% 2%
12% 19% 9% 3% 3% 4% 1% 5% 2% 3% 1% 3% 4% 2% 3% 3% 2% 2%
13% 4% 11% 0 7% 4% 1% 3% 5% 6% 6% 1% 1% 2% 0 2% 3% 3%
2% 1% 1% 1%
2% 1% 1% 1%
3% 1% 0 1%
4% 3% 2% 2%
<1% <1% <1%
1% 1% 0
1% 0 1%
5% 2% 2%
* 26 subjects in the all Precedex group and 10 subjects in the randomized Precedex group had exposure for greater than 24 hours.
Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of Precedex for sedation in the surgical intensive care unit setting in which 387 patients received Precedex for less than 24 hours. The most frequently observed treatmentemergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 3). Table 3: Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-Treated Patients in the Randomized Placebo-controlled Continuous Infusion <24 Hours ICU Sedation Studies Adverse Event
Randomized Dexmedetomidine (N = 387)
Placebo (N = 379)
28% 16% 11% 7% 5% 4% 4% 4% 3% 3% 3% 3% 2% 2% 2% 2% 2% 2% 2% 2% 2%
13% 18% 9% 3% 4% 6% 3% 4% 5% 4% 2% 1% 3% 3% 3% 2% 2% 2% 1% <1% <1%
Hypotension Hypertension Nausea Bradycardia Fever Vomiting Atrial Fibrillation Hypoxia Tachycardia Hemorrhage Anemia Dry Mouth Rigors Agitation Hyperpyrexia Pain Hyperglycemia Acidosis Pleural Effusion Oliguria Thirst
In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 4. The number (%) of subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the Precedex group is provided in Table 5. Table 4: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study* Adverse Event Hypotension1 Hypotension requiring intervention Bradycardia2 Bradycardia requiring intervention Systolic Hypertension3 Tachycardia4 Tachycardia requiring intervention Diastolic Hypertension3 Hypertension3 Hypertension requiring intervention† Hypokalemia Pyrexia Agitation Hyperglycemia Constipation Hypoglycemia Respiratory Failure Renal Failure Acute Acute Respiratory Distress Syndrome Generalized edema Hypomagnesemia
5% 28% 25%
1% 42% 44%
10% 12% 11%
10% 15% 15%
19% 9% 7% 7% 7% 6% 5% 5% 2%
30% 13% 2% 6% 2% 6% 6% 3% 1%
2% 2% 1%
1% 6% 7%
† Includes any type of hypertension. 1 Hypotension was defined in absolute terms as Systolic blood
pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value. 2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. 3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value. 4 Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.
The following adverse events occurred between 2 and 5% for Precedex and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%). Table 5. Number (%) of subjects who had a dose-related increase in Treatment Emergent Adverse Events by maintenance adjusted dose rate range in the Precedex group Precedex mcg/kg/hr Adverse Event
≤ 0.7* N = 95
> 0.7 to ≤ 1.1* N = 78
> 1.1* N = 71
6% 5% 5% 3% 2% 2%
5% 8% 5% 5% 4% 6%
14% 14% 9% 7% 9% 10%
Constipation Agitation Anxiety Oedema peripheral Atrial fibrillation Respiratory failure Acute Respiratory Distress Syndrome
*Average maintenance dose over the entire study drug administration
Procedural Sedation Adverse reaction information is derived from the two trials for procedural sedation in which 318 patients received Precedex. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, 30% ≥65 years of age, 52% male and 61% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 6. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see Warnings and Precautions (5.2)]. Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between Precedex and comparator groups in both studies. Table 6: Adverse Reactions With an Incidence > 2%—Procedural Sedation Population
Adverse Event Hypotension1
Respiratory depression2 Bradycardia3 Hypertension4 Tachycardia5 Nausea Dry mouth Hypoxia6 Bradypnea
Precedex N = 318 (%)
Placebo N = 113 (%)
54% 37% 14% 13% 5% 3% 3% 2% 2%
30% 32% 4% 24% 17% 2% 1% 3% 4%
Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or ≤30% lower than pre-study drug infusion value, or Diastolic blood pressure of <50 mmHg.
Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or > 25% decrease from baseline.
Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value.
Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or ≥30% higher than pre-study drug infusion value or Diastolic blood pressure of >100 mmHg.
Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value.
Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.
Postmarketing Experience The following adverse reactions have been identified during post approval use of Precedex. 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. Hypotension and bradycardia were the most common adverse reactions associated with the use of Precedex during post approval use of the drug.
Table 7: Adverse Reactions Experienced During Post-approval Use of Precedex Body System
Body as a Whole
Fever, hyperpyrexia, hypovolemia, light anesthesia, pain, rigors
Cardiovascular Disorders, General
Blood pressure fluctuation, heart disorder, hypertension, hypotension, myocardial infarction
Central and Peripheral Nervous System Disorders
Dizziness, headache, neuralgia, neuritis, speech disorder, convulsion
Gastrointestinal System Disorders
Abdominal pain, diarrhea, vomiting, nausea
Heart Rate and Rhythm Disorders
Arrhythmia, ventricular arrhythmia, bradycardia, hypoxia, atrioventricular block, cardiac arrest, extrasystoles, atrial fibrillation, heart block, t wave inversion, tachycardia, supraventricular tachycardia, ventricular tachycardia
Liver and Biliary System Disorders
Increased gamma-glutamyl transpepsidase, hepatic function abnormal, hyperbilirubinemia, alanine transaminase, aspartate aminotransferase
Metabolic and Acidosis, respiratory acidosis, Nutritional Disorders hyperkalemia, increased alkaline phosphatase, thirst, hypoglycemia Psychiatric Disorders
Agitation, confusion, delirium, hallucination, illusion
Red Blood Cell Disorders
Blood urea nitrogen increased, oliguria
Respiratory System Disorders
Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion
Skin and Appendages Disorders
Photopsia, abnormal vision
OVERDOSAGE The tolerability of Precedex was studied in one study in which healthy subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second degree heart block. No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute. Five patients received an overdose of Precedex in the intensive care unit sedation studies. Two of these patients had no symptoms reported; one patient received a 2 mcg/kg loading dose over 10 minutes (twice the recommended loading dose) and one patient received a maintenance infusion of 0.8 mcg/kg/hr. Two other patients who received a 2 mcg/kg loading dose over 10 minutes, experienced bradycardia and/or hypotension. One patient who received a loading bolus dose of undiluted Precedex (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.
Manufactured and Distributed by: Hospira, Inc. Lake Forest, IL 60045 USA Licensed from: Orion Corporation Espoo, Finland Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA
Pharmacy Practice News • May 2011
Senate Bill Addresses Drug Shortages
wo Democratic lawmakers have introduced a bill in the U.S. Senate that aims to improve the FDA’s capability to prevent drug shortages. In the past year, these shortages have become a national crisis, threatening patient safety and disrupting clinical trials. If the Preserving Access to LifeSaving Medications Act (S. 296) is signed into law, manufacturers would be required to notify the FDA of any discontinuation, interruption or other adjustment in the manufacture of a drug that “would likely result in a drug shortage.” Companies would be required to provide at least six months notice prior
to the date of a manufacturing stoppage or other action affecting a drug’s availability. This covers adjustments related to the supply of raw materials, including active pharmaceutical ingredients; adjustments to production capabilities; and business decisions that may affect the manufacture of the drug, such as mergers, discontinuations and changes in production output. Penalties for failing to notify the FDA will be worked out if or when the bill is enacted, according to the legislative language. The bill also would require the FDA to take several actions. These include publishing information on existing drug shortages on the agency’s Web site
and “to the maximum extent practicable, [distributing] such information to appropriate health care provider and patient organizations.” The FDA also would be responsible for implementing evidence-based criteria for identifying drugs that may be vulnerable to shortages and collaborating with manufacturers to establish and improve continuity of operations plans with regard to medically necessary drugs. The Association of Community Cancer Centers, the American Society of Clinical Oncology and other health care organizations are lobbying in support of the bill. Sens. Amy Klobuchar (D-Minn.) and Robert P. Casey Jr. (D-Pa.), introduced the bill in February, and at press time, the bill had been referred to the Committee on Health, Education, Labor, & Pensions. —Kate O’Rourke
For First Time, Exercise Linked to Alleviation of IBS Symptoms
new study has shown that drug therapy isn’t the only option for easing the symptoms of irritable bowel syndrome (IBS). Regular exercise seems to be a viable additional treatment modality. In the study, Elisabet Johannesson, a registered physiotherapist at the Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Sweden, and her colleagues randomly assigned 38 patients meeting ROME-II criteria for IBS to participate in moderate to vigorous physical therapy for 20 to 60 minutes between three and five times per week. The exercises included walking, cycling, swimming and running or jogging, depending on the subject’s previous level of physical activity and individual factors such as cost and available time or opportunity. The researchers randomly assigned another 37 patients with IBS to a control group, where they were asked not to increase their level of physical activity. IBS-SSS (i.e., Severity Scoring System) scores fell an average of 51 points after 12 weeks in the treatment group, compared with a five-point decline in the control group (P=0.003), the investigators reported in The American Journal of Gastroenterology (2011 Jan 4. [Epub ahead of print]). Additionally, significantly more individuals in the physical activity group experienced improvements on IBS-quality of life measures of sleep and energy, relative to their baseline scores. Furthermore, individuals in both groups experienced significant improvements in emotional and social health compared with their baseline scores. The researchers noted, however, that there were no significant between- or within-group changes in all other measures. Ms. Johannesson said it was unclear why physical activity improves IBS symptoms, but she speculated that physical activity may mitigate the effects of stress on neuroendocrine response and visceral perception alterations. The findings substantiate the value of exercise as an “effective, easy-to-access therapy,” said Amy Foxx-Orenstein, DO, associate professor in the Department of Gastroenterology and Hepatology, Mayo Clinic, in Rochester, Minn., who was not involved in the study. “There are no negative side effects of this treatment. And because IBS is a chronic condition, choosing a treatment that has an excellent safety profile as well as a broad range of long-term health benefits is ideal.” —David Wild
FDA: Heed Magnesium Levels in Patients Taking PPIs
he FDA has announced that prescription proton pump inhibitor (PPI) drugs may cause low serum magnesium levels if taken for prolonged periods, usually longer than one year. Hypomagnesemia can cause serious adverse events (AEs), including muscle spasm, arrhythmias and seizures. Individuals with hypomagnesemia are often treated with magnesium supplements, but in approximately 25% of the cases reviewed, magnesium supplements alone did not improve low serum magnesium levels and PPI use was discontinued. Health care professionals should consider obtaining serum magnesium
levels prior to initiating prescription PPI treatment in patients expected to be on the drugs for long periods of time and in patients who take PPIs in combination with digoxin, diuretics or other drugs that may cause hypomagnesemia. For patients taking digoxin, this warning is especially important because low magnesium levels can increase the likelihood of serious side effects, the FDA stated in a press release. Health care professionals should
consider obtaining magnesium levels periodically during treatment in these patients as well. Clinicians and patients are encouraged to report AEs, side effects or product quality problems related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program at www.fda.gov/Safety/MedWatch. For additional information, refer to the Data Summary section of the FDA Drug Safety Communication online, or call (800) 332-1088. —Staff
New Bariatric Tube-Feeding Formula Launched
estlé HealthCare Nutrition recently announced the launch of Peptamen Bariatric, a unique tubefeeding formula specifically designed for the critically ill obese patient. The announcement came during the American Society of Parenteral and Enteral Nutrition’s Clinical Nutrition Week meeting, which took place earlier this year. Experts in the area of nutrition suggested that current nutrition protocols, and the more than 200 existing formulas on the market, unless manipulated, do not adequately meet the nutritional needs of critically ill obese patients, according to a press release from Nestlé. Although there are “more than 236 formulas, until recently not one met the recommended amount of protein and calories suggested to help support improved patient outcomes for this patient population,” said Robert Martindale, MD, PhD, chief of general surgery at Oregon Health & Science University, in Portland. “The lack of consistent and appropriate nutrition interventions for the critically ill obese patient means that some patients may be overfed, others may be underfed and become malnourished and others may not have their nutritional needs assessed at all,” added Stephen McClave, MD, professor of medicine at the University of Louisville School of Medicine, in Kentucky. Many of the existing tube-feeding formulas do not contain enough protein or the appropriate micronutrients for obese patients as recommended in the 2009 Critical Care Nutrition Guidelines, Nestlé stated. To address this need, Nestlé developed Peptamen Bariatric with a unique protein-to-calorie ratio, specifically designed to meet the protein requirements of critically ill obese patients. Peptamen Bariatric formula provides 37% of calories from 100% whey protein enzymatically hydrolyzed to produce peptides. The lipid blend in Peptamen Bariatric contains 50% medium-chain triglycerides to support improved formula tolerance and successful enteral feeding in this patient population. Peptamen Bariatric tube-feeding formula is the latest addition to the Nestlé Peptamen family of peptide formulas. For more information about Peptamen Bariatric Formula and other Peptamen products, visit www. Peptamen.com/Bariatric. —Staff
Pharmacy Practice News • May 2011
Tracking Use of IVIG Products Urged Jerry Siegel, PharmD, FASHP Clinical Associate Professor The Ohio State University College of Pharmacy Columbus, Ohio
Q: Should IV immunoglobulin (IVIG) products be tracked by lot number? A: The simple answer to this question is yes, but why is the subject of this IVIG FAQ. Most IVIG preparations are not simply one vial administered to each patient. As a matter of fact, most adult patients receive doses in excess of 40 g, and the largest vial size on the market is 20 g. This necessitates either serial infusion of multiple vials or combining several vials into a final container with the full dose for administration. In either situation, multiple vials and multiple lot numbers for vials will be used. Keep in mind that because all IVIG products are derived from blood, there is a very tight chain of control over the lots as the product is made. Blood from as many as 10,000 donors could be used to make a single batch of IVIG, and screening the donor as well as polymerase chain reaction testing of the blood now are required steps in the process. In the mid-1990s, there was a major recall of batches of IVIG from one manufacturer because it was determined that hepatitis C could be transmitted to patients through this product. To warn the patients who had received this product, it was important to know who received the affected lots. At that time, it was not common practice in the inpatient setting to track IVIG to the patient by lot number. Some hospitals handled IVIG through their blood banks, and they were more likely to have used lotnumber tracking for IVIG, as they do for all blood products. Hospitals that purchased their IVIG through the pharmacy department might have been able to determine the lots they purchased but not really which patients received those specific lots. This issue was very serious because many more patients had to be warned and tested than necessary. After this incident, all of the manufacturers of IVIG products employed numerous methods to prevent viral transmission, such as solvent detergent, caprylate, and nanofiltration. However, because new viruses form and old ones mutate, it is never 100% guaranteed that viral transmission will not be a problem in the future. Besides these issues with viruses, there have been recalls of IVIG products, the most recent being recalls of Octagam (Octapharma) due to increasing reports of thromboembolism related
to the product and of Gammagard Liquid (Baxter) related to increased reports of allergic reactions. In these situations, it is very important that the products be sequestered but also that they be tracked to patients who have received them. Most adverse reactions related to IVIG occur during the infusion, but many others can be delayed in their onset and physicians and patients may not recognize that the reaction is related to IVIG.
Renal failure, aseptic meningitis, and thromboembolic disorders are among the potentially delayed adverse events that may be caused by IVIG infusions. As a standard practice for IVIG safety, it would be prudent for the patient to always know the brand of product that is being infused and that the physician record the brand in the patient’s chart. It is equally important that the pharmacy keep track of the lot num-
bers used to prepare the IVIG dose for that patient and store those records for potential future use. For ease of use, a bar-coded system could be employed but at least a manual log should be kept. One final word of advice is that the bar code on the box (ie, bulk packages contain more than one vial) is not always the same as the bar code on the vial, and the bar code on the vial is the one you want! Dr Siegel reported a consulting agreement with CSL Behring.
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62 Operations & Management
Pharmacy Practice News • May 2011
Leadership in Action
Leadership in Pharmacy: A Cheat Sheet of Best Practices “The greater part of instruction is being reminded of things you already know.” —Plato This month, we begin a new series based on the work of noted leadership author John Maxwell. Over the next several months, I will highlight pertinent points from “Leadership Gold” (Nashville, TN: Thomas Nelson; 2008) as they apply to us as pharmacy leaders.
Should It Be Lonely at the Top? We may have been taught that leaders need to distance themselves from the employees they lead. This is a philosophy that is long outdated. As leaders, we are in the business of developing leaders. The reality is that we have not achieved our current level without the help of others around us. Pharmacy and medicine have accentuated the team approach to patient care. As John Maxwell states, “There is a big difference between a boss and a leader. A boss says, ‘Go.’ A leader says, ‘Let’s go.’” The purpose of leadership is to take others to the top. It is imperative for the leader to connect to his or her employees and communicate to them that you have their best interest at heart. It’s all about relationships. You care about their development and advancement. You bring people along, rather than dictate based on your position. When people know you care about them, they usually are willing participants and not obligatory robots. Do your employees understand that your department is a team of high-quality patient caregivers, each charged with a role and responsibilities within that framework? The focus is on what we can accomplish as a group and not on the hierarchies. So if we are lonely at the top, it is a consequence of our choice to distance ourselves from our employees.
Leadership Starts With Us The reality is that self-leadership is our biggest challenge. If we look back over our careers, we realize that we have made leadership mistakes along the way. We pride ourselves on being a good judge of another’s character, but we also need to look in the mirror. Maxwell points out an interesting fact in this regard: We tend to judge others on actions, but we judge ourselves based on our intent and not necessarily our actions. We’re too close to the issue. This makes us harder on others than we may be on ourselves. So what are the keys to leading ourselves? 1. Know how to follow. We connect with our people because we’ve walked
in their shoes. We appreciate where they are coming from and the challenges they face each day. In the past, we were followers too. Good leaders need to know how to follow and how to lead. There is no place for autocratic, arrogant, authoritarian leadership; that only alienates people. By learning how to follow, good leaders do so in humble effectiveness out of respect for their employees.
career. That role taught me to value the pharmacy technicians whom I supervised. I cared about them and they knew it. As a result, they did an extraordinary job and we were a great team. Often, defining moments may include losing a job or deciding to move on to another position; one of those occurrences is unplanned and the other is planned. Both require a self-assessment and will have a leadership career impact. These defining moments show our character and resolve. Personal and professional accomplishments define our leadership. Decisions in a crisis often can cement our relationships if handled well, or turn people away if handled poorly. Our credibility is at stake.
“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Steward Health Care System, Boston, Mass. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ steward.org.
Ernest R. Anderson Jr., MS, RPh
have a realistic view of ourselves. There are times when we need to realize that the criticism is of our position and not us personally. Other times, unwarranted criticism is a reflection of someone’s weakness. However, if the criticism is accurate, then we need to take it to heart and make appropriate changes. One has to ask whether the criticism is constructive or destructive. When I am criticized, I usually look for the grain of truth in what is said. I also try to maintain an attitude of self-improvement. We also should not feel pressured to become someone we are not. We need to be ourselves, but be open to improvement within that context. Don’t pretend
Do you love your job? Are you challenged when you come to work and do you possess a sense of purpose in the big picture?
2. Demonstrate self-discipline. We rule ourselves. Consistently making good choices requires character, integrity and self-control. 3. Be patient. Things that are worthwhile in life take time. Looking back over my career, I realize that leadership is a never-ending process. Leadership is about bringing others with us. 4. Have accountability partners. Surround yourself with a few good “truth tellers,” those trusted individuals willing to give you necessary, honest feedback. Also, it is wise to seek the advice of these trusted individuals in your decision-making processes. We are obliged to fix ourselves first to earn the privilege to lead others. Do both a self-evaluation and a peer evaluation and determine your personal areas for improvement.
What are the moments that defined you and your career? For me, agreeing to write a monthly column on leadership in Pharmacy Practice News was a defining moment some five years ago. Although I have spent many weekends writing articles, the letters, emails and comments I get from people make it all worthwhile. The process has gotten me to read many leadership books that I might otherwise have never read. People often speak to me about balance in life. Sometimes crises force us to become more balanced. I know many people who have neglected their physical health until a health crisis forces them to commit to a diet and exercise program. Agreeing to run for executive office in the Association of Community Cancer Centers led to me becoming the first pharmacist elected as president of that organization—another defining moment in my career. The best advice is to look for defining moments in your life. Take advantage of them and do not let them pass by. These moments often are accompanied by a risk. Don’t fear to take the risk. As you mentor others in the pharmacy profession, speak to them about your defining moments to encourage your successors.
Looking at our careers, there are likely some defining moments in our lives that shaped us into the leaders we have become. I think back to my first role as a supervisor only a short time into my
As a leader, by definition you expose yourself to everyone with whom you work. People are watching, and some will be critical. So how do you handle criticism? Do you withdraw? We need to
to be someone else; people quickly see through a phony. Lastly, we need to be able to laugh at ourselves. Relating humorous stories of “I can’t believe I did this” shows our human side and reflects self-confidence in sharing our mistakes and shortcomings.
Follow Your Passion Do you love your job? Are you challenged when you come to work and do you possess a sense of purpose in the big picture? Certainly there are enough challenges in health care to go around. However, when you look at the patient-care aspect of what we do or the advancement of the profession of pharmacy, does your level of satisfaction keep you moving, energized, positive about your daily work life? Ask yourself, what is my passion? Over my professional years, my passion has been in leading others to be successful and seeking to move the pharmacy profession forward. When I can accomplish these goals in some way, I feel a great sense of reward. Finding your passion in your work is a great motivator. Passion encourages us to take risks; it focuses us to believe in ourselves; and it motivates our success and accomplishments. Knowing our passion requires self-assessment. Turning our passion into actions requires commitment. Are you in the place where you want to be? When you have found your “sweet spot,” your passion becomes your motivation. Help others to find their passion.
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64 Operations & Management
Pharmacy Practice News • May 2011
ACADEMY continued from page 1
and the issues that pharmacists face in terms of leadership are more demanding,” said Sharon Murphy Enright, president of EnvisionChange LLC, and course master and faculty for the PLA. “These issue require skills, capabilities and knowledge not typically part of pharmacy curricula.” Students in the PLA program complete nine different online courses over 15 months. And now, thanks to the new alliance between the Foundation and GlobalHealth Education, students who complete the six-week courses receive credit waivers for online master’s programs offered by colleges and universities in areas such as health administration, informatics and public policy. The PLA may be completed before, during or after the master’s program. “This is a great opportunity and a great value for our students seeking an advanced degree,” said Ms. Enright. In addition to earning PLA-equivalent credits—the number of which varies by school—PLA students receive a Leadership Certificate and 135 Accreditation Council for Pharmacy Education–accredited continuing education credits. PLA alumni can take advantage of the new advanced standing offer by taking two six-week capstone courses.
‘Almost all of the [PLA] students have called the experience ‘life-altering’ in how they approach their job.’ —Philip E. Johnson, MS, RPh Each of the nine modules has a unique focus and is taught by a renowned American Society of Health-System Pharmacists pharmacy practice leader. Through presentations and case-based interactive components, students gain
knowledge and skills in topics such as building presence with executive leadership, leading for results and leadership for safety and quality. Philip E. Johnson, MS, RPh, who teaches the “Leading People” module, believes
that the PLA provides pharmacists with “leadership tools and experience to more effectively apply what they already know, [to gain] broader insights into leadership opportunities in the increasingly complex and collaborative environment we work in. Almost all of the students have called the experience ‘life-altering’ in how they approach their job,” added Mr. Johnson, founding director of pharmacy at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., who also serves as vice president of Allied Health for GlobalHealth Education.
Take IV iron therapy to a proven place:
Educational & Commercial Reprints Reprinted from
How To Sift Through 340B Resources Call (800) 628-6297 or e-mail PSSC@ aphanet.org to request this service.
Katheryne Richardson, PharmD Senior Quality and Compliance Specialist
The 340B Journey
PSSC developed the 340B Journey, an Reprinted from extranet, as a place to put all of the most reliable 340B information. The 340B Journey is a collection of resources—links, documents, photos, videos, tools and presentations. PSSC has sifted through all of the 340B information available on the Volume 36 • Number 11 • December 2009 Internet and vetted that information so that only the best and most accurate 340B resources were posted on improved the site. For blood glucose control ... The site is organized into the following sections: Tip of the week: This section changes on a weekly basis and contains general information that offers quick assistance ithin a year of incorporating an FDA-approved software system into their to users. glucose Quick search: The quickblood search tool management protocols, staff at the 188-bed Kadlec Regional Medical Center in Richland, Wash., were able to provide improved blood allows users to search the site for (KRMC) key terms. This tool also glucose searchesmanagement the entire to patients in the adult intensive care unit (ICU) without raising the risk for hypoglycemia. APhA library for relevant information. journey started in 2001, when staff reviewed the literature and saw the need Getting started: ThisThe section contains to balance blood glucose management with the risk for hypoglycemia. comprehensive information for allgood entities follows an account of KRMC’s experience implementing the new protocol— in the 340B program.What Folders are istitled with an analysis with all of the differentalong entity types; users of its impact on key patient outcomes—authored by Pamela W. Renard, simply click on the folder of choice to find PharmD, pharmacy clinical coordinator at KRMC. Ricci, a PharmD student at Washington State University in Pullman, all of the information Benton they need to enroll assisted in preparing the manuscript. and implement the 340B program at the eligible site. Any entity-specific information also is listed in this section. Due Diligence Policy and education: Users can find to the ICU, to have a longer hospital relevant PowerPoint presentations, 340B glucose manageIn the past, blood length of stay and to be discharged to an educational modulesment and the hadmost notcurrent been a main focus area extended-care facility. policy information.inPSSC’s Policy Then Blast, in 2001, a seminal most ICUs. These new data prompted interest in a newsletter containing study policy by Vandevelopden Berghe et al revealed the question of whether blood glucose ments specific to the 340B program, can that maintaining blood glucose levels management through intensive insulin be found here. between 80 and 110 mg/dL in critically ill treatment could improve patient progPatient safety adult and quality initia-to an overall reducpatients leads nosis in the ICU. The data also raised tives: This sectiontion includes all of the in morbidity and mortality.1 With other concerns: How do we effectively latest information and resources relating this study in mind, our staff set out to manage blood glucose levels in a comthe HRSA Patient Safety and Clinical Pharprovide a level of care that would bring munity hospital ICU? Is intensive insulin macy Services Collaborative and other patients’ blood glucose within that range. therapy safe for our patients? These are federal and private sector programs relatHowever, managing individual insulin ing to improving patient safety.
Health Resources and Services Administration, Pharmacy Services Support Center
here are various sources of information on the 340B Drug Pricing Program, and it can be hard to decipher what information is good and what information is not. This article outlines some of the organizations and resources available to help you with the 340B program.
Community Hospital ICU Turns to Software Program
The Pharmacy Services Support Center The Health Resources and Services Administration (HRSA) Pharmacy Services Support Center (PSSC) is the government-approved resource for all 340B information. PSSC operates through a contract between HRSA and the American Pharmacists Association (APhA). PSSC was created to help federally funded clinics and other health care safety net providers develop clinically and costeffective pharmacy services. Central to this endeavor is optimal use of the 340B Drug Pricing Program, which is run by the Office of Pharmacy Affairs (OPA) in the HRSA Healthcare Systems Bureau. PSSC provides free information, education and technical assistance to increase patient access to affordable drugs and pharmacy services. Reach out to the PSSC call center (800) 628-6297 for any questions concerning 340B. This free resource is available to help with all of your 340B inquiries. Staff, trained in the various issues relating to the 340B program, is on hand to answer questions or direct your calls to the appropriate people. The call center operates 9 a.m. to
4:30 p.m. (Eastern Time). Or e-mail PSSC anytime at PSSC@aphanet.org. In addition to the call center, PSSC manages a free technical assistance (TA) program, PharmTA, in partnership with OPA. This resource provides 340B-eligible entities solutions directly from expert pharmacist consultants. An objective-based work plan guides the process, and TA is delivered via phone, e-mail or site visit.
Reprinted with permission from Pharmacy Practice News • Volume 37 • Number 1 • January 2010 • Pages 52–53
important questions, because a continuous infusion of insulin to achieve a relatively low blood glucose level could put our patients at risk for hypoglycemia. Then in 2003, Van den Berghe et al published another important study of blood glucose management, indicating an increased risk for hypoglycemia with intensive treatment. In the study, the rate of hypoglycemia (blood glucose <40 mg/dL) was 5.2% in the intensive treatment arm compared with 0.8% in the conventional treatment arm.4 Although the authors characterized the hypoglycemic episodes as “brief” and “clinically harmless,” the side effect nevertheless has the potential for causing serious patient harm and is as much a concern as hyperglycemia. If blood glucose falls low enough, a patient may lose consciousness or go into a coma, which may lead to long-term health complications.5 In March 2009, the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation)6 trial was released.
infusions outside of a clinical research setting can be time-consuming for physicians, nurses and pharmacists. Stressinduced hyperglycemia causes frequent fluctuations of blood glucose levels and insulin resistance, making blood glucose management in this patient population very difficult.2 In 2002, a study by Umpierrez et al compounded the issue by revealing that new-onset hyperglycemia may have more detrimental effects in patients without a history of diabetes than in those with an established history of the disease.3 The study showed that patients with new-onset hyperglycemia had a higher rate of in-hospital mortality (16%) than patients with a known history of diabetes (3%; P<0.01), no matter where in the hospital they were admitted. These same patients also were more likely to be admitted
Reprints of Pharmacy Practice News articles are available in minimum quantities of 500. Reprints can be ordered in black & white or 4-color versions and printed on 80-lb. glossy stock. Standard turnaround time is 4 weeks. For specific price quotes,
call Dave Kaplan at
IMPORTANT SAFETY INFORMATION: Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Serious hypersensitivity reactions have been reported in patients receiving Venofer®. In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration. Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving IV iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose delivered. In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were taste disturbance (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). In an additional study of Venofer® with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events, whether or not related to Venofer® reported by 5% of Venofer® exposed patients are as follows: diarrhea (16.5%), edema (16.5%), nausea (13.2%), vomiting (12.1%), arthralgia (7.7%), back pain (7.7%), headache (7.7%), hypertension (7.7%), taste disturbance (7.7%), dizziness (6.6%), extremity pain (5.5%), and injection site burning (5.5%).
(212) 957-5300 x912. Leading anemia management.™
Pharmacy Practice News • May 2011
Operations & Management 65
Leadership PLA students may not be the only ones who benefit from the program. Since its inaugural class, feedback from students and sponsoring organizations underscores the value to both the individual and organizations, according to Ms. Enright.
The ASHP Foundation’s Role Richard Walling, RPh, director of the ASHP Foundation’s Center for HealthSystem Pharmacy Leadership, said the center, an integral player in the new e-learning initiative, was created “to
‘This is a great opportunity and a great value for our students seeking an advanced degree.’ —Sharon Murphy Enright expand and develop the leadership capacity of the profession and individual professionals. The PLA is a key component.”
A rolling application process is under way for the PLA class of 2012. Pharmacists with at least five years of postdegree pharmacy practice experience and who aspire to assume greater pharmacy leadership responsibilities are encouraged to apply. Registration fees for ASHP members are $7,500, and slightly more for non-members or for those whose applications are received after June 30. Additional information can be found at www.ashpfoundation.org. Ernest Anderson Jr., MS, RPh, system vice president for Steward Health in
Over 9 million patients treated with 180 million units* 1
First-line IV iron for adult pre-dialysis CKD patients... In treatment of iron deficiency anemia • Raises hemoglobin levels and improves iron stores 2 • Effective with or without erythropoietin
With a demonstrated safety profile • Contains no dextran or modified dextran • No test dose required; no black box warning • Greater tolerability than oral iron with fewer gastrointestinal symptoms
For treatment of iron deficiency anemia in adult non-dialysis dependent-chronic kidney disease patients whether or not receiving an erythropoietin. Contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Serious hypersensitivity reactions have been reported in patients receiving Venofer ®.
Millions prescribed. Millions treated.
*100 mg vials and ampules worldwide from 1992 to February 2010.
Please see brief prescribing information and references on following pages. Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2010 American Regent, Inc. • Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com
Boston, and the author of the “Leadership in Action” column for Pharmacy Practice News, applauded the new e-learning initiative. “This is a premier opportunity for students to enhance their leadership advancement in the medical profession, applying the skills learned in the PLA and through the alliance with GlobalHealth Education,” he said. “I often wonder where the next generation of pharmacy leaders will come from, and programs like this ease some of my concerns.” —Lynne Peeples
Reference: 1. Data on file. American Regent, Inc., Shirley, NY. 2. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S, for the United States Iron Sucrose (Venofer®) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005;68:2846-2856.
(Table 2 continued)
Brief Summary (See Package Insert For Full Prescribing Information) Therapeutic Class: Hematinic CLINICAL INDICATIONS AND USAGE Venofer® (iron sucrose injection,USP) is indicated in the treatment of iron deficiency anemia in the following patients: • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin CONTRAINDICATIONS The use of Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. WARNINGS Hypersensitivity reactions have been reported with injectable iron products.See PRECAUTIONS and ADVERSE REACTIONS. PRECAUTIONS General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload.Patients receiving Venofer® require periodic monitoring of hematologic and hematinic parameters (hemoglobin,hematocrit,serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum iron values may be reliably obtained 48 hours after IV dosing.See DOSAGE AND ADMINISTRATION and OVERDOSAGE. Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving Venofer®. No life-threatening hypersensitivity reactions were observed in the clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening hypersensitivity reactions in patients receiving Venofer.See ADVERSE REACTIONS. Hypotension: Hypotension has been reported frequently in hemodialysis dependent chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose administered. Caution should be taken to administer Venofer® according to recommended guidelines. See DOSAGE AND ADMINISTRATION. Carcinogenesis,Mutagenesis,and Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer®. Venofer® was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Venofer® at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Venofer®. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response,this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Venofer® is excreted in milk of rats.It is not known whether this drug is excreted in human milk.Because many drugs are excreted in human milk,caution should be exercised when Venofer® is administered to a nursing woman. Pediatric Use: Safety and effectiveness of Venofer® in pediatric patients have not been established. In a country where Venofer® is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer®, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugs could be established. Geriatric Use:The five pivotal clinical trials did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients,but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Adverse Events observed in all treated populations The frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis dependent and 75 peritoneal dialysis dependent-CKD patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent-CKD patients for a total of 1,496 patients. In addition,over 2,000 patients treated with Venofer® have been reported in the medical literature. Treatment-emergent adverse events reported by 2% of treated patients with NDDCKD in the randomized clinical trials, whether or not related to Venofer® administration, are listed by indication in Table 2. Table 2. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Clinical Indication (Multidose Safety Population) NDD-CKD Oral Iron Adverse Events Venofer® (Preferred Term) (N=139) (N=139) % % Subjects with any adverse event 76.3 73.4 Ear and Labyrinth Disorders Ear Pain 2.2 0.7 Eye Disorders Conjunctivitis 0 0 Gastrointestinal Disorders Abdominal pain NOS* 1.4 2.9 Constipation 4.3 12.9 Diarrhea NOS 7.2 10.1 Dysgeusia 7.9 0 Nausea 8.6 12.2 Vomiting NOS 5.0 8.6 General Disorders and Administration Site Conditions Asthenia 0.7 2.2 Chest pain 1.4 0 Edema NOS 6.5 6.5 Fatigue 3.6 5.8 Feeling abnormal 0 0 Infusion site burning 3.6 0 Injection site extravasation 2.2 0 Injection site pain 2.2 0 Peripheral edema 7.2 5.0 Pyrexia 0.7 0.7 Infections and Infestations Catheter site infection 0 0 Nasopharyngitis 0.7 2.2 Peritoneal infection 0 0 Sinusitis NOS 0.7 0.7 Upper respiratory tract infection NOS 0.7 1.4 Urinary tract infection NOS 0.7 5.0 Injury, Poisoning and Procedural Complications Graft complication 1.4 0 Investigations Cardiac murmur NOS 2.2 2.2 Fecal occult blood positive 1.4 3.6 Metabolism and Nutrition Disorders Fluid overload 1.4 0.7 Gout 2.9 1.4 Hyperglycemia NOS 2.9 0 Hypoglycemia NOS 0.7 0.7 Musculoskeletal and Connective Tissue Disorders Arthralgia 1.4 2.2 Arthritis NOS 0 0
Treatment-emergent adverse events reported in 2% of patients by dose group are shown in Table 3. Table 3. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)
Adverse Events (Preferred Term) Subjects with any adverse event Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain NOS* Constipation Diarrhea NOS Dysgeusia Nausea Vomiting NOS General Disorders and Administration Site Conditions Asthenia Chest pain Edema NOS Fatigue Feeling abnormal Infusion site burning Injection site pain Peripheral edema Pyrexia Infections and Infestations Catheter site infection Nasopharyngitis Peritoneal infection Sinusitis NOS Upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications Graft complication Investigations Cardiac murmur NOS Fecal occult blood positive Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia NOS Hypoglycemia NOS Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp 0 Myalgia
NDD-CKD 200 mg 500 mg (N=109) (N=30) % % 75.2 80.0 0.9
1.8 3.7 6.4 9.2 9.2 5.5
0 6.7 10.0 3.3 6.7 3.3
0.9 0.9 7.3 4.6 0 3.7 2.8 5.5 0.9
0 3.3 3.3 0 0 3.3 0 13.3 0
0 0.9 0 0 0.9
0 0 0 3.3 0
1.8 1.8 3.7 0.9
0 6.7 0 0
(Table 3 continued)
NDD-CKD Venofer® Oral Iron (N=139) (N=139) % %
Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Back pain Muscle cramp0.7 Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Hypoesthesia Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Dyspnea exacerbated Nasal congestion Pharyngitis Rhinitis allergic NOS Skin and Subcutaneous Tissue Disorders Pruritus Rash NOS Vascular Disorders Hypertension NOS Hypotension NOS *NOS=Not otherwise specified
2.2 3.6 4.3
3.6 0 0
6.5 2.9 0.7
1.4 0.7 0.7
2.2 3.6 2.2 1.4 0 0.7
0.7 0.7 0.7 2.2 0 2.2
Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Pharyngitis Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension NOS Hypotension NOS
NDD-CKD 200 mg 500 mg (N=109) (N=30) % % 4.6
0.9 1.8 0
6.7 10.0 0
*NOS=Not otherwise specified
Drug related adverse events reported by 2% of Venofer® (iron sucrose injection, USP) treated patients are shown by dose group in Table 4. Table 4. Most Common Adverse Events Related to Study Drug Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)
Adverse Events (Preferred Term) Subjects with any adverse event Gastrointestinal Disorders Diarrhea NOS* Dysgeusia Nausea General Disorders and Administration Site Conditions Infusion site burning Injection site pain Peripheral edema Nervous System Disorders Dizziness Headache Vascular Disorders Hypotension NOS
200 mg (N=109) % 23.9
500 mg (N=30) % 20.0
0 7.3 2.8
0 3.3 0
3.7 2.8 1.8
0 0 6.7
*NOS=Not otherwise specified Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients In a multi-dose efficacy study in non-dialysis dependent-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were taste disturbance (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). In an additional study of Venofer® with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events, whether or not related to Venofer® reported by 5% of Venofer® exposed patients are as follows: diarrhea (16.5%), edema (16.5%), nausea (13.2%), vomiting (12.1%), arthralgia (7.7%), back pain (7.7%), headache (7.7%), hypertension (7.7%), taste disturbance (7.7%), dizziness (6.6%),extremity pain (5.5%),and injection site burning (5.5%). Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. In clinical studies,several patients experienced hypersensitivity reactions presenting with wheezing,dyspnea,hypotension,rashes,or pruritus. Serious episodes of hypotension occurred in 2 patients treated with Venofer® at a dose of 500 mg. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse,bronchospasm with dyspnea,or convulsion) associated with Venofer® administration. OVERDOSAGE Dosages of Venofer® (iron sucrose injection,USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis.Periodic monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation.Venofer® should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines . Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia. Symptoms associated with overdosage or infusing Venofer® too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution as recommended or at a slower rate may also alleviate symptoms. Preclinical Data: Single IV doses of Venofer® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation,hypoactivity,pale eyes,and bleeding in the gastrointestinal tract and lungs. DOSAGE AND ADMINISTRATION The dosage of Venofer® is expressed in terms of mg of elemental iron.Each mL contains 20 mg of elemental iron. Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron,administered over sequential sessions,to achieve a favorable hemoglobin response and to replenish iron stores (ferritin,TSAT). Administration:Venofer® must only be administered intravenously either by slow injection or by infusion. Recommended Adult Dosage: Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period.There is limited experience with administration of an infusion of 500 mg of Venofer®,diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated. (See CLINICAL TRIALS,Study D: Non-Dialysis DependentChronic Kidney Disease (NDD-CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients sections.) HOW SUPPLIED Venofer® is supplied in 5 mL and 10 mL single dose vials. Each 5 mL vial contains 100 mg elemental iron (20 mg/mL) and each 10 mL vial contains 200 mg elemental iron (20 mg/mL).Contains no preservatives.Store in original carton at 25°C (77°F).Excursions permitted to 15°-30°C (59°-86°F).[See the USP controlled room temperature]. Do not freeze. Sterile NDC-0517-2340-01 100 mg/5 mL Single Dose Vial Individually Boxed NDC-0517-2310-01 200 mg/10 mL Single Dose Vial Individually Boxed NDC-0517-2340-10 100 mg/5 mL Single Dose Vial Packages of 10 NDC-0517-2310-05 200 mg/10 mL Single Dose Vial Packages of 5 NDC-0517-2340-25 100 mg/5 mL Single Dose Vial Packages of 25 NDC-0517-2310-10 200 mg/10 mL Single Dose Vial Packages of 10 Rx Only REFERENCE:  National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis. 37:S182-S238,(suppl 1) 2001.
BS2340 Rev.5/10 Venofer® is manufactured under license from Vifor (International) Inc.,Switzerland.
VENJA Rev.5/2010 © 2010 American Regent,Inc
Pharmacy Practice News • May 2011
Another Telepharmacy Success Story C ‘Technology is not a way to replace pharmacists. If done
apitalizing on an upgrade to their facilities’ health information technology systems, pharmacists at seven rural Iowa hospitals gathered a few years ago to start a telepharmacy service offering around-the-clock (ATC) medication order review. As a result of the initiative, medication errors have been reduced and charge capture for the drugs administered has improved, at least anecdotally, according to Douglas S. Wakefield, PhD, an investigator studying the impact of the telepharmacy service. In addition to the improved outcomes, “physicians appreciate [the service] because it gives another set of eyes on some critical decisions,” said Dr. Wakefield, professor of health management and informatics at the University of Missouri Informatics Institute, in Columbia, and director of the university’s Center for Health Care Quality. Dr. Wakefield was formerly with the University of Iowa and coauthored a proposal that started the project, which was described in a recent article in the American Journal of Health-System Pharmacy (2010;67:2052-2057). The article focuses on the Mercy Health NetworkNorth Iowa, which serves 14 counties in north central Iowa with a population of more than 200,000. The program included Mercy Medical Center-North Iowa in Mason City, a larger rural 241bed referral hospital and six of the network’s nine critical access hospitals with 25 or fewer beds.
A Staffing Challenge At the start of the program, most of the participating hospitals had only one pharmacist on staff, generally working from 7 a.m. to 3 p.m. each day. Although some had pharmacy help from a larger referral hospital or on-call community pharmacists, for the most part nurses were legally authorized to enter the pharmacy to pull medications ordered by physicians, and leave a copy of the paperwork for the pharmacist to review. But “it could have been from Friday until Monday before [a pharmacist] looked at the orders,” said Nancy Abbas, RPh, director of pharmacy at Hancock County Memorial Hospital in Britt, Iowa, a 25-bed critical access hospital that was part of the telepharmacy initiative. Now, with the implementation of a number of shared computerized systems, including an electronic health record (EHR), computerized prescriber order entry (CPOE) and a pharmacy information system, medication orders written after hours, holidays or week-
correctly, it provides an opportunity to expand pharmacy coverage and our mission in taking care of the patient.’ —Karl Gumpper, RPh ends are entered electronically and emailed to covering pharmacists at a larger hospital in Dubuque, who typically review the orders within an hour
macy email account. Remote pharmacists then open the email containing the order as an attachment and process it in the system. Orders are then
‘One of the goals of this initiative was to decrease our rate of medication dispensing errors because of tighter control prior to the administration of medications to patients.’ —Kip Ewen, RPh of being sent, or quicker for stat orders. To initiate ATC medication order review, both on-site and remote pharmacists were given access to medication orders, the pharmacy information system and clinical data in EHRs. Pharmacists developed a standardized formulary, accessible through the pharmacy information system. Orders entered by a provider are automatically received by the remote pharmacy during hours of coverage through an integrated EHR (Cerner Corp.). A group email account was created through Trinity Health and is accessible to all regional and remote pharmacists. Each hospital has at least one scanner that can scan stat or regular orders to the email account. Nurses can scan written and signed orders, select the priority of the order and send it as an email message to the remote phar-
stored in site-specific folders, where the local pharmacists can review them when they return to work. After completing a review, the pharmacist selects the appropriate medication to dispense from the agreed-on formulary. Each drug in the formulary has a National Drug Code, embedded in bar codes, used for subsequent dispensing and bar code medication administration (BCMA). Between February and April 2009, the remote pharmacists reviewed more than 13,000 medication orders, approving 9,163, modifying 1,294, discontinuing 972 and voiding 179. The rural hospitals pay $4 per order reviewed remotely.
Integration Deemed Key Ms. Abbas stressed that proper integration is a crucial component to mak-
ing telepharmacy work. She said she helped ensure the telepharmacy system’s integration when employed by Mercy Medical Center-North Iowa. Ms. Abbas organized weekly conference calls to determine a standardized formulary, develop new policies and procedures, streamline workflow processes and organize how the seven hospitals would collaborate. Now, as patients are transferred between rural and larger hospitals in the network, pharmacists can see all patient records online, including laboratory and x-ray results, medication reconciliation and when patients last took medication. The pharmacists also can log in to the system from home to help out if necessary, “so patients get the right medication at the right dose, as approved by a pharmacist,” said Ms. Abbas, adding that standardizing has been “great. We all work together as part of a team. People know what to expect at each place. It’s easier to cover each other for vacations.” The group still talks monthly via conference call to discuss ongoing formulary issues.
Outcomes Data Elusive “One of the goals of this initiative was to decrease our rate of medication dispensing errors because of tighter control prior to the administration of medications to patients,” said Kip Ewen, RPh, director of pharmacy at Kossuth Regional Health Center in Algona, Iowa. Although there are no hard data on that outcome, the hospital did achieve a significant increase in the number of medication orders reviewed. “That suggests that there is a major opportunity for potential errors to be detected,” he noted. Mr. Ewen said the system also has cut down the time he spends having to charge patient accounts for medications, which is now taken care of automatically through the computer system. Dr. Wakefield acknowledged that there are no hard data on medication error reductions from the telepharmacy initiative. “The reduction in errors that we saw, along with improved charge capture, was based on
see TELEPHARMACY, page 68
Pharmacy Practice News • May 2011
TELEPHARMACY continued from page 67
anecdotal reports from nursing and other staffers,” he said. “It’s not something we actively tracked.” He stressed, however, that there is one outcome that is well established in the literature: the staff satisfaction that comes with having pharmacists review medication orders via telepharmacy. “Five studies cited in the AJHP paper show that satisfaction with pharmacist review of medication orders can be
About 11% of the time, the scanner triggered an audit alert for a variety of reasons. ... ‘Those alerts are helping us avoid potential medication errors.’ —Nancy Abbas, RPh quite high,” Dr. Wakefield said. “In the critical access hospitals, that was certainly the case: We interviewed all of the chief nurses and pharmacy directors, and they told us that physician response
to this system has been very positive.” As for future research efforts, he noted that several of the hospitals that implemented BCMA to verify drug orders and track near misses plan on publishing
those data. “Some of the anecdotes that have come back from nurses have been very positive,” he said. Actual data are in fact beginning to emerge, Ms. Abbas said. In 2010, she noted, the seven hospitals used mobile bar-code scanners to review and administer 331,726 medications. About 11% of the time, the scanner triggered an audit alert for a variety of reasons: giving the medication too early or late, needing to cut a pill in half, needing to scan an extra dose, a medication is expired, etc. “Those alerts are helping us avoid potential medication errors,” she said.
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Ann Rathke, telepharmacy coordinator for the North Dakota Telepharmacy Project of North Dakota State University’s College of Pharmacy, Nursing and Allied Sciences, in Fargo, said she was impressed by the Iowa project, including its novel use of email: “This network of hospitals developed infrastructure that allows participating rural hospitals to have increased access to pharmacy services … standardizing the drug formulary and medication-related policies and procedures also contribute to a high-quality system, which will ultimately result in higher patient safety. “The only thing that would [improve] this implementation would be the addition of a process for tracking, reporting and analyzing medication errors and near misses,” she said, as there is a continuing need for that kind of data. Dr. Wakefield agreed that such data in the published literature are lacking—a point he made in his AJHP paper.
ASHP’s Take Although the American Society of Health-System Pharmacists (ASHP) does not have statistics on the number of telepharmacy systems in operation, it is a growing trend, said Karl Gumpper, RPh, director of ASHP’s Section of Pharmacy Informatics & Technology. In a 2007 ASHP informatics survey of 1,066 hospitals, 23% reported using offsite medication order review and entry technology (Am J Health Syst Pharm 2008;65:2244-2264). ASHP added two telepharmacy goals from its Pharmacy Practice Model Initiative Summit last fall, stating that telepharmacy technology, to enable remote supervision, should be available for use in pharmacy departments, along with technology that allows pharmacists to interact with patients from a remote location. “Technology is not a way to replace pharmacists,” Mr. Gumpper said. “If done correctly, it provides an opportunity to expand pharmacy coverage and our mission in taking care of the patient.” —Karen Blum
Pharmacy Practice News • May 2011
In Brief FDA Launches WebBased Search Engine For Recalled Drugs and Other Products
s of April 4, the FDA has made searching for recalls of food, drugs and other products easier and faster. The Food Safety Modernization Act (FSMA), which was signed into law earlier this year by President Barack Obama, called for the FDA to provide a more consumer-friendly recall search engine within 90 days after the law went into effect. The act also requires the FDA to indicate whether a recall is ongoing or has been completed.
application for your clinical colleagues, but can’t see a way to develop it? Check out RockHealth, which has been called the first incubator devoted to seeding health care software. Founded by Apple alumna Halle Tecco, the San Francisco-based nonprofit has begun accepting applications for its first round of grants: $20,000 each, along with mentoring by experts from the worlds of medicine, law and business. RockHealth is partnering with the Mayo Clinic Center for Innovation and Cincinnati Children’s Hospital, and has
received funding from sources including Microsoft, Nike and Qualcomm. In addition to capital, winners will receive office space in San Francisco to work on their projects, counseling on marketing and messaging about the
product from an in-house expert, and other assistance. “We’re really trying to … reduce all the barriers and eliminate all the excuses that developers could possibly have, and give them a place where they can take their ideas and turn them into products and businesses,” Ms. Tecco told the San Francisco Chronicle. The deadline for the first round of funding is May 20, 2011. For more information, visit http://rockhealth.com/ program/. —Adam Marcus
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Tailoring Therapy in Metastatic Breast Cancer The FDA’s new search engine displays data from news releases and other recall announcements as a table, which can be organized by several parameters, including date since 2009, product brand name, product description, reason for the recall and the firm involved. If users want more detailed information, the table also provides a link to the news release on each recall. The new display of the recall results is markedly different from the previous one, which provided links in a scrolldown format. To most effectively and easily communicate recall information to the public, the FDA consulted with stakeholder groups, including the Center for Science in the Public Interest, Consumers Union, Food Marketing Institute, Grocery Manufacturers Association, the Pew Health Group and Safe Tables Our Priority. Prior to passage of the FSMA, the FDA did not have mandatory recall authority for food products except infant formula. The new status information will be provided for recalls that the FDA either ordered as mandatory or requested as voluntary under the FDA’s FSMA authority. For more information, visit the FDA’s Web page that provides information on recalls and safety alerts: www.fda.gov/ Safety/Recalls/default.htm. —Staff
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Pharmacy Practice News • May 2011
Medication Safety Technology Can Cause Its Own Errors San Diego—The new technologies that are increasingly being put in place in hospitals around the country to prevent medication errors can themselves be a cause of errors, experts said at the annual meeting of the Society of Critical Care Medicine. “We have a high level of technology in my hospital, and we have reduced many different kinds of errors, but now other types of errors have crept in,” said Henry Cohen, PharmD, professor of pharmacy practice at Long Island University and chief pharmacotherapy officer at Kingsbrook Jewish Medical Center, both in New York City. “Technology is a tremendous advance, and I wouldn’t have it any other way, but make no mistake, the technology is not foolproof.” The ideal technology for preventing medication errors is the closed-loop medication administration methodology, which includes computerized prescriber order entry (CPOE), in which the prescriber, usually a physician, enters the medication order, the pharmacist validates the medication order and the nurse charts the medication administration using bar-code technology. The medication dispensing process also uses technology, primarily robotic dispensing and/or automated dispensing cabinets. Robotic dispensing to repackage medications using bar-code technology is an almost infallible technology, with an error rate of 0.001%. When the same task is done by a pharmacy technician or a pharmacist, the error rate can be as high as 2% to 3%. “Two percent seems like a small number, but in my hospital, where we dispense about 10,000 medication unit doses a day, that would be 200 medications that might be going up to the floor on any given day that are incorrect,” Dr. Cohen said. The primary error that does manage to occur with robotic dispensing is placement of the wrong drug into the prepackaging unit of the robot. A prepackaging machine that uses bar-code technology can prevent this. “It is more expensive, but it is also a lot safer,” he said. Another useful technology is automated dispensing cabinets. These must be pharmacy profiled, Dr. Cohen emphasized. “The nurse or anyone who accesses those machines should not be able to get their hands on medication without pharmacy reviewing, validating and approving the order,” he said. In addition, they should be stocked by a pharmacist or pharmacist technician using a scanner aided by guided-light technology so that the right drug goes into the right slot inside the machine. “When possible, if you have those automated dispensing machines and you can afford the money and the space, guided-
light technology is the best way to prevent errors. With guided-light technology, the nurse does not just select any drug from a drawer full of drugs, but would select a drug that she is guided to with a light that shows her exactly where it is.”
Bar-coding Pitfalls Bar-code technology for nurse administration of medication is a tremendous advance in preventing medication errors, but it, too, has limitations, Dr. Cohen said. One problem is bar codes that are not readable. “Unreadable bar codes are still a real problem with bar-code technology. In one trial, 22% of 1,605 medications did not have readable bar codes, and 24% of hospitals reported a bar code that is not readable by the scanner. This is an everyday occurrence,” he said. “In addition, there are multiple generic brands of the same drug, which can complicate bar coding.” For the entire bar-code system to work, pharmacy needs to enter the bar code every time it purchases a drug. “All new brands or new lots of a medication must be scanned by pharmacy, but additionally should be scanned by the same scanning device that is used at the bedside by the nurse,” Dr. Cohen suggested. A lack of hospital-wide wireless barcode connectivity—i.e., the system fails to work in certain parts of the hospital—failing batteries in the handheld device, doorways that do not permit entry of the bar-coding device into the room, remotely stored medications such as refrigerated meds, and loud noises that prevent the nurse from hearing the scanner’s alarms are some of the common reasons technology does not always work properly. Unauthorized workarounds that lead to bar code medication administration (BCMA) failure include preparing, scanning and transporting medications for more than one patient at a time when administering; giving a partial dose but electronically documenting the administration of a full dose; and scanning bar codes from discarded drug packages. Currently, only about 7% of hospitals have a CPOE system, and fewer than 20% use BCMA checking, Dr. Cohen noted. “We’ve got a long way to go. It’s even worse with closed-loop medication management systems, which are used in less
‘The data and science around workarounds is better than the data from any studies showing value from BCMA.’ —John Poikonen, PharmD than 5% of hospitals in the United States today. Very few hospitals are close to where they need to be. Clearly, meaningful use is going to force this to move very quickly in the years to come.” “Meaningful use” refers to the proposed rule to implement provisions of the American Recovery and Reinvestment Act of 2009 that provide incentive payments for the meaningful use of certified electronic health records technology. Meaningful use will reward eligible professionals and hospitals that are “meaningful users” of the technology and start to penalize those who do not use the technology. “If, in the next two to three years, hospitals are not well on their way to implementing this technology, they are going to have to pay the federal government. So at a certain point, you’ll have to start using this technology, and if you don’t, you’ll pay millions of dollars every year until you do,” Dr. Cohen said.
Dennis Tribble, PharmD, FASHP, chief pharmacy officer, Baxa Corporation, agreed that there are strong economic incentives—and patient safety gains—that warrant a more widespread use of bar coding in hospitals. If some facilities are hesitating because of the problems with bar code scanning detailed by Dr. Cohen, he noted, they should rethink their position. “Bar codes have been variously reported as not being readable when the problem actually may be due to a missing or physically damaged bar code or a bar code that is oriented around a curved surface,” he explained. “Additionally, a bar code might be able to be scanned, but the data contained in the code are unrecognized. “All but the last cases are somewhat rare. In my experience, the biggest problem is the lack of accountability in the way NDCs [in the bar code] are created and used.” Dr. Tribble added that, with the exception of the Veterans Administration, “our profession sits and wrings its collective hands and does nothing constructive to address the problem [of nonscannable bar codes]. If we were to file MedWatch reports to the FDA on each and every truly unscannable bar code, if we were to refuse to do business with vendors whose bar codes routinely fail, if our GPOs were to include readability performance as part of their grant criteria, we would see a change.”
IV Smart Pumps Not Foolproof Another advance to increase medication safety in hospitals is IV smart pumps. But there are many problems with these as well, Katie Burenheide, PharmD, clinical manager, trauma pharmacist at Stormont-Vail Healthcare in Topeka, Kan., said during the SCCM session on pharmacy technology. Smart pumps do reduce medication errors, Dr. Burenheide said. However, a big problem with them is the lack of national standards for drug concentrations and administration rates. “The Institute for Safe Medication Practices has developed guidelines for the use of smart pumps for each institution, but there are no national standards. Drug concentrations vary all over
Pharmacy Practice News • May 2011
DRUG ERRORS continued from page 1
simply fatigue, can result in a patient receiving a potentially dangerous drug or dose, or not receiving any dose, Dr. Jayaram stressed. “The greater the number of steps, the higher the likelihood of error,” she added. “So we’ve reduced the number of steps from the point of prescription to the point of administration.” In 2004, the 88-bed psychiatric unit at Johns Hopkins Hospital implemented a computerized prescriber order entry (CPOE) system to streamline the process—and prevent physicians’ poor penmanship from compromising care. Over the next four years, the number of annual drug errors reported in the division dropped from 369 to 89, despite a near doubling of patient admissions. For every 1,000 patientdays, an average of 27.89 and 3.43 errors were reported in 2003 and 2007, respectively (P<0.002) (Figure). The new system “allows standardization and integration of ‘best practices’ into the ordering process,” noted Brian Pinto, PharmD, MBA, assistant director of medication use and policy informatics at The Johns Hopkins Hospital. In fact, fewer errors were reported in all areas of the process, including prescribing, transcription, preparation and administration. None of the reported errors led to death or other serious harm. The ratio of self-reported to audited errors remained consistent between 2005 and 2007: approximately one reported error for every 21 to 23 errors identified in the team’s review of 122 charts.
Error Reports Not Foolproof Still, basing results solely on the medication error reports rather than chart reviews concerned Matthew Grissinger, RPh, director of error reporting programs at the Institute for Safe Medication Practices in Horsham, Pa., especially when it took providers up to five minutes to enter an error into the departments’ new reporting system compared with less than 30 seconds with its old system. David W. Bates, MD, professor of medicine at Harvard Medical School, in Boston, agreed. His own research also found a higher adverse-event rate in a psychiatric unit of 10 per 1,000 patient-days (Gen Hosp Psychiatry 2007;29:156-162). He called the new study “exciting and persuasive,” given the decreased number of error reports, although he cautioned that such rates can be highly variable. “Few studies have been done in psychiatry,” added Dr. Bates. “Yet it’s an area in which medications are used a great deal with substantial adverse effects.” Although psychotropic drugs may be less likely to result in death or immediate disability compared with other medication classes, they could cause harm over the longterm if not used appropriately. Furthermore, in separate research, Dr. Bates’ team found high error rates among psychiatrists who prescribed nonpsychotropic drugs such as insulin. Before adoption of the CPOE system, prescriptions at Johns Hopkins were written and hand-carried to the pharmacist, who would record and dispense the medicine. The drugs then had to be manually brought back to the provider.
‘Unreadable bar codes are still a real problem with bar-code technology. This is an everyday occurrence.’ —Henry Cohen, PharmD the place. Nothing is standardized on a national level, and this really needs to be done,” she told Pharmacy Practice News. Another issue is that the premade medications available, such as dopamine and dobutamine, are in dextrose 5% water (D5W) solution. Unfortunately, D5W is not recommended for most disease states, including sepsis and trauma resuscitation. Instead, crystalloids, normal saline or Lactated Ringer’s are recommended. “In head trauma, hemorrhagic stroke or subarachnoid hemorrhages, D5W is not recommended at all because it can increase swelling in the brain and can further increase neurologic damage,” Dr. Burenheide said. Cardiovascular infusion rates also differ, sometimes even within the same institution, she said. “Some cardiovascular
infusions can be reported in micrograms per kilogram per minute, micrograms per kilogram per hour or micrograms per kilogram per milliliter, and these vary between each institution. Sometimes even within the hospital, different infusion rates may be reported, and this can cause further confusion. When patients transfer from another facility by ambulance, you have to be careful because [the new hospital] may be using different infusion concentrations or administration rates. You really have to be careful of transition-of-care issues to make sure everybody is on the same page.” Another area that needs to be standardized in critically ill patients is what weight to use. The weight to use for medication calculations could be stated weight, estimated weight, scale weight,
Now that most of these steps are eliminated, said Dr. Jayaram, the prescribing of wrong drugs, unusual doses or contraindicated medications is rare. “Let’s say I wrote an order for 500 mg of Serax, instead of 50 mg,” she explained. “A warning immediately pops up on my computer and on the pharmacist’s, who pages me and corrects it instantly.” Similarly, if a patient has an allergy to penicillin and a physician types the antibiotic into the system, a message appears noting that it can’t be prescribed. There is even a catch for the rare scenario of admitted patients with the same name. Two different services may each be caring for a Michael Smith, for example. Although providers likely would be unaware of the situation, the computer would know, said Dr. Jayaram. And it would ensure the right drug goes to the right Michael Smith. But the team acknowledged that the computerized system still is far from perfect. Dr. Pinto suggested that too many alerts could prove distracting and lead to “alert fatigue,” for example. As part of his involvement with the project, he helped put steps in place to monitor the volume and reduce unnecessary alerts. Complacency is also a worry if a prescriber begins to rely too heavily on technology to catch errors, said Dr. Pinto. He added that the system “is only as good as the humans who design or build it.” “We continue to tweak the system to suit our specific psychiatric needs,” Dr. Jayaram said, “adding new protocols and procedures for particular medications.” At the same time that they introduced the CPOE system, the psychiideal weight or adjusted body weight, Dr. Burenheide said. “There are no standards regarding what patient weight to utilize, and you really have to be careful to use the most accurate patient weight. This may also be an important issue when you start certain medications, like lipophilic drugs—for example, sedation medications, or hydrophilic drugs. However, limited information about this exists.”
An Emerging Field of Research “A new science in informatics is emerging, termed ‘eIatrogentics,’ or studying errors that are caused by technology,” John Poikonen, PharmD, clinical informatics director, UMass Memorial Health Care in Worcester, Mass., told Pharmacy Practice News. He said more centers are adopting the technology and disagreed with the numbers cited by Dr. Cohen. “From a recent survey [Pharm Purch Prod 2010;7], it’s more like 35% for CPOE and as high as 53% in hospitals with over 400 beds, with 89% saying they will be implementing the technology in the next five years. And 41% now use BCMA. But it is still just 5% for
Errors per 1,000 patient-days (n)
Medication Safety 30
20 10 3.43
Figure. Medication errors at Johns Hopkins Hospital pre- and post-CPOE implementation. atric department also instituted computerized reporting. With the Webbased Physicians Safety Net, caregivers throughout the hospital can see when mistakes are made in real time and can easily categorize the events, rather than manually digging through the data to identify trends. Dr. Jayaram is working to get pharmacists to keep and collate information on errors that were caught before they became incidents. Because these “nearmisses” are more likely to be reported than true errors, the information can educate residents and faculty about common errors. As it stands now, she is rarely informed if a pharmacist fixes a problem. “It’s probably time for psychiatry to get on the electronic prescribing bandwagon,” said Dr. Bates, estimating that less than one-fourth of psychiatry departments are currently on board. —Lynne Peeples closed-loop medication management systems,” Dr. Poikonen said. Nursing workarounds are a very large problem with BCMA, he emphasized. “They can give a false sense of error prevention—like the nurse who has all of the insulin bar codes on the inside of her uniform and scans them until she gets the right ‘beep,’” he noted. “Then there is reporting of how many errors were averted because of mis-scans, when all the time the mis-scans were really workflow issues and not averted errors.” Dr. Poikonen said he believes there is a woeful lack of evidence regarding the true medication error rate and the return on investment with BCMA. “The data and science around workarounds is better than the data from any studies showing value from BCMA,” he said. Finally, with regard to smart pumps, Dr. Poikonen said that, although national standards would be a good thing, individual health systems should not be waiting for them. “They should be working to standardize at their facilities.” —Fran Lowry
Pharmacy Practice News • May 2011
FDA Approves Yervoy for Metastatic Melanoma T he FDA has approved ipilimumab (Yervoy, Bristol-Myers Squibb) for patients with metastatic melanoma, based on results from a multinational trial. In the study, the 020 Phase III trial, 676 patients with previously treated, unresectable stage III/IV melanoma were randomized in a 3:1:1 ratio to ipilimumab (3 mg/kg every three weeks for four cycles) plus the glycoprotein (gp)100 peptide vaccine in a conventional dose, the same regimen of ipilimumab plus placebo, or gp100 vaccine plus placebo. All patients were HLA-A0201–positive, an entry criterion required because of the inclusion of the gp100 vaccine. Overall survival was the primary end point. Those who received the combination of ipilimumab plus the vaccine or ipilimumab alone lived an average of about 10 months, whereas those who received only the experimental vaccine lived an average of 6.5 months. Common side effects include fatigue, diarrhea, skin rash, endocrine deficiencies (gland or hormone) and colitis. Severe to fatal autoimmune reactions were seen in 12.9% of patients treated with ipilimumab (Table). When severe side effects occurred, ipilimumab was stopped and corticosteroid treatment was started. Not all patients responded to this treatment. Patients who did respond in some cases did not see any improvement for several weeks. The greatest risk for significant morbidity and death was associated with attacks in
the gastrointestinal system. Because of the unusual and severe side effects associated with ipilimumab, the drug is being approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about these serious risks. A medication guide also will be provided to patients to inform them about the therapy’s potential side effects. Data on the drug was first presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO), and at that time, experts cautioned oncologists about the drug’s side effects. “The immune-related toxicity of ipilimumab requires a committed multidisciplinary team. This is not your 5-fluorouracil/leucovorin diarrhea,” said Vernon K. Sondak, MD, chief of the Department of Cutaneous Oncology at the H. Lee Moffitt Cancer Center, in Tampa, Fla. The drug potentiates T-cell activation by blocking the cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor. The anti-tumor effect of ipilimumab is produced by blocking this receptor to keep T cells activated.
HemOnc Pharmacist’s Take Speaking at the seventh annual conference of the Hematology/Oncology Pharmacy Association the day before the FDA announced approval of ipilimumab, Robert T. Dorr, PhD, RPh, professor of pharmacology at Arizona Cancer Center,
Table. Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Patients, % Yervoy 3 mg/kg (n=131)
3 mg/kg+gp100 (n=380)
Any immune-mediated adverse reaction
Including fatal outcome;
Including intestinal perforation; Underlying etiology not established
‘Ipilimumab … upregulates cytotoxic T cells that then go out and recognize the melanoma tumors and attack them immunologically. I think the CTLA-4 target is very good.’ —Robert T. Dorr, PhD in Tucson, predicted that approval of the drug would generate $900 million in annual sales by 2015, with one course costing roughly $50,000. “This is not a trivial type of drug,” he said during his talk on investigational products due to come on the market within a year or two. Although Dr. Dorr acknowledged that the drug may well get approved within a day or two of his talk, he envisioned a possible delay resulting from the emergence of new data from the 024 trial—a Phase III study by BristolMyers Squibb that was not submitted to the FDA for approval. “There has been intense speculation on the business side as to whether or not the FDA will recommend approval on the basis of a trial that has a very atypical control group—in this case the gp100 vaccine, which is not itself an approved agent,” he said. “I’m guessing they may defer approval because the 024 data is now available, and they may want to look at that.” The 024 trial compares ipilimumab 10 mg/kg plus dacarbazine chemotherapy with dacarbazine alone in previously untreated patients with metastatic melanoma. The abstract is slated for presentation at the ASCO annual meeting in June, according to Bristol-Myers Squibb. Dr. Dorr underscored the importance of using dacarbazine as a control group in the 024 trial. The chemotherapeutic agent “is probably the best example of a drug that really has no primary efficacy but does have side effects,” he said. “So it’s basically a placebo with side effects, [and thus] an excellent control for a survival study.” In late March, Bristol-Myers Squibb announced that ipilimumab had met
its primary end point of improving overall survival. “Ipilimumab downregulates the CTLA4 receptor, which is a down-repressor of cytotoxic T-cell function, so basically, it upregulates cytotoxic T cells that then go out and recognize the melanoma tumors and attack them immunologically. I think the CTLA-4 target is very good,” added Dr. Dorr. Daniel G. Coit, MD, professor of surgical oncology at Memorial Sloan Kettering Cancer Center, New York City, and chief of the National Comprehensive Cancer Network (NCCN) guidelines committee on melanoma, said that ipilimumab represented the first real advance for the treatment of advanced melanoma since interferon, a drug with limited utility because of its extreme toxicity. At the recent NCCN annual conference, Dr. Coit said the melanoma guidelines committee would be prepared to incorporate the use of ipilimumab into the guidelines as soon as it was approved by the FDA. Asked to comment on whether the FDA or its advisory committee had reviewed the 024 trial, an FDA spokesperson replied via e-mail that “federal regulations prohibit the FDA from disclosing any information from a drug application not approved by the agency. This includes confirming or denying the existence of an application.” A follow-up request, pointing out that Yervoy had in fact already been approved, went unanswered. —Kate O’Rourke and Fran Lowry Dr. Dorr reported financial relationships with AmpliMed and Clinovel. Dr. Coit has reported no relevant financial interests.
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Comprehensive Pharmacy Review NAPLEX® Preparation CD-ROM, Sixth Edition
Leon Shargel; Alan Mutnick; Paul Souney
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 don’t find the book you want, email 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.
Pharmacological and Psychosocial Treatments inSchizophrenia, Second Edition
David Castle; David Copolov; Til Wykes; Kim Mueser, MD
Karen J. Tietze
Designed to assist pharmacy students with their preparation for their NAPLEX pharmacy board examination, this interactive CD-ROM contains all the review questions from Comprehensive Pharmacy Review, sixth edition and Comprehensive Pharmacy Review Practice Exams, sixth edition. Its advanced functionality helps students target their strengths and weaknesses for more effective and productive self-study and review.
Concise Clinical Pharmacology
Mosby’s Pharmacy Review for the NAPLEX®
Concise Clinical Pharmacology is a thorough introduction to the subject from which students can gain a rapid understanding of individual topics within the discipline. Pharmacologic principles and mechanisms are covered, with a focus on the therapeutic use of the drugs.
This new edition provides an authoritative review of pharmacologic and psychosocial treatment interventions for individuals with schizophrenia and related disorders. The text has been fully updated, revised, expanded and new chapters encompass comorbid general health issues, violence in schizophrenia, the special needs of women with schizophrenia, first-episode psychosis, and others.
Pharmacotherapy: A Pathophysiologic Approach
Joseph T. DiPiro; Robert L. Talbert; Gary C. Yee; Gary R. Matzke; Barbara G. Wells; L. Michael Posey 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 available for pharmacists and prescribers. Now in a new full-color format.
PharmPrep: AShP’S NAPLEX Review, Fourth Edition
The Pharmacy Leadership Field Guide: Cases and Advice for Everyday Situations
Lea Eiland; Diane Ginsburg
Using real patient cases accompanied by questions that address all NAPLEX competency statements, the new fully updated guide gives you the flexibility to review information by specific disease state and provides 78 sample cases, as well as calculations and law review sections. As drug therapy becomes more complex, PharmPrep has continued to update and revise cases so they reflect contemporary clinical practice.
Michael DeCoske; Jennifer Tryon; Sara J. White
Prepare for NAPLEX success on your first attempt! In this guide to the North American Pharmacy Licensure Examination, an outline format lets you review important test topics quickly and efficiently. Review questions cover areas such as the evaluation of patient conditions, communicating with the patient or health care professional and preparing and dispensing medications safely and effectively. A companion CD lets you practice with two 185-question exams that mirror the NAPLEX.
This new book was written to provide students and new practitioners with a useful resource as they begin their careers. Students and new practitioners need specific guidance on various aspects of leadership and face challenges that mid-career practitioners do not. The book is meant to act as an “in-print mentor,” with a friendly, personal tone, and information and advice presented by both veteran practitioners and new practitioners who have just gone through the same experience themselves. PPN0511
Celebrating Another Successful Year As 2010 came to a close, the McMahon Group took time out to recognize the best of an outstanding group of employees. During 2010, McMahon’s readership scores solidified the best-read status of many of its medical newsmagazines, and sales revenues increased despite a challenging economy. All of which proves yet again that a company powered by talented people will necessarily generate success. In 2010, McMahon’s publishing success was on display in the pages and on the Web sites of its publications and medical education platforms.
Here then is a look at the winners of the 2010 employee awards.
SUPPORT/PRODUCTION/IT/FINANCE PERSONS OF THE YEAR:
GRAPHIC DESIGNER OF THE YEAR:
Employees were asked to pick the two most outstanding members from these four departments. The winners were MARTIN BARBIERI, production manager, for his dedication to his publications; and MARIELLA SINDONI, financial accounts receivable, for her ability to round up stray dollars.
GABRIEL BERLIN won the award in recognition for his creative approach as art director for Gastroenterology & Endoscopy News, as well as his design work on several medical education and custom media projects.
ACE PERSON OF THE YEAR: There is a strict firewall separating those who work in our CME division, Applied Clinical Education—but not for voting. The 2010 winner was GEORGE OCHOA, whose ability to research, write and edit sometimes dense medical information, and do it by tomorrow, is legendary.
NEWSMAGAZINE/ COPY EDITOR OF THE YEAR: The 2010 winner was ADAM MARCUS, managing editor of Anesthesiology News. Adam’s pursuit of important stories led him to break several well before the competition, including a few of national importance.
PERSON OF THE YEAR
MOST IMPROVED SALESPERSON OF THE YEAR:
SPECIAL PROJECTS EDITOR OF THE YEAR:
In a crowded field of sales excellence, it can be difficult to stand out, but MATT SPOTO managed to do just that, honing his skills while working as account manager on Gastroenterology & Endoscopy News.
Despite first-rate competition, MEGAN BLOCK, managing editor, won the award for her superb work creating custom media of various kinds, including custom newsletters and podcasts.
SALES ACHIEVEMENT AWARD:
SALESPERSON OF THE YEAR:
JULIANNA DAWSON, publication director of Clinical Oncology News, was the 2010 winner in this category. Julianna sets herself up for success by working long hours for her clients.
Whereas their peers vote for the other award winners, this award is never subject to a vote. It’s a fact, not an opinion: The salesperson who brings in the most revenue receives this award. For a record-breaking fifth year in a row, the winner was RICHARD TUORTO, senior group publication director for Anesthesiology News and Pain Medicine News.
PERSON OF THE YEAR 2010:
PARTNERS SPECIAL RECOGNITION AWARD 2010:
Representing the very best of the best, the 2010 Person of the Year was KEVIN HORTY, editor of General Surgery News. With Kevin at the helm of GSN, readership scores have enjoyed a steady climb skyward, and with these advancing numbers has inevitably come increased revenue. Kevin has concentrated on making the editorial he oversees fully relevant to the complicated world of today’s general surgeon, and the reward has been a publication that is, by far, better than ever.
The partners of McMahon Publishing occasionally present an award to someone who has contributed to the success of the company over many years of service. This year’s winner was GARY SMITH, CEO of Fairfield (Conn.) County Bank (FCB), for his decades-long financial service. FCB financed all of the company’s expansions over the years. “Gary has been a great partner in helping the family and staff grow this company from a start-up to a major medical publisher,” said Ray McMahon, CEO. “Gary will retire from FCB in June; we wish him the best and have appreciated his wise counsel over many years.”
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of physicians surveyed (N=57) would recommend SAMSCA to a colleague 1 In this same survey (patient cases; N=150), physicians were satisﬁed or very satisﬁed with SAMSCA 90% of the time1
Indication and important limitations • SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA. It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients
Important safety information SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients. • Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors • Co-administration with hypertonic saline is not recommended • Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium Commonly observed adverse reactions: (SAMSCA vs placebo) thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%). Reference: 1. Market Rx 2010.
For more information about SAMSCA, visit samsca.com or call 1-877-726-7220.
Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on previous page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. US Patent Nos: 5,258,510 and 5,753,677. Samsca is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.
©2011 Otsuka America Pharmaceutical, Inc.