The May 2012 Digital Edition of Pharmacy Practice News by McMahon Group

A M at

ee bo

tin



The Pharmacist’s News Source

pharmacypracticenews.com

Volume 39 • Number 5 • May 2012



Printer-friendly versions available online

Changes Are Coming For Stress Ulcer Prevention Therapy

in this issue Up Front

In Brief Another reason for your patients to quit smoking.

Experts preview pending guidelines Houston—Health care professionals anxiously awaiting the updated stress ulcer prophylaxis guidelines will have to wait until the end of 2012, but they should be aware that a wealth of new data has turned the previous guideline document on its head. During a session at the recent annual meeting of the Society of Critical Care Medicine, speakers involved in the development of the guidelines offered a quick preview. The new guidelines touch on areas including preferred therapy choice, patient selection factors and when to start and stop therapy. Clinicians in doubt as to whether to initiate therapy should go ahead and start, said presenter Douglas Naylor Jr., MD, staff intensivist

•

see STRESS, page 7

Clinical

Critical Care Weight-based dosing in ER still taken too lightly. Medication errors and C. difficile infections pose big risks in ICUs.

Ipilimumab dose rounding and fixed dosing of rasburicase yield major cost savings.

Ethics

•

Operations & Mgmt

With CMS Pay Cuts Looming, Hospitals Eye Readmissions

see READMISSIONS, page 52

Hem/Onc Pharmacy

Reimbursement

early 18% of all Medicare patients who are admitted to hospitals are readmitted within 30 days after discharge, at a cost of $15 billion annually—about $7,200 per case—according to the Medicare Payment Advisory Commission (MedPac). The commission also asserts that two-thirds of those readmissions are avoidable. Starting in 2013, the Center for Medicare & Medicaid Services (CMS) will reduce payments to hospitals that log excessive readmissions related to heart failure (HF), acute myocardial infarction (AMI) and pneumonia. Private insurers are likely to follow suit, and the prospect has hospitals scrambling to reduce readmission rates. Fortunately, there are several strategies that hospitals can follow to keep patients at home. One effective approach—leveraging multidisciplinary care and pharmacy services to help patients avoid drug-related adverse events— was the focus of a recent Web-based seminar

A team approach to surviving RAC audits, maximizing reimbursement.

Policy Yet another retraction of published studies shines spotlight on research ethics.

FDA Watch New proposed rule on biosimilars inches the market closer to generic biologics.

Educational Review

Catheterrelated Bloodstream Infections See page 11

Drug Shortages Continue To Chip Away at Patient Care At HOPA annual meeting, pharmacists, FDA share coping strategies Orlando, Fla.—If the start of this year is any indication, the drug shortage crisis is likely to escalate in 2012. “By about the second week of February, we already had exceeded 40 new drug shortages,” said Dan Sageser, PharmD, BCOP, clinical pharmacy supervisor at the Huntsman Cancer Institute, Salt Lake City. That placed the hospital on track to exceed the 267 drug shortages it dealt with in 2011, Dr. Sageser said during a session on drug shortages at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). By early April, although the number of new shortages at the Institute has remained stable at 40, “we currently have 263 active shortages we are dealing with—most of which are holdovers from last year. So there’s not much relief in sight,” he noted via email after the HOPA meeting.

•

see DRUG SHORTAGES, page 28

Rivaroxaban Edges Standard Therapy for Pulmonary Embolism Regimen allows substantial reductions in hospital LOS Chicago—The factor Xa inhibitor rivaroxaban was as effective as standard therapy in the treatment of pulmonary embolism (PE) but yielded a 50% reduction in the incidence of major bleeding and allowed for a simplified regimen that enabled patients to spend less time in the hospital, according to the results of a large, multinational study.

Featured Service

GlobalHealth Education offers graduate credential in management program. See page 24.

The fixed-dose oral regimen could offer a viable alternative to subcutaneous injections of enoxaparin and vitamin K antagonist, which is complex and requires very close monitoring, reported investigator Harry R. Buller, MD, PhD, at the annual meeting of the American College of Cardiology (ACC).

•

see ADVANTAGES, page 32

New Product American Health Packaging introduces new unit-dose products. See page 25.

I need flexibility to work wherever I’m needed. Introducing the Pyxis ES platform—the next generation of Pyxis solutions that provide meaningful integration and ®

enterprise-ready technology for medication management. The Pyxis MedStation ES system, the cornerstone of the new ®

platform, enables centralized system management on the go, allowing pharmacists the option to step away from their desk and support clinicians at the point of care. That’s the CareFusion difference. Learn more at carefusion.com/MedES Join us for a CE webinar on medication management. Register today at carefusion.com/MedWebinar.

Pyxis

© 2012 CareFusion Corporation or one of its subsidiaries. All rights reserved. MedStation and Pyxis are trademarks or registered trademarks of CareFusion Corporation or one of its subsidiaries. The continuing education webinar on the Pyxis ES platform is supported by an educational grant from CareFusion. DI3709 (0412)

Pharmacy Practice News • May 2012

Up Front 3

Capsules

surf

Most C. difficile Infections Linked to Health Care Settings

MAY 2012

watch

Researchers call for more collaborative efforts to promote prevention

The five most-viewed articles last month on pharmacypracticenews.com: 1. Pain, Agitation and Delirium Guidelines To Be Unveiled 2. Safe Handling of Hazardous Drugs: Reviewing Standards for Worker Protection. 3. ISMP Launches New Oncology Med Safety Self-Assessment Tool 4. Hand and Glove Hygiene Keys to Safe Compounding 5. Taking Control of Pharmaceutical Waste Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here

‘What clinician wouldn’t be interested in a simple,

cheap drug that could save hundreds of thousands of lives.’

first

—Katherine Ker, MSc, See article, page 24

commenting on tranexamic acid, which a new study has shown can help stop dangerous bleeding episodes in the ER and OR.

verall, 94% of Clostridium difficile infections (CDIs) are related to health care exposures, according to a recent report from researchers at the Centers for Disease Control and Prevention (CDC; McDonald LC et al. MMWR Morb Mortal Wkly Rep 2012;61:157-162). Despite the known association between CDI and hospitals, the researchers found that 75% of these infections began among patients not currently hospitalized, including recently discharged patients, outpatients and nursing home residents. Fifty-two percent of CDIs treated in hospitals were present on admission. Some cases occurred in patients who were exposed to multiple health care settings, the investigators noted. For example, 20% of hospital-onset CDIs occurred in recent residents of nursing homes. Also, 67% of infections that had their onset in nursing homes occurred in patients who were recently discharged from an acute care hospital. Also of note was a 20% decline over approximately 21 months in the pooled CDI rate among 71 hospitals that participated in CDI prevention programs in three states (Illinois, Massachusetts and New York). The prevention programs focused primarily on infection control, although the Massachusetts program included an antibiotic stewardship component as well. Infection control strategies included early reliable detection of cases, isolation of infected patients and enhanced environmental cleaning. Antibiotic stewardship comprised administering the correct antibiotic, at the right dosage, the right time and for the right duration. Data for the MMWR paper was generated using population-based surveillance from the CDC’s Emerging Infections Program in 2010, in which 10,342 CDIs were identified. The researchers also used data from the CDC’s National Healthcare Safety Network, an Internet-based surveillance system, and from the three state-led prevention programs. According to the authors of the study, CDI incidence rates, mortality rates and medical care costs have reached historic highs, despite the fact that many of the infections can be prevented. They called for more to be done to prevent CDIs and suggested that infection control programs and antibiotic stewardship be extended to non-hospital settings. “State health departments and partner organizations have shown leadership in preventing CDIs in hospitals and can prevent more CDIs by extending their programs to cover other health care settings,” the authors concluded. “Clinicians and other health care providers, as well as inpatient and outpatient health care facilities, [and] state and federal public health officials … could benefit from increased collaboration in preventing CDIs.” —George Ochoa

EDITORIAL BOARD

Michele McMahon Velle, MAX Graphics/Creative Director

Administration

Frank Tagarello, Senior Art Director/Managing Director, MAX Graphics

Robert Adamson, PharmD, Livingston, NJ

James O’Neill, Senior Systems Manager

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

Volume 39 • Number 5 • May 2012 • pharmacypracticenews.com

Anesthesiology/Pain Julie A. Golembiewski, PharmD, Chicago, IL

Dan Radebaugh, Director of Production and Technical Operations

Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

Internal Medicine

EDITORIAL STAFF

Marty Barbieri, Production Manager

David S. Craig, PharmD, BCPS, Tampa, FL

Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP, Des Moines, IA

David Bronstein, Editorial Director davidb@mcmahonmed.com

Brandy Wilson, Circulation Coordinator

Robert L. Barkin, MBA, PharmD, Chicago, IL

NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

Cardiology

Oncology

C. Michael White, PharmD, Storrs, CT

Robert T. Dorr, PhD, RPh, Tucson, AZ

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

CNS/Psychiatry

Robert Ignoffo, PharmD, San Francisco, CA

Charles F. Caley, PharmD, Storrs, CT

Philip E. Johnson, MS, RPh, FASHP, Tampa, FL

Biotechnology Indu Lew, PharmD, Livingston, NJ

Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA Larry Ereshefsky, PharmD, San Antonio, TX Complementary and Alternative Medicine

Cindy O’Bryant, PharmD, Aurora, CO Ali McBride, PharmD, MS, BCPS, St. Louis, MO Sara S. Kim, PharmD, BCOP, New York, NY

Cathy Rosenbaum, PharmD, Cincinnati, OH Critical Care

Pediatrics

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

James Prudden, Group Editorial Director Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

SALES David Kaplan, Group Publication Director dkaplan@mcmahonmed.com Matt Spoto, Account Manager mspoto@mcmahonmed.com

McMAHON PUBLISHING Raymond E. McMahon, Publisher and CEO, Managing Partner Van Velle, President, Partner Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

McMahon Publishing mcmahonmed.com Sales, Production and Editorial Offices: 545 West 45th Street, 8th Floor, New York, NY 10036. Telephone: (212) 957-5300. Corporate Office: 83 Peaceable Street, Redding CT 00896

David P. Nicolau, PharmD, Hartford, CT

Technology

Robert P. Rapp, PharmD, Lexington, KY

Thomas Van Hassel, RPh, Yuma, AZ

ART/PRODUCTION STAFF

Copyright © 2012 McMahon Publishing, New York, NY 10036. All rights reserved. Pharmacy Practice News (ISSN 0886-988x) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Send address changes to Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036.

Want to subscribe? Change your address? Here’s How All U.S. hospital pharmacists should receive Pharmacy Practice News free of charge. If you are a hospital pharmacist and do not receive the publication, you must add your professional address or make your address change directly

with Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036. You can also fax your request to (212) 977-3645, or send it via email, circulation@mcmahonmed.com. If you are not a hospital pharmacist but would like to receive Pharmacy Practice News, please send a check for $70.00 (U.S.) or $90.00 (outside U.S.) for a year’s subscrip-

tion payable to Pharmacy Practice News to McMahon Pub lishing, 545 West 45th St., 8th Floor, New York, NY 10036. Please allow 8 to 12 weeks for delivery of the first issue. Individual issues are $7.00 (U.S.) or $10.00 (outside U.S.). McMahon Publishing is a 40-year-old, first-generation, family-owned publishing company dedicated to providing medical professionals with essential, up-to-date news. As

the second largest publisher of medical newspapers, McMahon produces Anesthesiology News, Clinical Oncology News, Gastroenterology & Endoscopy News, General Surgery News, Infectious Disease Special Edition, Pain Medicine News, Pharmacy Practice News. Rheumatology Practice News and Specialty Pharmacy Continuum.

Infectious Diseases Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH Peggy McKinnon, PharmD, Lexington, MA

Reimbursement Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

A family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers and several annual or semiannual Special Editions.

David Nathanson, Account Manager dnathanson@mcmahonmed.com Alina Dasgupta, Junior Sales Associate, Classified Advertising adasgupta@mcmahonmed.com

Grifols Albumin

Broad selection and reliable supply

Albutein 5%/25%

Plasbumin -5/25

Albumin (Human) U.S.P.

Albumin (Human) USP

5% Albumin Products Product Name

Size

NDC Number

Plasbumin® - 5

50 mL (2.5 grams)

13533-685-20

Plasbumin® - 5

250 mL (12.5 grams)

13533-685-25

Albutein® 5%

250 mL (12.5 grams)

68516-5214-1

Albutein® 5%

500 mL (25.0 grams)

68516-5214-2

25% Albumin Products Product Name

Size

NDC Number

Plasbumin® - 25

20 mL (5.0 grams)

13533-684-16

Plasbumin® - 25

50 mL (12.5 grams)

13533-684-20

Albutein® 25%

50 mL (12.5 grams)

68516-5216-1

Albutein® 25%

100 mL (25.0 grams)

68516-5216-2

Plasbumin® - 25

100 mL (25.0 grams)

13533-684-71

Available from all major distributors

Grifols’ albumin is available through a broad network of authorized distributors, group purchasing organizations (GPOs), or by contacting Grifols Customer Service at 1.800.243.4153 or customer.service@grifols.com.

Grifols Biologicals, Inc. 5555 Valley Boulevard, Los Angeles, California 90032 USA www.grifols.com

Grifols: A Reliable Supplier of Plasma Protein Therapies

Vertical integration with geographic diversity helps ensure uninterrupted production of albumin s 4HE LARGEST NETWORK OF SOURCE PLASMA DONOR CENTERS IN THE INDUSTRY 1 enables Grifols to collect 100% of the plasma needed to produce our albumin and other plasma protein therapies s 4WO 'RIFOLS OWNED STATE OF THE ART PLASMA TESTING FACILITIES s 4HE LARGEST PLASMA PROTEIN FRACTIONATION CAPACITY IN THE WORLD 1 s &OUR GLOBAL PLASMA PROTEIN MANUFACTURING FACILITIES

State-of-the-art production processes

Sterile Albumin Filling Facility, Los Angeles, CA, FDA approved in December 2009

Grifols Fractionation Facility, Los Angeles, CA

Grifols Fractionation Facility, Clayton, NC

1. Marketing Research Bureau data, July 2011

ÂŠ 2012 Grifols Biologicals Inc.

Printed in USA.

April 2012

AB12-0412

6 Up Front

Pharmacy Practice News • May 2012

In Brief ASCO Releases List Of Top Procedures To Question

Tobacco Smoking Doubles Cancer Risk In Patients With Barrett’s Esophagus

moking tobacco increases the risk for progression of Barrett’s esophagus (BE) to high-grade dysplasia (HGD) or cancer by twofold compared with never smoking, according to a new study. “This study has shown for the first time that smoking is a major reason for progression from BE to highgrade dysplasia/cancer,” according to lead author Helen Coleman, PhD, a postdoctoral research fellow at the Centre for Public Health, Queen’s University Belfast, in Northern Ireland. For their study, Dr. Coleman and colleagues analyzed data from a BE register of all adults diagnosed with columnar-lined epithelium of the esophagus between 1993 and 2005 in Northern Ireland (Gastroenterology 2012;142:233-240). The researchers identified 3,167 patients who had ever been diagnosed with specialized intestinal metaplasia, and they collected data on lifestyle and clinical and demographic characteristics from hospital case notes. Linking the

Colonoscopy Prevents Colorectal Cancer Mortality

or decades, physicians, researchers and patients alike have pondered the question: Does colonoscopy reduce mortality from colorectal cancer (CRC)? On Feb. 23, data published by National Polyp Study (NPS) researchers in The New England Journal of Medicine (2012;366:687-696) provided an answer: Yes. The study’s lead author, Ann G. Zauber, PhD, epidemiologist and biostatistician at Memorial Sloan-Kettering Cancer Center, in New York City, has been pursuing this question for some time. Data generated from the NPS has shown that removal of adenomas during colonoscopy results in a decreased incidence of CRC, but until now, researchers had not definitively linked that with a decrease in CRC mortality. The current study followed all patients with colon polyps who were prospectively referred for initial colonoscopy between 1980 and 1990 at NPS clinical centers. Among 2,602 patients who had adenomas removed during the study with a median follow-up of 15.8 years, 12 died from CRC. Researchers compared those numbers with data on CRC in the general population, which they derived from the Surveillance, Epidemiology and End Results program. The investigators

Northern Ireland BE register to the Northern Ireland Cancer Registry, the researchers identified which of these patients later developed esophageal HGD or adenocarcinomas of the esophagus or gastric cardia. By Dec. 31, 2008, a total of 117 patients with BE had developed esophageal HGD or adenocarcinomas of the esophagus or gastric cardia. Using Cox proportional hazard models, the researchers determined that current tobacco smoking was significantly associated with increased risk for progression compared with never smoking, across all strata of smoking intensity (hazard ratio, 2.03; 95% confidence interval, 1.29-3.17). Additionally, the researchers found that risk for progression of BE was not related to alcohol consumption. Body mass index was not associated with risk for neoplastic progression, although caution in interpretation was advised because of inconsistent collection of data on height and weight. The researchers recommended that

estimated an expected 25.4 deaths from CRC in the general population, which they said suggests a 53% reduction in mortality associated with colonoscopic polypectomy. These results are expected to bolster screening colonoscopy, which has so far only been presumed to prevent mortality from CRC. The news has been received with excitement from cancer screening professionals. The New York Times, which published the news as its top story in the Feb. 22 edition of the health section, quoted cancer epidemiologist Robert A. Smith, PhD, senior director for cancer control at the American Cancer Society, as saying, “This is a very big deal.” —Cynthia J. Gordon, PhD

Opioids May Delete Memory Trace Of Pain

team of Austrian researchers has discovered a surprising, new potential effect of opioids: The drugs not only temporarily dampen pain but in high doses may remove the spinal cord’s memory trace of pain (Science 2012;335:235-238). The memory trace, which can amplify a

smoking cessation strategies be considered in patients with BE. Previously, there was no “evidence base to specifically target these patients with dedicated smoking cessation programs,” Dr. Coleman said. “Therefore, this would be a change of practice.” —George Ochoa

person’s experience of pain and may lead to chronic pain syndrome, can be triggered by several mechanisms, including long-term synaptic potentiation. To study pain memory, the researchers recreated a surgical procedure in vivo, which allowed them to stimulate pain fibers under controlled conditions. Despite deep anesthesia, the researchers were able to reserve long-term synaptic potentiation in the spinal cord and found a memory trace for pain. When high doses of IV opioids were administered over the course of an hour, the researchers completely resolved the potentiation and thus deleted the memory trace for pain. Based on these results, a new project, sponsored by the Vienna Fund for Science, Research and Technology, is exploring whether this discovery can be used to treat patients. “If our approach turns out to be effective under clinical conditions, this would herald a paradigm shift in pain therapy,” wrote lead author Jürgen Sandkühler, MD, at the Center for Brain Research, Medical University of Vienna, Austria. “It would mean moving away from the temporary, purely symptom-based pain therapy to a long-term removal of the cause of pain based on pain mechanisms using opioids.” —Based on a study in Science

he American Society of Clinical Oncology (ASCO) has identified a list of top five most common and costly procedures in oncology that it says are not supported by evidence and should be questioned. As a participant in the American Board of Internal Medicine Foundation’s Choosing Wisely campaign, ASCO is one of nine specialty societies that have produced such top five lists within their respective fields. Developed by cancer specialists on ASCO’s Cost of Cancer Care Task Force, the top five list for oncology was based on a review of published studies and current guidelines. Oncology professionals from community and academic settings, state societies and cancer advocacy groups vetted the list. “Backed by the expertise of more than 30,000 member oncologists, ASCO is in a unique position to identify opportunities to prevent the misuse and overuse [of] cancer tests and treatments that are not supported by clinical evidence,” Lowell E. Schnipper, MD, chair of ASCO’s Cost of Cancer Care Task Force, said in a statement. “We hope this list will help oncology providers make more informed decisions and provide their patients with the best possible care.” In an article published in the Journal of Clinical Oncology (Epub ahead of print April 3, 2012 as 10.1200/ JCO.2012.42.8375), Dr. Schnipper and co-authors discussed the top five procedures in detail. For example, item 1 (box), about cancer-directed therapy, is based on evidence that cancer-directed treatments likely are to be ineffective for patients with solid tumors who meet these criteria, according to the ASCO report. Stopping cancer treatment should always be accompanied by appropriate palliative and supportive care and referral to hospice, the authors recommend. —George Ochoa

ASCO’s Top Five List 1. “Don’t use cancer-directed therapy for solid tumor patients with the following characteristics: low performance status (3 or 4), no benefit from prior evidencebased interventions, patient not eligible for a clinical trial and no strong evidence supporting the clinical value of further anti-cancer treatment.” 2. “Don’t perform PET [positron emission tomography], CT [computed tomography] and radionuclide bone scans in the staging of early prostate cancer at low risk for metastasis.” 3. “Don’t perform PET, CT and radionuclide bone scans in the staging of early breast cancer at low risk for metastasis.” 4. “Don’t perform surveillance testing (biomarkers) or imaging (PET, CT and radionuclide bone scans) for asymptomatic individuals who have been treated for breast cancer with curative intent.” 5. “Don’t use white cell stimulating factors for primary prevention of febrile neutropenia for patients with less than 20% risk for this complication.”

Pharmacy Practice News • May 2012

Clinical 7

Critical Care

STRESS continued from page 1

in the Surgical Intensive Care Unit at the Cleveland Clinic in Ohio. Dr. Naylor noted that the guidelines recommend that patients in the ICU who have two or more risk factors for stress-related mucosal disease, such as sepsis or acute renal failure, should receive stress ulcer prophylaxis (Table). The risk for hemorr hage outweighs any problems that may develop as a result of of therapy, he said.

Table. Risk Factors for Stress-related Mucosal Bleeding • Respiratory failure requiring mechanical ventilation for more than 48 h • Coagulopathy • Acute renal failure • Acute hepatic failure with coagulopathy • Sepsis syndrome • Prolonged hypotension • Severe head trauma • History of gastrointestinal bleeding

Shift in Preferred Therapy

• Thermal injury involving more than 35% of the body surface area

Clinicians may be surprised to learn that H2 receptor antagonists (H2RAs) now are the preferred initial agent for therapy, with IV therapy being the optimal route of administration. “PPIs [proton pump inhibitors] should be reserved for those who cannot tolerate H2 blockers, who have failed H2 blockers, who have evidence of GI bleed, or maybe have some other indication for a PPI,” said presenter Robert MacLaren, PharmD, associate professor in the University of Colorado School of Pharmacy, in Aurora. Antacids and sucralfate are not recommended and enteral nutrition should not be used alone as prophylaxis, he said. Discussing the pros and cons of specific H2RAs, presenter Henry Cohen, PharmD, noted that IV cimetidine is FDA-approved but that ranitidine, famotidine and nizatidine are used offlabel. “Ranitidine and famotidine have been extensively used off label, and there are many trials to support their use for stress ulcer prevention,” said Dr. Cohen, professor of pharmacy practice at the Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, and chief pharmacy officer at Kingsbrook Jewish Medical Center, in New York City. With increased use of these agents expected, Dr. Cohen said that clinicians should bear in mind that all the H2RAs except for famotidine have been shown to cause central nervous system adverse events (AEs), such as confusion, hallucinations, agitation, dizziness and headaches. Additionally, he said, cimetidine has significant cytochrome P450 (CYP) drug interactions and will significantly increase levels of agents such as phenytoin, warfarin and amiodarone. Ranitidine and nizatidine have a significantly lower risk for CYP drug interactions and famotidine has no interaction, he said. With regard to the PPIs, Dr. Cohen noted that the only PPI drug approved by the FDA for stress ulcer prevention is omeprazole but that lansoprazole, pantoprazole, rabeprazole (Aciphex, Eisai) and esomeprazole (Nexium, AstraZeneca) all are used off label. He pointed out that omeprazole, and to a lesser extent esomeprazole, will inhibit

• Major surgery that lasts more than 4 h Source: Crit Care Med 1999;27:2812-2817

‘PPIs [proton pump inhibitors] should be reserved for those who cannot tolerate H2 blockers, who have failed H2 blockers, who have evidence of a GI bleed, or maybe have some other indication for a PPI.’ —Robert MacLaren, PharmD CYP 2C19 and thus increase levels of drugs such as diazepam, phenytoin, warfarin and cyclosporine. He added that clinicians also should be aware

that inducers such as phenobarbital or St. John’s wort can decrease levels of all PPIs. Additionally, Dr. Cohen said, PPIs block the antiplatelet effects of clopi-

YES

Figure. Algorithm for stress ulcer prophylaxis. H2RA, H2 receptor antagonist; PPI, proton pump inhibitor

dogrel (Plavix, Bristol-Myers Squibb), whereas the H2RAs with the exception of cimetidine do not. Jill Rebuck, PharmD, director of pharmacy services at Lancaster General Hospital, in Pennsylvania, discussed AEs associated with stress ulcer prophylaxis that influenced the recommendations made in the guidelines. AEs, including community-acquired pneumonia (CAP), fractures, GI effects, headaches, rash, acute interstitial nephritis and hypomagnesemia have been associated with PPIs more frequently than with H2RAs, Dr. Rebuck said. Dr. Rebuck noted that since 2000, approximately 15 studies have focused a priori on evaluating the potential association of Clostridium difficile with PPIs alone or with H2RAs. Eleven of the 15 studies identified an association with C. difficile, only two of which involved H2RAs. None of these studies were randomized trials, she noted, adding that no randomized trials have established a link between C. difficile and these agents. A recent study revealed that PPI use during incident C. difficile treatment resulted in a 42% increased risk for recurrence; the risk was more prominent in elderly patients (Arch Intern Med 2010:170:772-778).

•

see STRESS, page 8

8 Clinical

Pharmacy Practice News • May 2012

Critical Care

STRESS continued from page 7

Dr. Rebuck highlighted five studies showing that PPI initiation increases the risk for CAP, with odds ratios ranging from 1.21 to 2.45 (Aliment Pharmacol Ther 2010;31:1165-1177; JAMA 2004;292:19551960; Arch Intern Med 2007;167:950955; Ann Intern Med 2008;149:391-398; Epidemiology 2009;20:800-806; Am J Med 2010;123:47-53). An increased risk for fractures has been associated with PPIs as well, accord-

ing to Dr. Rebuck. In 2006, a landmark study showed that the risk for hip frac-

ture was significantly increased among patients prescribed long-term, high-dose

PPIs (adjusted odds ratio, 2.65; P<0.001) compared with nonusers of acid suppression drugs (JAMA 2006;296:29472953). In 2011, three meta-analyses were published identifying an increased rate of hip and vertebral fractures with PPI use and a higher risk with higher doses. The three studies showed hazard ratios of 1.20 to 1.30 for hip fractures, roughly 1.50 for vertebral factures and 1.09 to 1.56 for other fractures (Am J Med 2011;124:519-526; Am J Gastroenterol 2011;106:1209-1218; Ann Fam Med 2011;9:257-267). In contrast, fracture risk has not been identified with H2RAs, according to Dr. Rebuck. Based on these sets of data, Dr. Rebuck said the new guidelines recommend that clinicians use “caution in prescribing PPIs” for patients at risk for pneumonia or fractures.

When To Stop Therapy The speakers agreed that physicians are not good at stopping stress ulcer prophylaxis, discharging almost onequarter of patients inappropriately on these agents (Ann Pharmacother 2007;41:1611-1616). “The overarching concept is to stop pharmacologic stress ulcer prophylaxis when the indication has gone away,” said Richard Savel, MD, associate professor of clinical medicine, Albert Einstein College of Medicine, Montefiore Medical Center, in New York City. “This has not been as easy as it sounds. There are certain patients for whom we would all agree don’t have any indications. They are extubated, they are eating, they have gotten through their sepsis and they are doing great. That patient doesn’t need to continue on the H2 blocker,” said Dr. Savel. However, he noted that residents “may be confused by that, and that is where we can intervene. I think that is the lowhanging fruit in this area.” When a patient leaves the ICU, a multidisciplinary team should have already considered whether the patient needs to continue stress ulcer prophylaxis. “I think the concept of checklists and quality improvement is really going to be the wave of the future,” Dr. Savel said. “Making it so [a patient] can’t leave the ICU unless [clinicians] address this is really the only way that this is going to be made better.” Dr. Cohen said a treatment algorithm can help physicians provide stress ulcer prophylaxis (Figure). For more detailed guidance, practitioners will have to wait for the release of the guidelines expected later this year. —Kate O’Rourke Dr. MacLaren disclosed receiving grant support from Hospira. Drs. Rebuck, Naylor, Savel and Cohen reported no relevant financial conflicts of interest.

Pharmacy Practice News • May 2012

Clinical 9

Critical Care

Overweight Patients Often Dosed Inaccurately in EDs Houston—Overweight patients seen in the emergency department (ED) are more likely to receive inadequate doses of etomidate and vancomycin, according to two studies presented at the recent annual meeting of the Society of Critical Care Medicine (SCCM). “These drugs have narrow therapeutic indexes and patient harm can actually occur if the medications are not dosed appropriately,” said Samantha JellinekCohen, PharmD, emergency medicine clinical pharmacy specialist at Beth Israel Medical Center-Petrie Division, in New York City, commenting on the findings. “Doctors have to understand the importance of weighing patients and the inaccuracies associated with estimating weights.”

Subtherapeutic Etomidate Dosing In one study, more than 68% of patients who were at least 100 kg received subtherapeutic doses of etomidate for rapid sequence intubation (RSI) compared with 2% of patients who were less than 100 kg (P<0.001) (abstract 837). Brittany Traylor, a postgraduate year 2 pharmacy resident in emergency medicine at the University of Arizona Medical Center, who led the study, said the 100-kg cutoff was used because the charts didn’t allow a comparison by body mass index. “Most people who are of an average height would be overweight at 100 kg,” she said. Patients were considered to have received a subtherapeutic dose of etomidate if

ACT NOW to continue receiving your FREE print subscription to Pharmacy Practice News!

You can renew your subscription online by visiting http://www.pharmacypracticenews. com/renew and filling out a brief form. You can also access the form by scanning the QR code above with your smartphone.

they received less than 0.2 mg/kg because this would fall below the recommended dosage range based on FDAapproved product labeling. Etomidate is one of the most commonly used sedatives in the ED because it has a rapid onset of action (less than one minute), a short duration of hypnosis (three to five minutes) and minimal respiratory and cardiovascular effects. The researchers studied data from 200

patients between the ages of 18 and 89 who were intubated using etomidate at the University of Arizona Medical Center, University Campus in Tucson, between March 1, 2008 and June 31, 2010. Patients were excluded if they did not receive etomidate for RSI, did not have their weight or dose of etomidate recorded, or if the a priori limit of 100 patients was reached for either the group in which patients weighed more

than 100 kg or the group with patients who weighed less than 100 kg. “This study provides some concrete evidence that we may be underdosing these patients with … etomidate at our institution,” said Dr. Traylor. “However, this study doesn’t elucidate what the complications of that might be, because it was a retrospective study, and we weren’t able to ask the patients if they

•

see OVERWEIGHT, page 26

LEVETERACITAM INJECTION, USP

Rx Only

INDICATIONS AND USAGE-Levetiracetam injection is an antiepileptic drug indicated for adjunct therapy in adult patients (16 years and older) when oral administration is temporarily not feasible. Partial Onset Seizures-Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy. Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy-Levetiracetam is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy. Primary Generalized Tonic-Clonic Seizures-Levetiracetam is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy. CONTRAINDICATIONS-None WARNINGS AND PRECAUTIONS Neuropsychiatric Adverse Reactions Partial Onset Seizures - In some adults experiencing partial onset seizures, levetiracetam causes the occurrence of central nervous system adverse reactions that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of levetiracetam-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of the treated patients, compared to 0% in the placebo group. About 3% of levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced. A total of 3.4% of levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued levetiracetam treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia. Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment. In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) of levetiracetam-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient. Two (0.3%) levetiracetam-treated patients were hospitalized and their treatment was discontinued. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. Two other events, reported as hallucinations, occurred after 1 to 5 months and resolved within 2 to 7 days while the patients remained on treatment. In one patient experiencing psychotic depression occurring within a month, symptoms resolved within 45 days while the patient continued treatment. A total of 13.3% of levetiracetam patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients. Approximately half of these patients reported these events within the first 4 weeks. A total of 1.7% of treated patients discontinued treatment due to these events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of treated patients and in 0.5% of placebo patients. A total of 0.8% of treated patients had a serious behavioral event (compared to 0.2% of placebo patients) and were hospitalized. In addition, 4 (0.5%) of treated patients attempted suicide compared to 0% of placebo patients. One of these patients completed suicide. In the other 3 patients, the events did not lead to discontinuation or dose reduction. The events occurred after patients had been treated for between 4 weeks and 6 months.

Myoclonic Seizures -During clinical development, the number of patients with myoclonic seizures exposed to levetiracetam was considerably smaller than the number with partial seizures. Therefore, under-reporting of certain adverse reactions was more likely to occur in the myoclonic seizure population. In some patients experiencing myoclonic seizures, levetiracetam causes somnolence and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with JME. In the double-blind, controlled trial in patients with juvenile myoclonic epilepsy experiencing myoclonic seizures, 11.7% of levetiracetam-treated patients experienced somnolence compared to 1.7% of placebo patients. No patient discontinued treatment as a result of somnolence. In 1.7% of levetiracetam-treated patients and in 0% of placebo patients the dose was reduced as a result of somnolence. Non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of the levetiracetam-treated patients compared to 0% of placebo patients. Non-psychotic mood disorders (reported as depressed mood, depression, and mood swings) occurred in 6.7% of levetiracetam-treated patients compared to 3.3% of placebo patients. A total of 5.0% of levetiracetam-treated patients had a reduction in dose or discontinued treatment due to behavioral or psychiatric events (reported as anxiety, depressed mood, depression, irritability, and nervousness), compared to 1.7% of placebo patients. Primary Generalized Tonic-Clonic Seizures During clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to levetiracetam was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with levetiracetam treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and levetiracetam treatment groups and no appreciable discontinuations. Although it may be expected that drug related events seen in partial seizure patients would be seen in primary generalized epilepsy patients (e.g., somnolence and gait disturbance), these events may not have been observed because of the smaller sample size.In some patients experiencing primary generalized tonic-clonic seizures, levetiracetam causes behavioral abnormalities. In the double-blind, controlled trial in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures, irritability was the most frequently reported psychiatric adverse event occurring in 6.3% of levetiracetam-treated patients compared to 2.4% of placebo patients. Additionally, non-psychotic behavioral disorders (reported as abnormal behavior, aggression, conduct disorder, and irritability) occurred in 11.4% of the levetiracetam-treated patients compared to 3.6% of placebo patients. Of the levetiracetam-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression. Non-psychotic mood disorders (reported as anger, apathy, depression, mood altered, mood swings, negativism, suicidal ideation, and tearfulness) occurred in 12.7% of levetiracetam-treated patients compared to 8.3% of placebo patients. No levetiracetam-treated patients discontinued or had a dose reduction as a result of these events. One levetiracetam-treated patient experienced suicidal ideation. One patient experienced delusional behavior that required the lowering of the dose of levetiracetam. In a long-term open label study that examined patients with various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior. Behavior in one case was characterized by auditory hallucinations and suicidal thoughts and led to levetiracetam discontinuation. The other case was described as worsening of pre-existent schizophrenia and did not lead to drug discontinuation. Withdrawal Seizures-Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency. Hematologic Abnormalities -Partial Onset Seizures -Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant ()2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant ()1.0 x 109/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts. Juvenile Myoclonic Epilepsy -Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients. Hepatic Abnormalities-There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment. ADVERSE REACTIONS Clinical Studies Experience-Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reactions that result from levetiracetam injection use include all of those reported for levetiracetam tablets and oral solution. Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent Cmax, Cmin, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15 minute infusion. The prescriber should be aware that the adverse reaction incidence figures in the following tables, obtained when levetiracetam was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied. Partial Onset Seizures Table 3 lists treatment-emergent adverse reactions that occurred in at least 1% of adult epilepsy patients treated with levetiracetam tablets participating in placebocontrolled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 3: Incidence (%) of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Studies in Adults Experiencing Partial Onset Seizures by Body System (Adverse Reactions Occurred in at Least 1% of Levetiracetam-Treated Patients and Occurred More Frequently than Placebo-Treated Patients) Body System/Adverse Reaction Levetiracetam Placebo (N=769)% (N=439)% Body as a Whole Asthenia Headache Infection Pain Digestive System

15 14 13 7

9 13 8 6

Anorexia Nervous System Somnolence Dizziness Depression Nervousness Ataxia Vertigo Amnesia Anxiety Hostility Paresthesia Emotional Lability Respiratory System

15 9 4 4 3 3 2 2 2 2 2

8 4 2 2 1 1 1 1 1 1 0

Pharyngitis Rhinitis Cough Increased Sinusitis Special Senses

6 4 2 2

4 3 1 1

Diplopia

Myoclonic Seizures Table 4 lists treatment-emergent adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam tablets and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 4: Incidence (%) of Treatment-Emergent Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients with Myoclonic Seizures by Body System (Adverse Reactions Occurred in at Least 5% of Levetiracetam-Treated Patients and Occurred More Frequently than Placebo-Treated Patients) Body System/Adverse Reaction Levetiracetam Placebo (N=60)% (N=60)% Ear and labyrinth disorders Vertigo Infections and infestations

Pharyngitis Inﬂuenza

7 5

0 2

Neck pain Nervous system disorders

Somnolence Psychiatric disorders

Depression

Musculoskeletal and connective tissue disorders

Primary Generalized Tonic-Clonic Seizure Table 5 lists treatment-emergent adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 5: Incidence (%) of Treatment-Emergent Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 4 Years of Age and Older with PGTC Seizures by MedDRA System Organ Class (Adverse Reactions Occurred in at Least 5% of Levetiracetam-Treated Patients and Occurred More Frequently than Placebo-Treated Patients) Body System/Adverse Reaction Levetiracetam Placebo (N=79)% (N=84)% Gastrointestinal disorders Diarrhea

Fatigue Infections and infestations

Nasopharyngitis Psychiatric disorders

Irritability Mood swings

6 5

2 1

General disorders and administration site conditions

DRUG INTERACTIONS In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely. Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients. USE IN SPECIFIC POPULATIONS Pregnancy-Pregnancy Category C-There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses *350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m2 basis). There was no overt maternal toxicity at the doses used in this study. Treatment of pregnant rabbits during the period of organogenesis resulted in increased embryo fetal mortality and increased incidences of minor fetal skeletal abnormalities at doses *600 mg/kg/day (approximately 4 times MRHD on a mg/m2 basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m2 basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m2 basis). Maternal toxicity was also observed at 1800 mg/kg/day. When pregnant rats were treated during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study. Treatment of rats during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis). Patients may enroll in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free). Labor and Delivery-The effect of levetiracetam on labor and delivery in humans is unknown. Nursing Mothers-Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use-Safety and effectiveness of levetiracetam injection in patients below the age of 16 years have not been established. Geriatric Use-Of the total number of subjects in clinical studies of levetiracetam, 347 were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients. A study in 16 elderly subjects (age 61 to 88 years) with oral administration of single dose and multiple twice-daily doses for 10 days showed no pharmacokinetic differences related to age alone. Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Use in Patients with Impaired Renal Function-Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis. OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of oral levetiracetam received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses in postmarketing use. Treatment or Management of Overdose - There is no specific antidote for overdose with levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam. Hemodialysis- Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Storage-Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature). How Supplied-Levetiracetam injection 500 mg/5 mL is a clear, colorless, sterile solution. It is supplied in single-use 5 mL vials, available in cartons of 25 vials (NDC 0517-3605-25).

AR126 Iss. Date 1/2012

Pharmacy Practice News • May 2012

Clinical 11

Educational review

Catheter-related

Bloodstream Infections

Cybele L. Abad, MD

Nasia Safdar, MD, PhD

Clinical Director Early Intervention Program Milwaukee Heatlh Services, Inc. Milwaukee, Wisconsin

Assistant Professor Section of Infectious Diseases Department of Medicine University of Wisconsin Madison, Wisconsin

ealth care–associated infections (HAIs)

are an important cause of morbidity and mortality and place a significant economic

burden on the health care system.1-3 An estimated

1.7 million HAIs (4.5 infections per 100 hospital admissions) occurred in the United States in 2002, resulting in nearly 100,000 deaths.4

Catheter-related bloodstream infections (CRBSIs), most of which are associated with central venous catheters (CVCs), account for 11% of all HAIs.4-6 Agencies such as the National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infections Surveillance System) of the Centers for Disease Control and Prevention (CDC) were formed in response to the growing awareness that HAIs are urgent public health and patient safety issues.1 The recent action plan proposed by the Department of Health and Human Services identified CRBSIs as a priority area for prevention.7 In 2002, the National Quality Forum created and endorsed a list of Serious Reportable Events (SREs) to increase public accountability and consumer access to critical information about health care performance. These SREs soon became known as “never events.” Following this lead, in 2007 the Centers for Medicare & Medicaid Services (CMS) declared it would no longer reimburse HAIs such as CRBSIs, increasing the urgency for rational and effective prevention and treatment strategies to reduce the morbidity, mortality, and costs associated with them.8 The policy, which went into effect in late 2008, was created to help improve the care of patients by incentivizing hospitals to prevent serious hospital-associated adverse events. CMS mandated that beginning in January 2011, hospitals must report CRBSI rates through

the NHSN. This CMS regulation makes CRBSI reporting a national requirement for receiving full Medicare inpatient payments; facilities that fail to report will not receive the annual 2% Medicare payment increase. A recent meta-analysis of patients in the intensive care unit (ICU) found that mortality rates were significantly higher when a CRBSI occurred (random effects model: odds ratio [OR], 1.96; 95% confidence interval [CI], 1.253.09). 9 Each episode significantly increases hospital length of stay, with additional health care costs ranging from $4,000 to $56,000 per episode.6,10,11 The NHSN has published surveillance criteria for defining CRBSIs. The criteria for patients older than 1 year of age are the following: isolation of a recognized pathogen from blood culture(s), the presence of clinical signs of sepsis and/or shock (eg, fever, chills, or hypotension), a determination that the infection is not from other sources, and confirmation that the organism is not a contaminant.1 Intravascular devices (IVDs) include peripheral vascular catheters (venous and arterial), pulmonary artery catheters, midline catheters, peripherally inserted central catheters (PICCs), and various CVCs, including tunneled (usually long-term devices) and nontunneled catheters (percutaneously placed CVCs commonly used in ICUs).3,5,6,12 This review covers the pathogenesis, microbiology, and treatment of CRBSIs,

highlighting advances in the areas of prevention and government policy.

Microbiology Antimicrobial resistance, now considered a global crisis, continues to loom large, and the organisms that cause CRBSIs are no exception. In the past 2 decades, the proportion of CRBSIs caused by antimicrobial-resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant gramnegative bacilli, and fluconazole-resistant Candida species, has been increasing at an alarming rate.3,13-15 Overall, the organisms most frequently responsible for nosocomial CRBSIs are coagulase-negative staphylococci (CoNS, S. aureus, enterococci, Escherichia coli, Klebsiella species, and Candida species. A large prospective surveillance study using data from SCOPE (Surveillance and Control of Pathogens of Epidemiological Importance) that included 24,179 cases of CRBSIs from a 7-year period at 49 hospitals found that the rates of MRSA isolates increased from 22% in 1995 to 57% in 2001 (P<0.001). Rates of ceftazidime-resistant Pseudomonas aeruginosa isolates increased from 12% in 1995 to 29% in 2001 (P<0.001), and 60% of isolates contained vancomycin-resistant Enterococcus faecium.15 Text continues on page 12

12 Clinical

Pharmacy Practice News • May 2012

Educational Review

Complicated

Uncomplicated

Endocarditis, septic thrombosis, osteomyelitis, etc.

Coagulase- negative Staphylococcus

Staphylococcus aureus

Enterococci

Gram-negative bacilli

Candida species

Short-term CVC/AC and long-term CVC/port: Remove, SATª for 4-6 wk or 6-8 wk for osteomyelitis Tunnel infection or port abscess: Remove, SAT for 7-10 d

Short term CVC/AC: Remove, SAT for 5-7 d OR Retain,b SAT + ALT for 10-14 d Long-term CVC/port: Retain,b SAT + ALT for 10-14 d

Short-term CVC/AC: Remove, SAT for minimum of 14 d Long-term CVC/port: Remove,c SAT for 4-6 wk

Short-term CVC/AC: Remove, SAT for 7-14 d Tunneled CVC/port: Retain,b SAT + ALT for 7-14 d

Short-term CVC/AC: Remove, SAT for 7-14 d Long-term CVC/port: Remove, SAT for 10-14 d OR Retain, SAT + ALT for 10-14 d, remove if no response

Short-term CVC/AC and long-term CVC/port: Remove, SAT for 14 d after first negative blood culture

Figure. Management of CRBSIs. AC, arterial catheter; ALT, antibiotic lock therapy; CRBSIs, catheter-related bloodstream infections; CVC, central venous catheter; SAT, systemic antimicrobial therapy a

Choose most appropriate systemic antimicrobial therapy based on current published guidelines.

Remove retained catheter if there is clinical worsening, relapsing, or persisting infection.

Current guidelines recommend considering catheter salvage therapy; however, outcomes may be poor.

Adapted from reference 19.

Text continued from page 11

Pathogenesis

of the double-lumen catheter had been sampled.21 A number of techniques for the diagnosis of CRBSIs have been studied, including catheter-sparing and non–catheter-sparing methods.

The pathogenesis of CRBSIs can be attributed to 2 primary causes: bacterial colonization of the device and contamination of the fluid being administered.16 Contaminat- Management The management of CRBSIs relies ed infusate leads to the majority of epidemic IVD-related BSIs, but it is on 2 major clinical decisions: 1) the rare.16,17 Colonization of the device appropriate and timely administramay be either extraluminal (from tion of systemic antimicrobial treatsurrounding skin or hematogenous ment (SAT) and 2) catheter removal seeding of the catheter tip) or intra- or catheter salvage treatment. SAT luminal (caused by an organism should be selected based on the adhering to the device followed by suspected or proven presence of the creation of a biofilm, a process causative agents in accordance with responsible for persistent infections published guidelines and resources.19 and hematogenous spread).3,16,17 In The decision to remove the cathshort-term devices, the extralumi- eter is based on the type of cathnal route is more frequent, whereas eter being used and the organism the intraluminal route is more com- in question. This decision becomes mon in long-term devices (≥10 days) more complex when specific patient or short-term devices left in longer characteristics are considered, such than 4 to 7 days.16,18 as the type of device required (tunneled or implanted) and the ease of Diagnosis venous access. Guidelines from the The clinical diagnosis of CRBSIs is Infectious Diseases Society of Amerdifficult because both the sensitivi- ica (IDSA) recommend the removal ty for clinical signs of inflammation of nontunneled catheters in all comat the catheter site and the speci- plicated infections (eg, thromboficity for signs of systemic infection sis, endocarditis, osteomyelitis) and are low.19,20 Blood culture speci- in all infections caused by S. aureus, mens from the catheter should be gram-negative bacilli, Enterococcus drawn from all available lumens to species, and Candida species. The avoid missed infections. In a recent catheter may be retained with CoNS retrospective analysis of CRBSIs if systemic antibiotics are given in at a single institution, 27.2% would conjunction with antibiotic lock therhave been missed if only one lumen apy (ALT).19 In CRBSIs associated

with tunneled or implantable devic- and 14 days from the first negative es, the catheters also require remov- blood culture for Candida infections al for any complicated infections (eg, (Figure).12,19 Transesophageal echocardiograthrombosis, endocarditis, osteomyelitis), tunnel or pocket infections phy (TEE) should be performed in and port abscesses, and all infec- all patients with a CRBSI caused by tions caused by S. aureus and Can- S. aureus because of the propensity of this organism to cause endodida species. According to the recent guide- carditis. Rosen et al determined that lines, catheter salvage regimens— screening all patients who had a clinincluding the use of ALT—may be ically uncomplicated CRBSI caused attempted when necessary for infec- by S. aureus with TEE was a costtions caused by organisms other effective way to determine therapy than S. aureus, fungi, P. aeruginosa, duration (as short as 2 weeks if the Bacillus species, Micrococcus spe- TEE result was negative).34 cies, propionibacteria, and mycobacteria.19 Although device-sparing Catheter Salvage Strategies When the need to retain an existregimens with longer treatment durations and using antibiotic lock ing long-term catheter in a patient solutions have been attempted for with a CRBSI is significant, salvage uncomplicated S. aureus, gram-neg- can be attempted by using ALT as ative bacilli, and even fungal patho- an adjunct to systemic therapy.12,19,35 gens, the data supporting its efficacy Approximately 2 mL of solution is are scant and catheter salvage for S. infused into the lumen of the cathaureus and other virulent organisms eter and remains there for a certain amount of time per day during the is not recommended.12,19,22-33 The duration of therapy varies course of treatment.12,35 Solutions based on the organismand whether consist of the appropriately selector not the device has been removed. ed antibiotic combined with heparin Systemic therapy for CoNS infec- (if compatible). In the lock, antibitions ranges from 5 to 7 days when otic concentrations range from 100 the catheter is removed and from to 1,000 times the usual systemic 10 to 14 days when it is retained in concentrations. This increased conconjunction with ALT. With catheter centration is more likely to kill organremoval and uncomplicated infec- isms embedded in biofilm.35 Current tions, the duration of systemic ther- guidelines recommend that ALT be apy for CRBSIs caused by S. aureus used for 10 to 14 days in conjuncis greater than 14 days, 7 to 14 days tion with SAT.19 Vancomycin, cefazofor gram-negative bacilli infections, lin, and ticarcillin-clavulanic acid

Pharmacy Practice News • May 2012

Clinical 13

Educational review

Prevention

Table. Novel Strategies for the Prevention of CRBSIs

Antimicrobial lock solution

Strategy

Antimicrobial catheters

(Timentin, GlaxoSmithKline)—all in combination with heparin—have excellent stability when used in ALT, retaining 90% of their activity after 10 days of dwell time in the presence of susceptible organisms.36 CRBSIs caused by Candida species necessitate prompt removal of the catheter; however, this may not always be immediately possible. A solution of ethylenediamine tetraacetic acid (EDTA) with amphotericin B lipid complex showed promise during an in vitro model of a Candida biofilm formation, but more research is urgently needed.37 We do not recommend catheter salvage in the setting of S. aureus CRBSIs because of the high risk for metastatic infection and the slim likelihood of cure without removal of the catheter.

Study

Design

Technology

Outcome

Safdar et al 200641

Meta-analysis

Vancomycin-containing locks vs heparin

50% risk reduction RR, 0.49; 95% CI, 0.26-0.95

Yahav et al 200844

Systematic review and meta-analysis

Various antibioticsa Antibiotic plus antisepticb Antisepticc

Antibiotic solutions: RR, 0.44; 95% CI, 0.38-0.5 Non-antibiotic antiseptic solutions + other prevention methodsd: RR, 0.25; 95% CI, 0.13-0.5 Non-antibiotic antiseptic solutions alone: RR, 0.9; 95% CI, 0.48-1.69

Sanders et al 200847

Double-blind randomized trial

Ethanol-containing locks vs heparin

OR, 0.18; 95% CI, 0.05-0.65

Veenstra et al 199943

Meta-analysis

Antiseptic-impregnated CVCse

OR, 0.56; 95% CI, 0.37-0.84

Ramritu et al 200840

Systematic review

Antibiotic-impregnated CVCsf

RR, 0.39; 95% CI, 0.17-0.92

Crnich et al 20025

Meta-analysis

Silver-impregnated CVCs

RR, 0.40; 95% CI, 0.24-0.68

Chlorhexidine bathing

Mupirocin Cutaneous prophylaxis antisepsis

Chlorhexidine dressings

The Healthcare Infection ConRamritu et al Systematic review Antibiotic vs first-generation RR, 0.12; 95% CI, 0.02-0.67g trol Practices Advisory Committee 200840 antiseptic-impregnated CVCs (HICPAC) of the CDC has published extensive guidelines for the prevenHockenhull Systematic review Anti-infective CVCs (all types) OR, 0.49; 95% CI, 0.37-0.64h tion of CRBSIs,with a recent update et al 200946 released in 2011. 2,3 They emphaCatheter or exit-site colonization: Ho et al Meta-analysis Chlorhexidine-impregnated size the following: 1) educating and 14.3% vs 27.2%; OR, 0.4; 200639 dressing vs placebo or training all health care personnel 95% CI, 0.26-0.61 povidone-iodine dressing who insert and maintain catheters; CRBSIs: 2) using maximal sterile barrier pre2.2% vs 3.8%; OR, 0.58; 95% CI, 0.29-1.14; P=0.11 cautions during CVC insertion; 3) using a greater than 0.5% chlorhexTimsit et al Randomized Chlorhexidine-impregnated 0.4 vs 1.3 CRBSIs per 1,000 idine skin preparation with alcohol 200945 controlled trial dressing vs standard dressing catheter-days; HR, 0.024; for antisepsis; 4) avoiding routine 95% CI, 0.09-0.65; P=0.005 replacement of CVCs as a strateChaiyakuMeta-analysis Chlorhexidine vs RR, 0.49; 95% CI, 0.28-0.88i gy to prevent infection; and 5) using napruk et al povidone-iodine antiseptic/antibiotic-impregnat200238 ed short-term CVCs and chlorhexidine-impregnated sponge dressings if the rate of infection is not decreasTacconelli Meta-analysis Mupirocin prophylaxis in Decrease in S. aureus bacteremia ing despite adherence to prior stratet al dialysis patientsj in hemodialysis patients by 78%; egies. The guidelines also emphasize 200342 RR, 0.22; 95% CI, 0.11-0.42 implementation of bundle strategies and documentation and reporting of compliance rates for all components Decrease in risk for bloodstream Silva et al Meta-analysis Daily chlorhexidine bathing of the bundle as benchmarks for infection 201048 (impregnated cloths or solution) RR, 0.32; 95% CI, 0.22-0.46; compared with soap and water quality assurance and performance P<0.0001, fixed-effects; I2=17% baths improvement.2 Novel strategies for the prevention of CRBSIs are summarized in the Table.5,38-48 Highlighted below are important CI, confidence interval; CVC, central venous catheter; HR, hazard ratio; OR, odds ratio; RR, relative risk a topics for the prevention of CRBGentamicin; gentamicin + citrate; gentamicin + vancomycin; gentamicin + cefazolin; cefotaxime. b Minocycline with ethylenediamine tetraacetic acid. c Citrate; citrate with taurolidine. d Nasal mupirocin and exit-site iodine dressing. e Chlorhexidine-silver sulfadiazine. f Minocycline and rifampin. SIs. The recommendations are rated g Reduced risk with antibiotic catheters. h Reduced risk with anti-infective catheters: all types combined, see text for subgroup analysis. i Reduced risk with chlorhexidine. based on the strength of evidence j Six studies used intranasal mupirocin 2 to 3 times daily for 5 to 14 days with various maintenance schedules; 4 studies used mupirocin applied to catheter exit site. supporting them as follows: IA, strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies; IB, suggestive clinical or epidemiolog- that a 2% chlorhexidine prepara- suggested that the use of chlorhexistrongly recommended for imple- ic studies or a theoretical rationale.3 tion is the superior agent for pre- dine rather than povidone-iodine for venting CRBSIs. A meta-analysis of CVCs would result in a 1.6% decrease mentation and supported by some 4,143 catheters found that chlorhex- in the incidence of CRBSIs, a 0.23% experimental, clinical, or epidemi- Cutaneous Antisepsis Historically, iodophors, such as idine preparations reduced the risk decrease in the incidence of morologic studies and a strong theoretical rationale; IC, required by 10% povidone-iodine, have been the for CRBSIs by 49% (95% CI, 0.28- tality, and cost savings of $113 per state or federal regulations, rules, most widely used skin antisepsis 0.88) compared with povidone- catheter used.51 Currently, the CDC or standards; and II, suggested for agents in the United States.5,49,50 iodine.38 Also, an economic decision recommends a 2% chlorhexidine Text continues on page 14 implementation and supported by However, recent studies demonstrate analysis based on available evidence

14 Clinical

Pharmacy Practice News 窶｢ May 2012

Educational Review Text continued from page 13

preparation as the first choice agent for cutaneous antisepsis (rating IA).2

Topical Antimicrobials The HICPAC/CDC guidelines specifically recommend against the use of topical antibiotic ointments or creams at the catheter insertion site (except in the case of hemodialysis catheters) to avoid promotion of fungal infections and antimicrobial resistance (rating IA).2,3 The guidelines also discourage the administration of intranasal antimicrobials before insertion or during the use of a catheter (rating IA).3 Reports of emerging mupirocin resistance are becoming commonplace.52-57 Routine use of topical or intranasal mupirocin for prophylaxis against CRBSIs is not recommended. The limitations of mupirocin suggest that other topical approaches for the prevention of CRBSIs should be studied. The antibacterial properties of some types of honey have made this a promising agent to study. Preliminary results with Medihoney (pooled antibacterial honey including Leptospermum species honey; Medihoney Pty Ltd) are promising.58 However, a larger trial powered to show equivalence or superiority is needed to establish the utility of this product for the prevention of CRBSIs in patients receiving hemodialysis through tunneled, cuffed catheters.

Maximal Barrier Precautions Maximal barrier precautions, including cap, sterile gown, mask, large sterile drape, and sterile gloves, significantly reduce the rate of CRBSIs when used during catheter insertion.3,59 In a study comparing maximalﾂｭ barrier precautions with control precautions (eg, sterile gloves and small drape), the rate of CRBSIs was 6.3 times higher in the control group (P=0.06).59 The HICPAC/CDC guidelines recommend that maximal barrier precautions be used for all CVC insertions (rating IB).2,3

Insertion Site According to the HICPAC/CDC guidelines, the preferred insertion site of nontunneled CVCs for adult patients is the subclavian vein (rating 1B).2,3 The femoral site is associated with higher rates of catheter colonization as well as increased risk for deep vein thrombosis.3,60-63 The internal jugular site has been associated with higher rates of CRBSIs than the femoral and subclavian sites in several studies.3,62,64 However, a recent RCT comparing

the jugular and femoral sites found no difference in the rate of CRBSIs between the 2 sites (2.3 vs 1.5 per 1,000 catheter-days, respectively; P=0.42).65 A prospective, observational study comparing the subclavian, internal jugular, and femoral insertion sites found colonization lowest at the subclavian site but found no difference in rates of infection between sites.66 Although no RCT to date has compared the 3 insertion sites, based on available data, the subclavian site is the preferred site for CVC insertion with the use of real-time ultrasound to minimize mechanical complications.

Chlorhexidine-Impregnated Dressings The placement of a chlorhexidine-impregnated sponge dressing (BioPatch, Ethicon) over the CVC insertion site has been shown to decrease CRBSIsﾂｭ in several randomized trials.5,45,67,68 The recent HICPAC/ CDC guidelines for the prevention of CRBSIs recommend the use of chlorhexidine-impregnated sponge dressings with short-term CVCs in patients older than 2 months when institutional rates of CRBSIs are higher than the institutional goal, despite the consistent use of now-standard prevention measures (using welltrained personnel, chlorhexidine skin antisepsis, and maximal barrier precautions; rating 1B).2

Antimicrobial-Impregnated Catheters The HICPAC/CDC guidelines recommend the use of antimicrobial-coated catheters if the device is expected to remain in place longer than 5 days if, despite use of a comprehensive CRBSI reduction strategy, the rate of infections is not decreasing (rating IA). 2,3 However, the majority of the studies have focused on the use of antimicrobial-coated CVCs used as short-term devices; few data are available on their use as long-term devices.18,40 Several types of antimicrobialimpregnated catheters are available: catheters coated either externally (first generation) or externally and internally (second generation) with chlorhexidine and sulfadiazine silver (CH-SS), catheters coated with minocycline or rifampin, and silverimpregnated catheters.12 Silver-coated catheters include silver-, platinum-, and carbon-coated catheters and silver ion/alloy catheters.5 The choice of which catheter to use is governed by many factors, including efficacy, cost, cost-effectiveness, and risk for promoting drug

resistance. A 2008 analysis found an estimated cost savings of approximately $227 for every a n t i - i n fe c t i ve catheter inserted.69 Antibiotic resistance is a particular concern with antibiotic-impregnated catheters, although trials assessing the efficacy of minocyclinerifampin窶田oated catheters found no evidence of the emergence of drug resistance.40

Antibiotic Lock Therapy The major mechanism for CRBSIs in patients with long-term devices is intraluminal colonization. For this reason, ALT has been considered as a logical step to prevent colonization of the intraluminal surfaces of longterm devices and thereby reduce the rate of CRBSIs. A small amount of the antibiotic solution is instilled into the lumen of the catheter and allowed to remain for a specific amount of time, after which it is either flushed or removed. A meta-analysis of 7 randomized trials (primarily involving cancer patients) demonstrated a significantly reduced risk for CRBSIs (RR, 0.49; 95% CI, 0.26-0.95) when vancomycin-containing lock solutions were used.41 A systematic review and metaanalysis of patients undergoing hemodialysis included data on several lock solutions: various antibiotic combinations, minocycline with EDTA, and nonantibiotic antiseptic solutions including citrate and citrate with taurolidine. All lock solutions included in this meta-analysis showed benefit for the prevention of CRBSIs.44 Ethanol also has been shown to be safe and effective as an antibiotic lock solution.47,70,71 Although a number of new antibiotics have shown promise as lock solutions during in vitro studies, more research on their efficacy is needed.72 In general, antiseptic lock solutions are preferred over antibiotic lock solutions because of their greater spectrum of activity and smaller risk for promoting antibiotic resistance. The HICPAC/CDC guidelines include a recommendation for the use of antibiotic/antiseptic lock solutions in patients with long-term catheters who have had multiple CRBSIs despite good aseptic technique (rating II).2 The use of antibiotic lock solutions is also recommended for the prevention of CRBSIs in long-term devices for patients with episodes of CRBSIs and a high risk for recurrence, such as

those on hemodialysis. Chlorhexidine bathing has been proposed and evaluated as a strategy for reducing rates of CRBSIs.73-76 The HICPAC/CDC guidelines recommend daily chlorhexidine bathing as a strategy for reducing the rates of CRBSIs (rating II)2; however, the conflicting results of recent reports warrant further research in this area.48,73,77

Coated Luer-activated Devices In addition to the previously described protection measures, the role of needleless connectors warrants attention. Needleless connectors were developed in response to demands for the improved safety of health care workers (to prevent needlestick injuries) and are integral components of infusion systems across North America. Although needleless connectors, when properly used, clearly reduce the risk for needlestick injuries during access of an IVD or injection port,7881 reports published over the past decade have raised concerns about their potential to increase the risk for iatrogenic BSIs.82-87 Most of these studies have been retrospective and uncontrolled; suboptimal manipulation of the device, rather than the device itself, may have been responsible for the increased incidence of CRBSIs in some settings. Typically, health care personnel disinfect the connector with 70% (v/v) isopropyl alcohol before IV administration. Although needleless connectors appeared to reduce contamination compared with standard caps,88 a recent study by Menyhay et al found that conventional methods of disinfection may not prevent microbial entry if the luer-activated device (LAD) is heavily contaminated, which may account for the increased risk for CRBSIs observed in some reports.89 The HICPAC/CDC guidelines made no recommendation for or against LADs, given the lack of RCTs on this device. However, chlorhexidine may be the preferred agent for cleaning the ports of needleless devices.2 A recent study evaluated the effect of switching to chlorhexidine for this purpose in a pre-post intervention design on a pediatric hemopoietic stem cell transplant ward.90 In this study, switching from 70% isopropyl alcohol alone to 2% chlorhexidine in 70% isopropyl alcohol for catheter connector antisepsis was associated with a reduction in the rates of Text continues on page 16

Switch to Privigen

Guarantee your IVIg supply

Choose the IVIg therapy that is:

Simple. Ready-to-use 10% liquid IVIg 36-month room temperature storage

Sophisticated.

Minimize your hospital’s supply risk Ensure your patients’ needs are met

First and only IVIg stabilized with proline Sucrose-free IgA 25 mcg/mL

Safe.

Guarantee your IVIg supply for up to 5 years

For more information, call 1-888-310-2525 or visit www.Privigen.com

3-step virus inactivation/removal process, including nanoﬁltration to approximately 20 nanometers, reduces the risk of pathogen transmission. The risk of virus transmission cannot be completely eliminated

Important Safety Information Privigen is indicated as replacement therapy for 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, WiskottAldrich syndrome, and severe combined immunodeficiencies. Privigen is also indicated to raise platelet counts in patients with chronic immune thrombocytopenic purpura (ITP). WARNING: Use of Immune Globulin Intravenous (IVIg) products, particularly those containing sucrose, have been associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death. Privigen does not contain sucrose. Administer Privigen at minimum rate practicable in patients at risk of renal dysfunction or acute renal failure. At-risk patients include those with preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia; over 65 years of age; or receiving known nephrotoxic drugs. See full prescribing information for complete boxed warning. Privigen is contraindicated in patients with history of anaphylactic or severe systemic reaction to human immune globulin, in patients with hyperprolinemia, and in IgA-deficient patients with antibodies to IgA and history of hypersensitivity.

treatment. In patients at risk for developing renal failure, monitor urine output and renal function, including blood urea nitrogen and serum creatinine. Also monitor patients with risk factors for thrombotic events; consider baseline assessment of blood viscosity for those at risk of hyperviscosity. Patients could experience increased serum viscosity, hyperproteinemia or hyponatremia; infrequently, aseptic meningitis syndrome (AMS) may occur (most often with high doses and/or rapid IVIg infusion). There have been reports of IVIg-related hemolysis, hemolytic anemia, and pulmonary adverse events, including transfusion-related acute lung injury (TRALI). Avoid highdose regimen where ﬂuid volume is of concern. 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. In clinical studies of patients being treated with Privigen for PI, the most serious adverse reaction was hypersensitivity (one subject). Adverse reactions observed in >5% of subjects with PI were headache, pain, nausea, fatigue, chills, vomiting, joint swelling/effusion, pyrexia, and urticaria.

Monitor patient vital signs throughout infusion of Privigen. In cases of severe hypersensitivity or anaphylactic reactions, discontinue administration and institute appropriate medical

In clinical studies of patients being treated with Privigen for chronic ITP, the most serious adverse reactions were AMS (one subject) and hemolysis (eight subjects). Adverse reactions seen in >5% of subjects with chronic ITP were headache, pyrexia/hyperthermia, positive DAT, anemia, vomiting, nausea, increases in conjugated and unconjugated bilirubin, hyperbilirubinemia, and increased blood lactate dehydrogenase.

Privigen is manufactured by CSL Behring AG and distributed by CSL Behring LLC. Privigen is a registered trademark of CSL Behring AG. The Privigen Promise is a trademark of CSL Behring LLC.

Treatment with Privigen might interfere with a patient’s response to live virus vaccines and could lead to misinterpretation of serologic testing.

Please see brief summary of full prescribing information on following pages.

16 Clinical

Pharmacy Practice News • May 2012

Educational Review Text continued from page 14

CRBSIs from 12 to 3 per 1,000 catheter-days (P=0.004). Novel technologies have been developed to address the association of these devices with increased rates of CRBSIs. The V-Link with VitalShield (Baxter Healthcare) is LAD protected, with an interior and exterior antimicrobial coating (silver). In vitro studies comparing the V-link with VitalShield with control devices demonstrated that the antimicrobial coating is more than 99.99% effective in killing

the most common organisms respon- a needleless LAD system. A recent sible for CRBSIs.91 It also prevented prospective, in vitro study compared downstream spread and intra-device standard disinfection techniques for biofilm formation when Enterobacter common LADs using 70% isoprocloacae was inoculated and allowed pyl alcohol with the Saralex-CL.92 to dry on the septal membrane, fol- The Saralex-CL, which uses a solulowed by the infusion of Lactated tion of 0.25 mL of 2% chlorhexidine Ringer’s running solution at 0.5 mL gluconate in 70% isopropyl alcohol per minute for 72 hours through the to bathe the connector septum, was effective in preventing transmission connected device. Another promising device, the of pathogens across the membranes Saralex-CL (Menyhay Healthcare of precontaminated LADs compared Systems), is an antimicrobial-barri- with standard techniques (positive er cap that threads onto the end of control = 100% transmission, standard

technique = 20 of 30; 67% transmission; Saralex-CL = 1 of 60; 1.6% transmission; P<0.001). Data on the clinical efficacy of antimicrobial-coated LADs and antimicrobial-barrier caps are awaited.

Catheter Securement Sutureless securement devices avoid disruption around the catheter entry site and may decrease the degree of bacterial colonization. 93 Catheter stabilization also helps decrease the risk for phlebitis

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Privigen®, Immune Globulin Intravenous (Human), 10% Liquid Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information.

5.6

Hemolysis

vivo

WARNING: ACUTE RENAL DYSFUNCTION/FAILURE

containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death.1 Patients at risk of acute renal failure include those with any degree of pre-existing renal insufﬁciency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Privigen does not contain sucrose. Privigen at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]). 4

see Adverse Reactions [6]

5.7

Transfusion-Related Acute Lung Injury (TRALI) 11

CONTRAINDICATIONS

see Description [11] 5 5.1

see Warnings and Precautions [5.1] WARNINGS AND PRECAUTIONS Hypersensitivity see Contraindications [4]

5.9

see Dosage and Administration [2.2] Transmissible Infectious Agents

5.10

. Interference with Laboratory Tests

see Description [11]).

5.2

Renal Dysfunction/Failure

Boxed Warning Dosage and Administration [2.3]

see 6.1 Clinical Trials Experience Because different 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.

5.4

Administration [2.3] 5.5 Aseptic Meningitis Syndrome (AMS) [6]

see Clinical Studies [14.1]

Thrombotic Events

see Dosage and see Adverse Reactions irrespective of causality

Pharmacy Practice News • May 2012

Clinical 17

Educational review and catheter migration/dislodgement while diminishing the risk for needlestick injury to the health care provider.2 Device securement options include sutures, tape, and catheterspecific devices such as the StatLock (Venetec). Sutures may be uncomfortable for the patient, pose a risk for needlestick injury to the provider, and foster inflammation at the catheter insertion site, increasing the risk for infection. StatLock, a sutureless catheter securement device, reduces

catheter-related complications, including CRBSIs.93-95 A randomized trial comparing sutures with StatLock for PICC securement found significantly fewer CRBSIs in the StatLock group than in the suture group (2 vs 10, respectively; P=0.032).93 The HICPAC/CDC guidelines recommend the use of a securement device for all intravascular catheters (rating II).2

Intensive Insulin Therapy The appropriate level of glycemic control for critically ill patients

Table 2: PI Pivotal Study – Adverse Events Occurring in >5% of Subjects During a Privigen Infusion or Within 72 Hours After the End of an Infusion, Irrespective of Causality Number (Rate) of Number (%) of Subjects Adverse Event Infusions with Adverse (Excluding Infections) [n=80] Event [n=1038]

Adverse Reaction

Number (%) of Subjects [n=80]

Table 6: Chronic ITP Study – Adverse Events Occurring in >5% of Subjects During a Privigen Infusion or Within 72 hours After the End of a Treatment Cycle, Irrespective of Causality (Two consecutive daily infusions) Number (%) of Subjects [n=57]

Number (Rate) of Infusions With Adverse Event [n=114]

Table 7: Chronic ITP Study – Adverse Reactions Occurring in >5% of Subjects, Irrespective of Time of Occurrence

Number (Rate) of Infusions with Adverse Reaction [n=1038]

Adverse Reaction

Number (%) of Subjects [n=57]

Number (Rate) of Infusions With Adverse Reaction [n=114]

†

6.2

Postmarketing Experience

see Dosing and Administration [2.3]

irrespective of causality

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

[14.2]

see Clinical Studies

compared with standard therapy (11 studies; pooled RR, 0.66; 95% CI, 0.57-0.76; P<0.001). However, no difference in infection rates among medical ICU patients was observed. Pending the results of ongoing and future research, the use of intensive glycemic control for surgical ICU patients to reduce the risk for HAIs, particularly CRBSIs, is recommended. However, avoiding severe hypoglycemia is crucial, and a glycemic target that can be safely achieved should be used.

Multifaceted Approach Using a Checklist

Adverse Event

Table 3: PI Pivotal Study – Adverse Reactions Occurring in >5% of Subjects, Irrespective of Time of Occurrence

is controversial. Studies have provided conflicting data. 96-101 Most recently, a meta-analysis of 20 RCTs evaluated the effect of intensive insulin therapy on the incidence of infections in medical and surgical ICU patients. The analysis revealed an overall reduction in the incidence of infections among all pooled studies (RR, 0.80; 95% CI, 0.71-0.90; P=0.0002; I 2=53.5%).101 Subgroup analysis revealed significantly fewer infections in surgical ICU patients in the intensive insulin therapy group

CSL Behring AG

CSL Behring LLC

A multifaceted approach must be used to effectively reduce the risk for CRBSIs. The Institute for Healthcare Improvement (IHI) developed the concept of “bundles” to aid risk reduction. According to the IHI, a bundle is a structured way of improving the processes of care and patient outcomes using a checklist of 3 to 5 practices that, when performed collectively and reliably, have led to improved patient outcomes.102 The IHI-recommended evidence-based bundle for CVC care includes the following: 1) hand hygiene; 2) maximal barrier precautions upon insertion; 3) chlorhexidine skin antisepsis; 4) optimal catheter site selection, with the subclavian vein as the preferred site for nontunneled catheters; and 5) daily review of line necessity, with prompt removal of unnecessary lines.102 A large multicenter study by Pronovost et al that used evidence-based interventions nearly identical to the IHI CVC bundle for 18 months found a significant reduction in CRBSIs from baseline.103 Bhutta et al undertook a prospective quasi-experimental study in a children’s hospital, which included the stepwise introduction of interventions over a 5-year period.104 The interventions included maximal barrier precautions, transition to antibiotic-impregnated CVCs, annual hand-washing campaigns, and use of chlorhexidine in lieu of povidoneiodine. Significant reductions in CRBSI rates occurred over the intervention period, and were sustained over the 3-year follow-up. The investigators agreed that multifaceted interventions of this nature reduce the rates of CRBSIs but require a multidisciplinary team and institutional support. Furthermore, the implementation of a multifaceted approach that included CVC insertion and maintenance bundles, chlorhexidine-impregnated dressings, staff education, and Text continues on page 18

18 Clinical

Pharmacy Practice News • May 2012

Educational Review reliability of the publicly reported the addition of a unit-based infection data on CRBSI rates. The authors control nurse in one pediatric cardi- then emphasize the need to change ac ICU, resulted in a reduction in the and validate the existing definition. rates of CRBSIs from 7.8 to 2.3 infec- They propose the inclusion of an tions per 1,000 catheter-days in less “indeterminate source” category for than 2 years.105 some CRBSIs, which is “more epiThe HICPAC/CDC guidelines rec- demiologically and clinically useful ommend that multifaceted perfor- than data derived from current defmance improvement strategies be initions, which are inconsistent with “bundled” to enhance compliance common clinical practice.”109 with evidence-based best practices Similarly, in a recent retrospec(rating IB).2 tive cohort study involving 4 medical institutions, Lin et al assessed “Getting to Zero”: whether or not surveillance data are The CRBSI Mandate consistent across institutions, conThe concept of “Getting to Zero” tending that public reporting and was first applied by the IHI for ven- interhospital comparisons of infectilator-associated pneumonia. Since tion rates are only valid if the surveilthen, the concept has been used lance methods are uniform.110 The for other HAIs, including CRBSIs. In authors compared a computer algothe effort to “get to zero,” the CMS rithm reference standard for CRBSI recently partnered with the NHSN rates with reported rates from the and listed CRBSIs as a “never event.” institution’s infection preventionists. This partnership creates greater The expected rate varied significanttransparency, builds accountability ly by medical center, suggesting that within the health care system, and there is indeed local variation among promotes support for infection con- medical centers. This then raises trol programs and professionals.106 doubt as to the validity of comparCertainly, by making CRBSI rates ing published rates of CRBSIs among available, the public has the oppor- various institutions.110 tunity to make informed decisions The “getting to zero” initiative has regarding health care. However, there many advantages. It has spurred diaare both concerns and controversy logue about CRBSI prevention, prosurrounding the concept of “getting pelled institutions to devote more to zero” and the CRBSI mandate. resources to CRBSI prevention, and Infection control experts have increased awareness of these infecshared concerns that “getting to zero” tions. However, the campaign to is an oversimplification of the com- publicly report CRBSIs should incorplexity of HAIs and does not convey porate a uniform application of stanthe important message that although dardized definitions in institutions the majority of HAIs are prevent- and a greater emphasis on process able, some are not.107 A commentary measures known to reduce the overby Victoria Fraser, MD, Washington all incidence of CRBSI. University School of Medicine in St. For complete references, please visit Louis, MO, pointed out that this slowww.pharmacypracticenews.com. gan is controversial because it seems scientifically unrealistic. Moreover, patients and the general public may References misinterpret the message to mean 1. Am J Infect Control. 2008;36(5):309-332. that any HAI is the result of an error 2. Am J Infect Control. 2011;39(4 suppl 1): or a suboptimal process.108 S1-S34. The concern regarding the CRBSI 3. Infect Control Hosp Epidemiol. mandate stems mainly from the 2002;23(12):759-769. CDC’s definition of a CRBSI itself. 4. Public Health Rep. 2007;122(2):160-166. The definition is highly sensitive 5. Clin Infect Dis. 2002;34(9):1232-1242. but poorly specific. The high sensi- 6. Mayo Clin Proc. 2006;81(9):1159-1171. tivity allows it to capture all cases 7. http://www.hhs.gov/ophs/initiatives/hai/ of CRBSIs, but the low specificity draft-hai-plan-01062009.pdf. Accessed February 24, 2012. causes it to suffer from the inclusion of infections that may not be 8. Pear R. Medicare says it won’t cover hospital errors. New York Times. August CRBSIs. In a thoughtful commen18, 2007. 109 this limitatary by Sexton et al, tion of the surveillance definition 9. Crit Care Med. 2009;37(7):2283-2289. is highlighted by specific examples 10. JAMA. 1994;271(20):1598-1601. where it seemed that the assigna- 11. Am J Infect Control. 2008;36(10):S173. e1-S173.e3. tion of cases as CRBSIs was done 12. Lancet Infect Dis. 2007;7(10):645-657. by default (ie, simply because of the absence of proof for a secondary 13. Crit Care Med. 2007;35(10):2424-2427. source of infection). The low spec- 14. Clin Infect Dis. 2002;35(5):627-630. ificity also greatly undermines the 15. Clin Infect Dis. 2004;39(3):309-317. Text continued from page 17

16.

Intensive Care Med. 2004;30(1):62-67.

68. Ann Hematol. 2009;88(3):267-272.

17.

J Clin Microbiol. 1985;21(3):357-360.

18.

Clin Infect Dis. 2002;34(10):1362-1368.

69. H ealth Technol Assess. 2008;12(12):iii-iv, xi-xii, 1-154.

19.

Clin Infect Dis. 2009;49(1):1-45.

20. Crit Care Med. 2002;30(12):2632-2635. 21.

Clin Infect Dis. 2010;50(12):1575-1579.

22. Am J Med. 1991;90(1):128-130. 23. Nephrol Dial Transplant. 1993;8(3): 231-234. 24. Clin Infect Dis. 1998;27(3):478-486. 25. Intern Med J. 2005;35(suppl 2):S45-S62. 26. Cancer Invest. 2002;20(7-8):1105-1113. 27.

Infect Control Hosp Epidemiol. 2004;25(8):646-649.

28.

Pediatr Infect Dis J. 1994;13(10):930-931.

29. Medicine (Baltimore). 2009;88(5): 279-283. 30. Arch Intern Med. 1995;155(22): 2429-2435. 31.

Infect Control Hosp Epidemiol. 1998; 19(11):846-850.

32. Clin Infect Dis. 1999;29(1):102-105. 33. Nephron. 1997;75(3):354-355. 34. Ann Intern Med. 1999;130(10):810-820. 35. Ann Pharmacother. 2005;39(2):311-318. 36. Antimicrob Agents Chemother. 1999;43(8):2074-2076. 37.

Int J Antimicrob Agents. 2008;32(6): 515-518.

70. JPEN J Parenter Enteral Nutr. 2007; 31(4):302-305. 71.

Infect Control Hosp Epidemiol. 2005; 26(8):708-714.

72. Ann Pharmacother. 2009;43(2):210-219. 73. Arch Intern Med. 2007;167(19):2073-2079. 74.

Crit Care Med. 2009;37(6):1858-1865.

75.

Infect Control Hosp Epidemiol. 2009; 30(11):1031-1035.

76.

Infect Control Hosp Epidemiol. 2009; 30(10):959-963.

77.

Intensive Care Med. 2010;36(5):854-858.

78.

Healthc Mater Manage. 1993;11(8): 44-46, 48-49.

79.

Infect Control Hosp Epidemiol. 1997;18(3):175-182.

80. Infect Control Hosp Epidemiol. 1998;19(6):401-406. 81.

Am J Infect Control. 1993;21(1):39-41.

82. Infect Control Hosp Epidemiol. 1998;19(1):23-27. 83. J Infect Dis. 1999;179(2):442-448. 84. J Pediatr. 1996;129(5):711-717. 85. Infect Control Hosp Epidemiol. 1998;19(10):772-777. 86. Clin Infect Dis. 2007;44(11):1408-1414.

38. Ann Intern Med. 2002;136(11):792-801.

87.

39. J Antimicrob Chemother. 2006;58(2): 281-287.

88. J Hosp Infect. 2003;54(4):288-293.

40. Am J Infect Control. 2008;36(2):104-117. 41.

Clin Infect Dis. 2006;43(4):474-484.

42. Clin Infect Dis. 2003;37(12):1629-1638. 43. JAMA. 1999;281(3):261-267. 44. Clin Infect Dis. 2008;47(1):83-93. 45. JAMA. 2009;301(12):1231-1241. 46. Crit Care Med. 2009;37(2):702-712. 47. J Antimicrob Chemother. 2008;62(4): 809-815. 48. Silva GLM, Safdar N. Presented at: Fifth Decennial International Conference on Healthcare-Associated Infections; March 18-22, 2010; Atlanta, GA.

Infect Control Hosp Epidemiol. 2007;28(6):684-688.

89. Infect Control Hosp Epidemiol. 2006;27(1):23-27. 90. Am J Infect Control. 2009;37(8):626-630. 91.

Clin Infect Dis. 2010;50(12):1580-1587.

92. Am J Infect Control. 2008; 36(10):S174. e1-S174.e5. 93. J Vasc Interv Radiol. 2002;13(1):77-81. 94.

Infus Nurs. 2006; 29(1):34-38.

95.

J Infus Nurs. 2006;29(4):225-231.

96. 97.

N Engl J Med. 2001;345(19):1359-1367. N Engl J Med. 2006;354(5):449-461.

98. JAMA. 2008;300(8):933-944.

49. Am J Infect Control. 1995;23(1):5-12.

99. N Engl J Med. 2009; 360(13):1283-1297.

50. Lancet. 1991;338(8763):339-343.

100. CMAJ. 2009;180(8):821-827.

51.

101. Safdar N, Ziegler M, Abad C, Silva G. Presented at: Fifth Decennial International Conference on HealthcareAssociated Infections; March 18-22, 2010; Atlanta, GA.

Clin Infect Dis. 2003;37(6):764-771.

52. J Clin Microbiol. 2009;47(7):2279-2280. 53. Ren Fail. 2008;30(4):417-422. 54. Infect Control Hosp Epidemiol. 2008;29(3):284; author reply 284-285. 55. Jpn J Infect Dis. 2008;61(2):107-110. 56. Mil Med. 2008; 173(6):604-608. 57.

Euro Surveill. 2008;13(14):pii=8084.

58. J Am Soc Nephrol. 2005;16(5):1456-1462.

102. http://www.ihi.org/IHI/Topics/ CriticalCare/IntensiveCare/ ImprovementStories/WhatIsaBundle.htm. Accessed February 24, 2012. 103. N Engl J Med. 2006;355(26):2725-2732. 104. BMJ. 2007;334(7589):362-365.

59. I nfect Control Hosp Epidemiol. 1994;15 (4 pt 1):231-238.

105. Pediatrics. 2008;121(5):915-923.

60. Infect Control Hosp Epidemiol. 1998; 19(11):842-845.

106. http://www.infectioncontroltoday.com/ articles/zero-tolerance.html. Accessed February 24, 2012.

61.

Chest. 2000;117(1):178-183.

62. Am J Med. 1991;91(3B):197S-205S. 63. JAMA. 2001;286(6):700-707. 64. J Clin Microbiol. 1990;28(11):2520-2525. 65. J AMA. 2008;299(20):2413-2422. 66. Intensive Care Med. 2008;34(6):1038-1045. 67.

M aki D, Mermel LA, Kluger DM. Presented at: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto, Ontario.

107. Infect Control Hosp Epidemiol. 2009;30(1):71-73. 108. Infect Control Hosp Epidemiol. 2009;30(1):67-70. 109. Infect Control Hosp Epidemiol. 2010;31(12):1286-1289. 110. JAMA. 2010;304(18):2035-2041.

Drs. Abad and Safdar reported no relevant conflicts of interest.

THREE OPTIONS TO BALANCE YOUR VANCOMYCIN NEEDS

Vancomycin Injection, USP 1 g/200 mL s 750 mg/150 mL s 500 mg/100 mL In GALAXY Plastic Containers

For more information or to place an order, please call Baxter Center for Service at 888-229-0001.

Baxter, Galaxy and the More Balance Delivered logo are trademarks of Baxter International Inc.

Medication Delivery

111636 11/11

20 Clinical

Pharmacy Practice News • May 2012

Critical Care

Med Errors and C. difficile Infections Pose Big Risks in ICUs Pharmacists are well positioned to foster prevention Orlando, Fla.—Recognizing that the environment and complexity of care in an ICU places patients at increased vulnerability to adverse events such as medication errors and infections, speakers in a session on safety in the ICU at the annual meeting of the Society of Critical Care Medicine presented strategies pharmacists and hospitals can take

to address these problems. Pointing out that clinicians in the ICU see patients “when they’re down,” session coordinator Robert Hyzy, MD, associate professor and director of the Critical Care Medicine Unit at the University of Michigan Health System, in Ann Arbor, noted that some of the actions clinicians take in the ICU to help

patients “puts them at greater risk for things like infections.” Medication errors account for nearly 80% of serious medical errors in critical care environments (Crit Care Med 2005;33:1694-1700). Reducing that number begins with error detection—something ICUs don’t typically do very well, said speaker Sandra Kane-Gill, PharmD,

Presents

Bridging the gap between the hospital and post-discharge care

In This Issue Ask the Expert

For smaller operators, how to get into a limited drug distribution network.

Volume 1 • Number 2 • Spring 2012

Reports from the PBMI conference

Cost Containment In Specialty Pharmacy

Q&A

Jay Mirtallo, MS, RPh, on why nutrition needs to be a higher priority.

Practice Profile

The Apothecary Shops applies a personal touch to disease management.

Operations & Mgmt

New study underscores savings potential of alternate-site infusions.

Clinical

Anti-EGFRs linked to increased risk for thromboembolic events.

Disease State Spotlight

UIC Specialty Pharmacy’s primer on managing hepatitis C patients.

Excelera Eyes Market Growth For Hospitals

everal health systems have made the foray into the specialty pharmacy market. But with their limited scale and lack of national exposure, it is difficult for them to convince manufacturers and insurers that they can supply medications and patient management programs at a reduced cost, and also deliver the utilization and outcomes data that Pharma needs for research and marketing. Now some health systems are tackling the size challenge. A group led by Fairview Health System in Minnesota and Henry Ford Health System in Michigan has established a national network of hospital pharmacies called ExceleraRx, LLC

•

Scottsdale, Ariz.—Specialty pharmacy medications represent a significant source of pharmacy costs for most employers trying to keep their pharmacy benefits in check. Although they make up fewer than 20% of overall prescriptions today, according to Medco Health Solutions’ 2011 trend report, specialty drug spending saw a 22% increase in its total market share between 2008 and 2010 and further growth is predicted for the coming decade. The nonprofit accrediting body URAC has predicted that specialty drugs will make up the majority of new drug approvals in coming years and will account for approximately 40% of a health plan’s drug spending by 2020. With numbers like these, it’s little wonder that specialty pharmacies are emphasizing cost containment initiatives. Such initiatives were key topics in many of the presentations at the Pharmacy Benefit Management Institute’s 2012 Drug Benefit Conference in February. For example, Walgreens has a number of cost containment strategies for its specialty pharmacy program, such as compliance management, divided dispensing and site of care optimization (related article, page 11). Aggressive management of patient compliance/adherence is one such initiative, Michael Einodshofer, director of utilization management for Walgreens Specialty Pharmacy told Specialty Pharmacy Continuum. In addition to influencing patient outcomes (Table, page 11), compliance can have a huge affect on cost. Mr. Einodshofer noted that Walgreens has preliminary results showing that a compliant

•

see CONTAINMENT, page 10

Educational Review Medication Errors: A Year in Review by ISMP See specialtypharmacy continuum.com

see EXCELERA, page 8

A new quarterly publication from the editors and publisher of Pharmacy Practice News. Each issue will provide essential clinical and business information for stakeholders in specialty pharmacies, home infusion providers, insurers and managed care organizations.

Breadth of problem is ‘scary’

Do MTX Drug Interactions Fall Below Radar?

dangerous interaction between proton pump inhibitors (PPIs) and methotrexate that prompted the FDA to issue a warning late last year represents just the tip of the iceberg of potentially serious interactions that can occur when common medications are given concomitantly with methotrexate. “It’s pretty scary how many of these interactions there are,” said Ali McBride, PharmD, clinical pharmacy specialist at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital in St. Louis.

•

see INTERACTIONS, page 17

The Book Page

Our goal: to help foster high-quality, cost-effective treatment across the entire patientcare continuum. To subscribe, visit pharmacypractice news.com

Fundamentals of Pharmacognosy and Phytotherapy, Second Edition Michael Heinrich See page 27.

bridging the gap between the hospital and post-discharge care

MSc, FCCM, associate professor of pharmacy at the University of Pittsburgh School of Pharmacy. “It’s imperative that health care institutions in general, and ICUs specifically, establish reliable methods of detection and reporting medication errors,” said Dr. Kane-Gill. Most ICUs heavily rely on voluntary reporting of drug errors and adverse drug events (ADEs), which can result in drastic underestimations of their true frequency and does little to illuminate the circumstances that caused them. Dr. Kane-Gill urged a comprehensive approach to surveillance that includes targeted medical record reviews, patient and family interviews and direct observation of real-time drug administration. All require more time and resources than voluntary reporting, yet each technique tends to expose errors that are not picked up by the others, she said. She advised fostering a nonpunitive “culture of safety,” in which staff know with certainty that reporting a medication error or ADE won’t result in retribution. Another problem, according to Dr. Kane-Gill, is that errors often go unreported because there are no, or poorly established, definitions of what constitutes an error or standard procedures for how to report errors. Reviewing ICU transfer summaries is another approach that involves a relatively small time commitment that can reveal a substantial number of ADEs. “If you can’t do an entire comprehensive chart review of everything that’s happened, looking only at ICU transfer summaries may be very beneficial for identifying errors,” Dr. Kane-Gill said. Technology is another source that can be tapped to identify medication errors and ADEs, said Mitchell S. Buckley, PharmD, FCCM, BCPS, critical care clinical pharmacist at Banner Good Samaritan Medical Center in Phoenix. “Reports from technology such as automated dispensing cabinets, computerized prescriber order entry, clinical decision support software and smart infusion pumps are likely to reveal errors,” he said. For example, some automated dispensing machines can be programmed to generate reports of “tracer drugs” that commonly are used to treat some ADEs (phytonadione, diphenhydramine and naloxone, to name a few). Pharmacists can have a major effect on reducing medication errors and ADEs in the ICU, said Rob MacLaren, PharmD, FCCM, FCCP, critical care pharmacist and associate professor at the University of Colorado Skaggs School of Pharmacy, in Aurora. “Ideally, a pharmacist is directly involved at the bedside in the ICU

Pharmacy Practice News • May 2012

Clinical 21

Critical Care when drugs are ordered and decisions are made,” he said. “That’s the best time to ensure that the medication and dosing are appropriate, adjust for drug interactions and discontinue drugs that are no longer necessary.” Pharmacist involvement in direct patient care in the ICU is becoming more common, he added, but even at large academic and community hospitals, a pharmacist’s immediate presence typically is limited to daytime shifts; at smaller facilities, ICU pharmacists are rare. Pharmacists not involved in bedside care can contribute to drug safety in the ICU in a number of ways, such as helping to develop drug use protocols. “Protocols have been shown to reduce errors and increase safety,” Dr. MacLaren noted. Such efforts by pharmacists can result in tremendous savings. Drs. Kane-Gill and Buckley estimated that the cost avoided by 129 pharmacist interventions that circumvented potential and preventable ADEs in ICUs over a 4.5-month period ranged from $206,000 to $280,000 (Kane-Gill SL, Buckley M. Safe drug use in critically ill patients. In: Critical and Urgent Care. Lenexa, KS: ACCP, 2010).

Growing Problem of Clostridium difficile Another formidable danger in the ICU is Clostridium difficile infection. In March, the Centers for Disease Control and Prevention reported that “the incidence, deaths, and excess health-care costs resulting from [C. difficile infections] in hospitalized patients are all at historic highs.” Prevention is the cornerstone of any effort to stem infections, said Marya Zilberberg, MD, MPH, FCCP, founder, president and CEO of EviMed Research Group, LLC, in Goshen, Mass., during the SCCM session. “Most important is to limit antibiotic exposure for patients, both in terms of the numbers of antibiotics they receive, as well as the spectrum and duration of exposure,” she said. Patients who have contracted or are suspected of having the bacterial infection should be isolated promptly. Thorough environmental cleaning and hand washing among health care workers also are important components of prevention. Dr. Zilberberg noted that in the presence of a C. difficile outbreak, disinfecting gels containing alcohol should not be used. “Soap and water is the best and only way to get rid of C. difficile spores on people’s hands,” she said. She also favors hospital-wide antibiotic stewardship programs to address the spread of C. difficile and other emerging infections, and to stem antimicrobial resistance. Such programs require a significant commitment of staff and funds, but the consequences of a C. difficile outbreak can prove far more costly.

‘Soap and water is the best and only way to get rid of C. difficile spores on people’s hands.’ —Marya Zilberberg, MD, MPH, FCCP “It’s not an inexpensive disease,” Dr. Zilberberg said, adding that the infection costs the country $1 billion to $3 billion annually, and each case costs about $6,000 and three additional days

of hospitalization. “The fact that there are bacteria that we have no effective weapons against should alone serve as a wake-up call for hospitals to institute antibiotic stewardship programs.”

Pharmacists are well positioned to recognize when patients no longer need a therapy that may contribute to C. difficile or to recommend alternative antibiotics, added Dr. MacLaren. “Prescribers increasingly rely on pharmacists to make these decisions, and often we’re the ones saying, for instance, it’s time to stop this medication or reduce the dosage of that one. Obviously, it’s a team in the ICU, but more responsibilities are falling on the pharmacist’s shoulders.” —Steve Frandzel

Now Available... Optimizing the Selection and Use of Topical Hemostats To participate in this FREE CE/CME activity, visit Release Date: April 1, 2012

www.topical-hemostats.com

Chair

Cataldo Doria, MD, PhD, FACS Nicoletti Family Professor of Transplant Surgery Director, Division of Transplantation Co-Director, Jefferson Kimmel Cancer Center - Liver Tumor Center Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Faculty

Danial E. Baker, PharmD Professor of Pharmacotherapy Associate Dean for Clinical Programs Director, Drug Information Center College of Pharmacy Washington State University Spokane, Washington Bradley A. Boucher, PharmD, FCCP, FCCM Professor, Vice-Chair for Institutional Programs Department of Clinical Pharmacy Associate Professor Department of Neurosurgery University of Tennessee Health Science Center Memphis, Tennessee

Medical Writer

Mary Culpepper

Sponsored by

Expiration Date: April 1, 2013

Program Goal

To educate clinicians on the selection and use of topical hemostats in the hospital setting.

Learning Objectives

After completing this activity, participants should be better able to: 1 Appraise the clinical and economic effects of excessive intraoperative or postoperative bleeding and common preoperative strategies for minimizing bleeding events. 2 Describe key clinical factors that influence the selection and use of topical hemostats as adjuncts for achieving surgical hemostasis. 3 Delineate clinical characteristics and pharmacoeconomic (direct and non-medication costs) considerations by which topical hemostats should be evaluated, acquired, and used in hospitals. 4 Develop a plan for reconciling cautionary guidance and clinical best practices with regard to the selection and use of the full range of topical hemostats.

Accreditation Statements Physician: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of AKH Inc., Advancing Knowledge in Healthcare, and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians. AKH Inc. designates this enduring activity for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Pharmacist: AKH Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. AKH Inc. approves this application-based activity for 2.0 contact hours (0.2 CEUs). UAN 0077-9999-12-013-H04-P. Initial release date: April 1, 2012. Nurse: AKH Inc. is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s COA. AKH Inc. designates this educational activity for 2 contact hours (0.2 CEUs). Accreditation applies solely to educational activities and does not imply approval or endorsement of any commercial product by the ANCC-COA.

Supported by an educational grant from

Distributed via

A Bristol-Myers Squibb Company

To participate in this FREE CE/CME activity, visit www.topical-hemostats.com

22 Clinical

Pharmacy Practice News • May 2012

Critical Care

Texas Study: MRSA Screening Stems Infections, Saves Money Houston—An active methicillin-resistant Staphylococcus aureus (MRSA) program in an intensive care unit (ICU) can have a significant effect on MRSA infection rates and save money, according to a recent study. The annual savings for a hospital in Texas that implemented active surveillance in all of its ICUs was more than $100,000 per year. “A strategy that screens high-risk patients for MRSA and isolates them is useful in controlling in-house transmission of the infection,” said Luis Ostrosky-Zeichner, MD, presenting the study at the recent annual meeting of the Society of Critical Care Medicine (SCCM; abstract 53). All patients admitted to the ICU are screened for MRSA and they “get placed on either full contact precautions or modified contact precautions,” explained Dr. Ostrosky-Zeichner, professor of medicine at the University of Texas Medical School at Houston and medical director for epidemiology at Memorial Hermann-Texas Medical Center, in Houston. “When the test result comes back, people who are positive [for MRSA] get placed on full contact precautions if they hadn’t been before, and those contact precautions remain not only for the duration of the ICU stay but for the whole hospitalization.” Dr. Ostrosky-Zeichner and his colleagues launched their program after other studies suggested that screening high-risk hospital admissions for MRSA reduced in-hospital MRSA transmissions. In March 2007, Memorial Hermann tested a pilot active surveillance program for ventilator-associated pneumonia (VAP) and bloodstream infections (BSI) involving MRSA in two of their ICUs. An analysis of data from March to May 2007 showed a reduction in rates compared with data from December 2006 to February 2007. Although the data was not statistically significant, it showed a trend for improvement, and the researchers thus launched the active surveillance for MRSA in all seven ICUs in the hospital. In the study presented at SCCM, rates of infection were tallied for a baseline period, between 2003 and 2006, and for the intervention period, between 2007 and 2010. Researchers also analyzed data to determine if the program resulted in a cost savings. The costs of the MRSA test plus supplies needed for isolation were compared with the standardized costs of dealing with MRSA infections. The researchers determined expected/ avoided infections by volume-adjusted rate projections. Counts of positive patients were tabulated in the baseline and intervention periods and analyzed

by chi-square test. The investigators identified a 35% reduction in the proportion of cases of VAP and BSI that were related to MRSA (9.85% post-intervention vs. 6.38% pre-intervention) (P=0.04). The average annual cost of the surveillance program was $264,060, with the MRSA testing costing $77,863 and contact isolation running $186,195. (A previous study in the American Journal of

Infection Control [2011;39:27-34] had estimated that the cost to a hospital for a MRSA infection was $23,000). Using that figure and an estimate of 69 avoided infections over four years, the Memorial-Hermann team estimated annual avoided cost of approximately $398,000 and net savings of approximately $134,000. The new study’s outcomes seem to conflict with the findings from a recent

study published in The New England Journal of Medicine by Huskins et al (2011;364:1407-1418). In that study, researchers screened roughly 54,000 admissions in 10 ICUs for MRSA and vancomycin-resistant enterococci (VRE) and compared infections rates with more than 3,700 admissions in eight ICUs for which there was no active surveillance. The intervention, which included culture-based active

Presents

Bridging the gap between the hospital and post-discharge care

In This Issue Ask the Expert

For smaller operators, how to get into a limited drug distribution network.

Volume 1 • Number 2 • Spring 2012

Reports from the PBMI conference

Cost Containment In Specialty Pharmacy

Q&A

Jay Mirtallo, MS, RPh, on why nutrition needs to be a higher priority.

Practice Profile

The Apothecary Shops applies a personal touch to disease management.

Operations & Mgmt

New study underscores savings potential of alternate-site infusions.

Clinical

Anti-EGFRs linked to increased risk for thromboembolic events.

Disease State Spotlight

UIC Specialty Pharmacy’s primer on managing hepatitis C patients.

Excelera Eyes Market Growth For Hospitals

•

see CONTAINMENT, page 10

Educational Review Medication Errors: A Year in Review by ISMP See specialtypharmacy continuum.com

see EXCELERA, page 8

Breadth of problem is ‘scary’

Do MTX Drug Interactions Fall Below Radar?

•

see INTERACTIONS, page 17

The Book Page

Our goal: to help foster high-quality, cost-effective treatment across the entire patientcare continuum. To subscribe, visit pharmacypractice news.com

Fundamentals of Pharmacognosy and Phytotherapy, Second Edition Michael Heinrich See page 27.

bridging the gap between the hospital and post-discharge care

Pharmacy Practice News • May 2012

Clinical 23

Critical Care The Memorial-Hermann team estimated annual cost avoidance of approximately $398,000 and net savings of approximately $134,000. surveillance and expanded use of barrier precautions, was not effective in reducing the incidence of MRSA or VRE colonization or infection.

However, the researchers of the NEJM study noted that two factors could have limited their program’s benefit. First, the turnaround time for reporting a positive result on a surveillance culture was prolonged, which increased the proportion of days that patients who were colonized were assigned to universal gloving. Second, adherence to hygiene standards was less than required. So, which hospitals should consider enacting an active surveillance program? “I think it would be important for

hospitals to look at their baseline positivity for MRSA in ICU admissions,” said Dr. Ostrosky-Zeichner. “If you have one that is similar to ours, in the 10% range, it is maybe a worthwhile intervention for your hospital.” —Kate O’Rourke Dr. Ostrosky-Zeichner had no relevant disclosures. Dr. Huskins has received consulting fees from Roche Diagnostics and served on an advisory board for GlaxoSmithKline.

www.CMEZone.com Your premier source for practical, relevant and timely continuing medical and pharmacy education

Here are FREE educational activities available now on CMEZone.com The Atrial Fibrillation Revolution: Refining the Evidence-Based Approach to Stroke Prevention

WC106

Expires July 19, 2012

Tailoring Therapy in Metastatic Breast Cancer: Novel Clinical Approaches

MN1113

Expires October 1, 2012

Optimizing the Selection and Use of Topical Hemostats Expires April 1, 2013

MN1112

24 Clinical

Pharmacy Practice News • May 2012

Critical Care

New Study Supports Expanded Use of Tranexamic Acid in Trauma

ranexamic acid, an inexpensive generic drug that was first approved for use in patients with hemophilia, is increasingly being used to reduce bleeding in trauma and surgery settings in the United States, and, according to a new study, has the potential to prevent many deaths every year. The study combined data from the large CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Hem-

orrhage-2) trial (Lancet 2010;376:2332)—which had provided evidence that tranexamic acid safely lowered the risk for death due to bleeding in trauma patients—with World Health Organization mortality data and a systematic literature review (BMC Emerg Med 2012;12:3). The authors estimated that each year approximately 400,000 trauma patients worldwide die in-hospital from bleeding. If all these patients were

treated with tranexamic acid within an hour of injury, up to 128,000 (uncertainty range [UR], 72,000-172,000) of these premature deaths could be averted. If they were treated within three hours, up to 112,000 (UR, 68,000-148,000) such deaths could be averted. The study’s lead author, Katharine Ker, MSc, research fellow at the London School of Hygiene & Tropical Medicine, considers use of tranexamic acid

in your Inbox ... to receive the monthly e-newsletter from

at www.pharmacypracticenews.com

a no-brainer. “What clinician wouldn’t be interested in a simple, cheap drug that could save hundreds of thousands of lives,” she said, when asked to comment on the clinical relevance of the study. Other experts see use of the drug increasing and cautiously support its use, pointing out some caveats. For example, Aryeh Shander, MD, FCCM, FCCP, chief of the Department of Anesthesiology, Critical Care and Hyperbaric Medicine at Englewood Hospital and Medical Center, in Englewood, N.J., called the latest study “all extrapolation.” Noting that co-author of the study, Ian Roberts, MD, was also the chief investigator of the CRASH-2 trial, he said of the authors, “As strong advocates of tranexamic acid therapy, their therapeutic approach will favor [that drug].” He also said that “there has been a lot of criticism of CRASH-2, especially about methodology.” Additionally, he said, “CRASH-2 doesn’t explain why tranexamic acid improved survival but had no impact on bleeding and transfusion. We could use more data.” Still, he considered the drug to be safe, apart from concerns about rare instances of seizures and hypercoagulability. “There is little downside to use of tranexamic acid. But we should probably

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

GlobalHealth Education Offers Graduate Management Credential

lobalHealth Education makes it possible for you to earn an added graduate credential in management through programs built in collaboration with the ASHP Research and Education Foundation and some of the most trusted, traditional colleges and universities in the United States. GlobalHealth is dedicated to building a better tomorrow, offering you smart degrees to equal better care for a growing population that needs you. Classes start in May; call (877) 775-5990 today to speak to one of our student advocates. There is no better time than now. GlobalHealth Education

3111 South Dixie Highway, Suite 101 West Palm Beach, FL 33405 Phone: (561) 253-2213 Fax: (866) 431-5159 infoPLA@globalhealtheducation.com www.gheprograms.com/mba-mha

Pharmacy Practice News • May 2012

Clinical 25

Critical Care re-examine the use of this drug at some point to reassess its effect.” When use of tranexamic acid is being considered, patient selection is important, noted Rachel Stratman Wolfe, PharmD, BCPS, clinical pharmacist at Barnes-Jewish Hospital, in St. Louis. “Clinicians should be aware of the contraindications and precautions associated with tranexamic acid, which are extremely important in patients at high risk for thrombus. When evaluating patients who should and should not receive tranexamic acid, consideration

of the risk for bleeding versus the risk for thrombus is essential. In addition, there should be appropriate dosing based on renal function, weight and age.” But, like Dr. Shander, Dr. Wolfe said that the drug generally is considered to be safe, based on clinical trials and surgeon experience. Thus, use of the agent at

Barnes-Jewish “has been increasing over the last two years,” she said. “We use it intraoperatively, during cases such as cardiothoracic surgery, total hip and knee arthroplasty and some trauma cases.” Sid Patanwala, PharmD, BCPS, assistant professor at the University of Arizona College of Pharmacy, in Tucson, said his hospital had not yet started using tranexamic acid, but “the level 1 trauma center physicians have shown interest in it. I’m pretty sure that soon they will start using it.” Of CRASH-2, he said, “A

randomized controlled trial with 20,000 patients is as good as it gets in terms of data.” Dr. Patanwala commented that at his hospital, tranexamic acid would cost $160 per course for each patient, compared with $5,000 to $10,000 for coagulation products such as recombinant factor VIIa (NovoSeven, NovoNordisk). —George Ochoa Ms. Ker and Drs. Patanwala, Shander and Wolfe reported no relevant financial disclosures.

New Product

American Health Packaging Launches New Unit-Dose Products merican Health Packaging recently launched four additional products to its growing unitdose line: • Atorvastatin Calcium 40-mg tablets (AB-rated to Lipitor®) • Lamivudine 150-mg tablets (AB-rated to Epivir®) • Quetiapine Fumarate 25-mg, 50-mg, 100-mg, 200-mg, 300-mg and 400-mg tablets (AB-rated to Seroquel®) • Ziprasidone HCl 20-mg, 40-mg, 60-mg and 80-mg capsules (AB-rated to Geodon®) Atorvastatin Calcium 40 mg and Lamivudine 150 mg items are AHP industry exclusives—only available in the marketplace from AHP in a bar-coded package format. The exclusive UD items help the hospital pharmacy to avoid additional packaging tasks in order to better focus on core patient care activities, according to the company. The AHP line of products now stands at nearly 350 SKUs— over 90 of which are industry exclusives, AHP noted in a press release. The company added that these unit-dose launches are part of AHP’s ongoing commitment to support health systems’ bar-code medication administration initiatives while promoting efficiency in pharmacy operations. For additional information, visit americanhealthpackaging.com.

MEROPENEM.

IMIPENEM.

Advertisement ANTI-INFECTIVES

COME AND GET ‘EM. APP, a leader in injectables, introduces two new products to our extensive portfolio: • Meropenem for Injection, USP (I.V.) • Imipenem and Cilastatin for Injection, USP (I.V.) Both products are now readily available for order and distribution.

RELY ON OUR SUPPLY. Medical Information 800-551-7176 Customer Service 888-386-1300 www.APPpharma.com

Reference: 1. As of March 2012.

NO SHORTAGE OF COMMITMENT.

26 Clinical

Pharmacy Practice News • May 2012

Critical Care

OVERWEIGHT continued from page 9

remembered any of the procedure or had pain.” According to Dr. Jellinek-Cohen, the study’s findings should spur ED physicians to consider using a tool such as the Ramsay Sedation Scale to assess the patient’s level of sedation. “It is a timesensitive issue when you have to intubate a patient, but you do have some time to see if the dose of etomidate that you have administered is working before you go ahead and administer the paralytic,” she said.

Vancomycin Underdosing In a second study presented at SCCM, researchers showed that patients who received vancomycin in the ED were more likely to be underdosed if they were overweight (abstract 33). Weight-based dosing of vancomycin is recommended for treating methicillinresistant Staphylococcus aureus infections, but there is minimal data to guide clinicians on empiric dosing of vancomycin in critically ill obese patients. The retrospective observational cohort study included 662 patients who received vancomycin in the ED and were admitted to the intensive care unit at Barnes-Jewish Hospital, in St. Louis, during an 18-month period. Overall, 77.9% of patients received doses of vancomycin that were outside of the appropriate range, defined as 15 to 20 mg/kg. In a univariable model,

‘It is a time-sensitive issue when you have to intubate a patient, but you do have some time to see if the dose of etomidate that you have administered is working before you go ahead and administer the paralytic.’ —Samantha Jellinek-Cohen, PharmD significant predictors of dosing inaccuracy included increasing age (P=0.016), weight (P<0.0001), serum creatinine (P=0.004), non-white race (P=0.007) and male sex (P=0.008). In the multi-

ratio, 9.65; P<0.0001). The researchers concluded that initial ED dosing of this common antibiotic may be important to achieve the pharmacokinetic and pharmacodynamic goals of vancomycin dosing and that obese patients deserve special attention, because each 10-kg increase in patient weight is associated with a significantly increased likelihood that they will be incorrectly dosed. According to Dr. Jellinek-Cohen, clinicians might not feel comfortable in administering high doses of vancomycin because of toxicity concerns, and it is unclear whether the underdosing had clinically meaningful effects. She said both studies presented at SCCM are limited by their retrospective nature, but they highlight a common problem in the ED (See related story, below). “The emergency department itself is a frenetic environment. You have time constraints, a lack of adequate resources and workflow issues, which don’t always permit for weighing patients prior to administering these medications,” said Dr. Jellinek-Cohen. “Whether the patient is obese or not, you still run into the same problem of usually estimating the person’s weight prior to the administration.” —Kate O’Rourke

variable model, however, only increasing weight was predictive of dosing inaccuracy. For each 10-kg increase in patient weight, patients were 10 times more likely to be underdosed (odds

Drs. Traylor and Jellinek-Cohen have reported no relevant financial conflicts of interest.

ER Docs Often Underdose Antibiotics in Obese Patients From American Journal of Emergency Medicine

mergency physicians frequently underdose cefepime, cefazolin and ciprofloxacin in obese patients, report researchers at the Washington University School of Medicine, in St. Louis (Am J Emerg Med 2011 Dec 14. [Epub ahead of print]). In a retrospective analysis, the investigators collected data from emergency department (ED) pharmacy records for a three-month period in 2008 and found 1,910 first orders for cefepime (775), cefazolin (625) and ciprofloxacin (510) to be administered to patients who weighed more than 100 kg and had a body mass index greater than 40 kg/m2. The team did not exclude patients based on creatinine clear-

ance or liver function, noting that such parameters would alter only dosage interval and not the first dose. Researchers then compared these orders to hospital guidelines to determine adherence rates and noted whether nonadherent initial dosages were corrected within four hours. Of the orders for cefepime, only 62 (8%) met dosing criteria for patients in that population. Of those, 61 were initially ordered correctly as 2 g, and one patient had two 1-g doses ordered within minutes of each other. Only 19 orders (3%) for cefazolin were dosed appropriately, and of those, 17 were initially dosed correctly as 2 g, with two patients receiving two 1-g doses approximately one hour apart. A mere six (1.2%) orders for ciprofloxacin were dosed appropriately. None of those were corrected within four hours.

COMMENTARY Nicole M. Acquisto, PharmD, BCPS Emergency Medicine Clinical Pharmacy Specialist Assistant Professor Department of Emergency Medicine University of Rochester Medical Center Rochester, N.Y.

This is a great retrospective study that highlights a common problem we see in the ED. Antibiotics are the second most commonly prescribed drugs in the ED, obesity is on the rise, and the authors did a good job stating what the challenges are. Cefepime, cefazolin and ciprofloxacin were reasonable choices to include in the study because they are commonly used in the ED and often are readily available in medication-dispensing machines. However, availability can guide therapy. For example, if an antibiotic is ordered in

a specific dose, and the nurse says it is readily available in another dose, a prescriber often will change the order. The low numbers for adherence were shocking because this hospital has an institutional guideline. This just shows the importance of constant re-education on guidelines. Re-education on the guidelines would probably result in a lot of improvement at this hospital. The findings also point to the need for educating incoming residents. I’m in a teaching hospital, where we have a new influx of residents every year who are not even aware that guidelines exist to help them. It is our responsibility to bring them up to speed. As the authors noted, one limitation of the study was they did not look at outcomes. They had a low adherence rate, but how does that correlate to outcomes? Another retrospective study might provide some answers.

The Growing Pfizer Injectables Portfolio Now Includes Heparin Sodium Injection, USP Reasons to look to Pfizer Injectables for Heparin Sodium Injection, USP: Pfizer’s heparin is manufactured and packaged at the Pfizer Michigan facility using raw materials supplied by facilities in Iowa and Toronto Color-coding of caps and labels helps identify individual potencies1 Prominent vial warnings (including NOT FOR LOCK FLUSH) clearly presented on flip-off top, overseal, and label1 The sterile formulation of heparin sodium is porcine derived2 Data matrix 2D label code provides lot number, NDC number, and expiration date1

Visit www.pﬁzerinjectables.com for more information on

heparin and full Prescribing Information.

References: 1. Data on file. Pfizer Inc, New York, NY. 2. Heparin Sodium Injection, USP [prescribing information]. New York, NY: Pfizer Inc; 2011. USI00186B/430709-01

100 Route 206 North, Peapack, NJ 07977

February 2012

Hem/Onc Pharmacy

Pharmacy Practice News • May 2012

In Focus

DRUG SHORTAGES

they follow suit—or may not even have the funds on hand to build up such a stockpile. A key element to dealing with shortages is communication. “We found that if we could communicate to people very early, there was a whole lot less screaming and hollering, naysaying and finger pointing, and we could get to what we were going to do while we had a shortage,” Dr. Sageser said. He pointed out that pharmacists are like grief counselors. “Part of your job in the health care team is to move your fellow practitioners from these early [drug shortage–induced] stages of denial, anger and bargaining to acceptance quickly, so you can start building plans for what are you going to do about the shortages affecting your health system,” he said.

continued from page 1

In the past two years, drug shortages have hit oncology care particularly hard. Four cancer drug shortages were documented in 2009, 23 in 2010 and 26 in 2011, Dr. Sageser noted. The list of chemotherapy agents that have been in short supply include—but are not limited to—liposomal doxorubicin (Doxil, Janssen), cisplatin, paclitaxel, etoposide, mechlorethamine, daunorubicin, cytarabine, fluorouracil, leucovorin and vinblastine. And it’s not scarcities of chemotherapy agents that are affecting cancer patients—opiate and antibiotic shortages also are wreaking havoc on oncology care, presenters noted at the HOPA annual meeting. Dr. Sageser said his pharmacy spends an extra 40 to 80 hours of manpower in the first couple weeks of a drug shortage to mitigate its effects on patient care. One of the more time-intensive tasks, he noted, involves going through all of the patients’ charts to figure out who is taking the drug that is in short supply, where they are in their course of therapy, when the drug is going to run out, and whether there are viable plans in place to obtain the drug from alternate sources or to switch to another agent.

A Plan of Action

‘As you hoard drugs, you end up disrupting supply and demand, and that can actually [cause] more severe shortages or rolling shortages.’

A Costly Problem Experts estimate labor costs associated with managing drug shortfalls to be $216 million annually (Am J Health Syst Pharm 2011;68;1811-1819). And that is just labor costs—sometimes the substituted drug has a higher price tag. A recent study concluded that a paclitaxel shortage that would affect 50% of women initiated on chemotherapy for untreated ovarian cancer would cost third-party payers an additional $8,699,872 monthly (Gynecol Oncol 2012 Mar 23. [Epub ahead of print]). This model included the costs of chemotherapy, neuropathy, febrile neutropenia and anemia. Then there is the issue of derailed patient care. According to an Institute for Safe Medication Practices survey of 1,800 clinicians, 25% of respondents said that an error had occurred at their site because of drug shortages (ISMP Medication Safety Alert! 2010;15:4). In a survey of purchasing agents and pharmacists at 549 hospitals, 12% reported awareness of a product authenticity issue, medication error or adverse drug reaction associated with the use of gray-market products in the past two years (ISMP Medication Safety Alert! 2011;16:4).

—Dan Sageser, PharmD bicin shortage had affected patient care (poster T54). Clinicians addressed the problem by substituting generic doxorubicin during the induction phase for patients with acute lymphoblastic leukemia (ALL) receiving either the Cancer and Leukemia Group B (CALGB) 9511 or 10403 regimens. Doxorubicin was deemed a suitable replacement because it had been used during the post-induction phases when treating patients with ALL. The researchers presented data on 65 patients receiving the CALGB 9511 regimen between 2009 and 2011. Five of these patients received doxorubicin. All five patients who received doxorubicin achieved a complete response, but they had more sepsis (60% vs. 28%) and mucositis (100% vs. 33%), higher rates of admissions to the intensive care unit (50% vs. 16.1%; P=0.0230) and higher mortality (30% vs. 2.2%; P<0.01). “We need more patients to fully conclude whether [doxorubicin] might be too toxic, but, as of now, it looks like it might be heading in that direction,” said Dat Ngo, PharmD, oncology pharmacy resident at Stanford University Medical Center, who led the study.

I’ve Met Daunorubicin, And You’re No Daunorubicin!

Blame Game

At the HOPA meeting, researchers at Stanford University Hospital, Stanford, Calif., discussed how a daunoru-

Dr. Sageser stressed that although the media has been focused on identifying someone to blame for mounting shortag-

es of critical medications, drug manufacturing and distribution are very complicated processes and shortages have many causes. According to research conducted at the Drug Information Center at the University of Utah, in Salt Lake City, the most common reasons for shortages are manufacturing difficulties (25%), supply and demand changes (12%), a drug being discontinued (6%) and a raw materials shortage (3%). The cause of 54% of the shortages, however, is simply unknown. “There are a lot of times that drug manufacturers don’t want to tell you [about an impending shortage] because it damages their credibility or helps their competition,” Dr. Sageser said. He pointed out that the only category that health care professionals have control over is supply and demand. “As you hoard drugs, you end up disrupting supply and demand, and that can actually [cause] more severe shortages or rolling shortages.” But the practice continues, and there are pharmacists who don’t view it as a problem. “As a ‘hoarder,’ I resent that,” an attendee said during the questionand-answer session. If you keep a few months of a scarce drug in stock, “is that seriously unethical?” he asked. Dr. Sageser said his hospital keeps the usual three- to four-month supply of problem drugs on hand if possible. He pointed out that smaller hospitals might run into storage issues if

Mary Mably, RPh, BCOP, pharmacy oncology coordinator at the University of Wisconsin Hospital and Clinics, in Madison, said her hospital has designed a drug allocation plan that is based in part on three levels of shortages. At the warning level, Ms. Mably explained, the hospital has less than a four-week supply of drug and is unable to order it. At the critical chemotherapy shortage level, the hospital has less than a two-week supply. The last level is a true shortage in which a chemotherapy review council is tasked with using guidelines to rank patients to receive a drug, and no drug is dispensed without the council’s approval. The chemotherapy review council has created prioritization guidelines to allocate drugs, with the first priority being curability of disease. “A [patient with] curable ALL [acute lymphoblastic disease] or testicular cancer would [be treated] before a patient with metastatic disease who is no longer curable,” Ms. Mably said during the HOPA meeting. The second priority is the possible number of years of life remaining—a pediatric patient, for example, would be prioritized before an adult. The third priority is patients on research protocols, to maintain the integrity of the research. The fourth priority is patients undergoing treatment who have a demonstrated response to therapy. When methotrexate was seen as a potential problem, the chemotherapy review council examined the different disease states the drug is used in, and developed guidelines for determining which patients would be considered first in line to receive the medication, which patients the drug could be used in and which patients would be denied the drug. In the case of a true drug shortage of methotrexate, the council will use these guidelines to review and rank all patient cases.

Hem/Onc Pharmacy 29

Pharmacy Practice News • May 2012

In Focus The hospital keeps abreast of looming shortages by checking the Web sites of the American Society of Health System Pharmacists and the FDA. The chemotherapy council group then discusses ways to conserve drugs that are in stock by using evidence-based alternative chemotherapy regimens. The chemotherapy consent form now includes wording that alerts patients that if a chemotherapy shortage arises, the hospital may have to use an alternative regimen or delete a drug from a regimen.

A Similar Approach for Determining the Neediest In an interview with Pharmacy Practice News, Dwight Kloth, PharmD, FCCP, BCOP, director of pharmacy at Fox Chase Cancer Center, in Philadelphia, said his institution had a similar system in place, and he likened it somewhat to an organ transplant list. When a drug is in such short supply that there won’t be enough to treat all patients who need it, a committee of doctors and pharmacists determines how many patients can be treated with the amount of drug on hand and which patients are in the greatest need. “First priority would be for frontline therapy in potentially curative settings and for the comparator arm of IRB [institutional review board]-approved clinical trials, followed by palliative use in patients with advanced disease and where there are other applicable regimens,” Dr. Kloth said. If supply of a drug is dwindling, Fox Chase tries to obtain the drug from any and all manufacturers as well as an informal network of neighboring hospitals, including, but not limited to, Temple University Hospital, Jefferson University Hospital, Hospital of the University of Pennsylvania, Children’s Hospital of Philadelphia and Jeanes Hospital. “If one of us has a little bit of a cushion of drug A, they loan it to us; if they need drug B and we have a bit of a cushion, we can loan it to them, and so forth,” Dr. Kloth said. “I would describe it as a self-defense network of a number of hospitals in the geographic area.” He said that cancer centers the size of Fox Chase spend at least eight hours of manpower per day, often much more,

‘If it is a generic, sterile injectable, it has been, is now or will be in shortage in the near future, and that has been the experience we have been suffering with for several years now on an escalating basis.’ —Dwight Kloth, PharmD working on strategies to deal with shortages in an effort to avoid disruptions in patient therapy. According to Jorge Avila, PharmD, BCOP, infusion services pharmacy manager at Moffitt Cancer Center, in Tampa, Fla., the hospital doesn’t routinely try to acquire drugs in short supply from other hospitals, and they don’t have a formalized committee devoted to handling the issue. However, the institution certainly takes a teamwork approach to handling drug shortages. “Our pharmacy management team, along with our purchasers, work together to communicate information regarding shortages,” Dr. Avila said. “If we get wind of anything that potentially might be difficult to acquire, we meet as a group and discuss a plan. We review our options for trying to acquire the medication in question, whether it’s through our primary wholesaler, other wholesalers or directly through the pharmaceutical companies.” For the liposomal doxorubicin shortage, Dr. Avila said that each potential use of the drug was evaluated based on a strict protocol. “We require that any prescriber wanting to initiate liposomal doxorubicin for one of their patients must first receive approval from our medical director,” he explained. “Each patient’s case is reviewed on a case-by-case basis, taking into consideration medical history, previous treatments and performance status.” Once a patient is approved, his or her name is put on a list. “We are keeping a spreadsheet and are essentially assigning six to eight cycles worth of drug for that particular patient, which is an estimation of their need.” In addition to liposomal doxorubi-

We Want Your Pearls Do you have an interesting practice pearl you’d like to share? If so, send it to smtilyou@mcmahonmed.com. Pearls should: •F ocus on a clinical or operational problem at your institution, with tips (“tricks of the trade”) on how to manage the problem via an innovative system or strategy

cin, the drugs giving Dr. Avila the most trouble at press time were leucovorin, pentostatin and mitomycin.

FDA Response At the HOPA meeting, Emily Thakur, RPh, senior program management officer at the FDA’s Center for Drug Evaluation and Research Drug Shortage Program, said the agency had taken several steps to address drug shortages. These include working with firms to address issues, asking other manufacturers to increase production if possible and, in some cases, temporarily importing product from overseas. In 2011, temporary importation was allowed for foscarnet, ethiodol, thiotepa, norepinephrine, levoleucovorin and leucovorin. In 2012, liposomal doxorubicin and methotrexate have so far been imported. Most recently, the FDA has allowed importation of LipoDox (Sun Pharma) from India as an alternative to Doxil. Since President Obama signed an executive order in October, the number of FDA staff assigned to address the drug shortages has grown from four to 11, Ms. Thakur said. The FDA has attempted to expedite applications related to drug shortages, such as those that involve new manufacturers, increased expiry, increased capacity, new sources of raw materials or changes in specifications. The agency also has made greater efforts to work with manufacturers regarding quality problems. “The way we show flexibility is using regulatory discretion, so that we can allow a manufacturer of a medically

•O ffer insights that are not widely known, understood or published •E xplain why the pearl should be implemented on a widespread basis •N ot exceed 1,000 words Readers whose Practice Pearls are accepted for publication will be paid a $100 honorarium.

necessary product to still allow product out that has minor, low-risk issues to it,” Ms. Thakur said. Since the executive order requiring manufacturers to notify the FDA of possible shortages was issued, the agency has had a sixfold increase in notifications, according to Ms. Thakur. The increased notification, she added, has allowed more time for backup plans to be created. But even with these measures, pharmacists don’t seem terribly optimistic about the drug supply. “If it is a generic, sterile injectable, it has been, is now or will be in shortage in the near future, and that has been the experience we have been suffering with for several years now on an escalating basis,” said Dr. Kloth. In a recent editorial in the Journal of Clinical Oncology, Michael Link, MD, past president of the American Society of Clinical Oncology and other experts pointed out that “manufacturers have little incentive to produce drugs with low profit margins and often shift their resources to drugs for which higher profit margins can be anticipated.” Unless things change, the rollercoaster drug shortage problem looks to be the new normal. —Kate O’Rourke All sources quoted in this article have no relevant financial conflicts of interest.

Hem/Onc Pharmacy

Pharmacy Practice News • May 2012

In Focus

Strategies for Holding Down Cost of New Cancer Drugs Orlando, Fla.—These days, cancer centers across the United States are doing everything they can to contain costs. At the recent annual meeting of the Hematology/Oncology Pharmacy Association (HOPA), pharmacists presented strategies for reducing costs involved with ipilimumab (Yervoy, Bristol-Myers Squibb) and rasburicase (Elitek, Sanofiaventis) (posters 9 and 7, respectively).

Cost Cutting With Ipilimumab A study by researchers from the Roswell Park Cancer Institute in Buffalo, N.Y., demonstrated that dose rounding of ipilimumab to the nearest 50 mg has the potential to result in a significant cost savings without adversely affecting patient care. Ipilimumab was approved in March 2011 for the treatment of metastatic melanoma at a dose of 3 mg/kg every 21 days for four doses. The drug is supplied as 50- or 200-mg single-use vials, each with 10 or 40 mL, respectively, of a 5-mg/mL sterile solution. Prescribing directions advise that partially used vials should be discarded after 24 hours. The acquisition cost of the drug is $120 per milligram. “When we looked at this drug before it came out, we thought that if we are going to use exact doses in these patients according to their actual body weight, we are going to have a significant amount of drug waste,” said Anthony Jarkowski III, PharmD, BCOP, clinical pharmacy specialist at Roswell Park, who led the study. “You can bill for drug waste, but currently we don’t do that at our site, so our physicians agreed that dose rounding would be a good idea.” In the study, ipilimumab was dosed at 3 mg/kg according to the package directions, but the exact total milligram dose was rounded to the nearest 50 mg, with 1 to 24 mg rounded down to the nearest 100-mg, 25 to 49 mg rounded up to nearest 50-mg, 51 to 74 rounded down to the nearest 50 mg, and 75 to 99 mg rounded up to the nearest 100 mg. Waste was defined as the amount of drug that would have been discarded if the actual calculated dose had been used in the treatment regimen instead of the

rounded dose. Overall, 22 patients received at least one dose. At the time of the analysis, 20 patients had completed therapy and two were still receiving therapy. Clinicians rounded down in nine patients and up in 12; one patient did not require rounding. Of the 20 patients who completed therapy, 11 received all four doses of therapy and nine received fewer than four doses. The researchers determined that patients received an average of 2.86 doses, and the maximum potential cost savings for the 22 patients was $155,400. “We had one response and one patient with stable disease,” said Dr. Jarkowski. He noted that these results were in the range of those seen in the literature, as were the grade 3/4 adverse events, which occurred in approximately 20% of the patients.

‘[Rounding of ipilimumab doses] is a fantastic idea and we are going to implement it.’ —Niesha Griffith, MS, RPh, FASHP Some pharmacists who visited his poster at the meeting said they also were rounding doses of ipilimumab at their institution, and others said they intended to change their policy to implement rounding. “A few people came by and said, ‘I’m going to take this back to my director at my institution and tell him we should be doing this,’” he said. Other pharmacists noted that their institutions “are billing for drug waste, but that can get a little complicated with the documentation,” he added. Niesha Griffith, MS, RPh, FASHP, director of pharmacy and infusion services at The Arthur G. James Cancer Hospital, The Ohio State University, in Columbus, is one pharmacist who saw the poster and said her hospital will be adopting the practice. “I think this is a great idea,” she said, noting that dose rounding is an

effective cost containment strategy for many oncology drugs. “We don’t use as much ipilimumab here because we only have two physicians who treat melanoma, and only one of them does so full time. Regardless, this is a fantastic idea and we are going to implement it.” Ms. Griffith pointed out that many institutions have electronic order entry systems that can be programmed to do the rounding. “For now,” she said, “we are going to do it manually, but I am going to ask for a build that includes the rounding parameters.”

Reeling in Rasburicase In another study, researchers from the University of Michigan College of Pharmacy, in Ann Arbor, showed that use of a single, fixed dose of rasburicase resulted in a significant cost savings and normalized uric acid levels within 24 hours in patients who received the drug to prevent or treat tumor lysis syndrome. Rasburicase is approved for the treatment of hyperuricemia at a weight-based dose of 0.2 mg/kg per dose. Because several studies have shown that a single fixed dose can be effective, the Michigan researchers set out to determine how often patients who receive a single fixed dose require at least one additional dose within five days of the initial dose and to determine the cost savings associated with a single fixed dose. “Most of the literature that we identified used a variety of doses, 1.5 mg all the way up to 7.5 mg,” said Melinda Tran, PharmD, hematology/oncology specialty pharmacy resident at the University of Michigan Hospitals and Health Centers, who led the study. In 2009, the University of Michigan Hospital implemented a fixed 6-mg rasburicase dose for adults, based on results from a variety of studies (Pharmacotherapy 2006;26:806-812). At the same time, they implemented two fixed doses for children, depending on weight. Children weighing less than 30 kg received 1.5 mg of rasburicase and those weighing more than 30 kg received 3 mg. Patients in the study primarily had leukemia, lymphoma and multiple myeloma. Reviewing the

charts of adult patients seen one year before and one year after fixed dosing was implemented and pediatric patients seen 1.5 years before and after implementation, they compared 40 adult patients and eight children in the weight-based group with 74 adults and 11 children in the fixed-dose group. No significant difference was identified between patients who received a weightbased dose and those who received a fixed dose with respect to additional doses required or average number of doses used. The fixed-dose regimen provided an approximate annual cost avoidance of $227,400. As was found in other studies, the fixed dose was effective at normalizing uric acid levels in adults and children, with one exception. Among the pediatric patients with Burkitt’s lymphoma, those “in the weight-based group didn’t require additional doses and they normalized uric acid in 24 hours” but “three of the four patients in the fixed-dose group required additional dosing within five days and also didn’t seem to normalize uric acid within 24 hours,” noted Dr. Tran. “This is hypothesis generating and perhaps we need to increase the dose.” According to Ms. Griffith, using fixeddose rasburicase is a good cost containment strategy and her institution has been using a fixed dose of 4.5 mg for several years and has studied this strategy. “The literature at the time supported both 3 and 6 mg. Since it comes in 1.5-mg vials, we decided to look at the effectiveness of a 4.5-mg dose. Our study and other studies have shown that doses of 4.5 mg and even lower can be effective,” said Ms. Griffith. “I think most institutions have already gone to using a fixed dose. Although this is not necessarily a new cost containment strategy [Dr. Tran] is to be commended for helping her organization identify cost-savings opportunities.” —Kate O’Rourke Drs. Jarkowski and Tran had no relevant disclosures. Dr. Griffith serves on the advisory board of Sanofi-aventis.

Study Supports Use of Shorter Bevacizumab Infusion Patient population limited to colorectal cancer patients Orlando, Fla.—Clinicians have further evidence that shortening the infusion time of bevacizumab (Avastin, Genentech) does not compromise patient safety. A short 0.5 mg/kg per minute infusion of bevacizumab does not increase the risk for proteinuria or

hypertension in patients with colorectal cancer, according to a study presented at the recent annual meeting of the Hematology/Oncology Pharmacy Association (poster 20). “This study provides key supporting evidence that it is safe to administer

shorter infusions of bevacizumab,” said Sachin Shah, PharmD, hematologyoncology clinical pharmacist at Texas Tech University Health Sciences Center, in Dallas, who led the study. “We are talking about 15 minutes, at the most, if a patient gets 7.5 mg/kg, and 10

minutes if they get 5 mg/kg. So, it is a significant saving in time for patients as well as chair time, which is a big issue for chemotherapy infusion centers.” The FDA label for bevacizumab indicates that the first infusion should be

•

see BEVACIZUMAB, page 32

Solutions that can help your patients stay ahead of access barriers What your patients need for access—from benefits investigations through patient assistance options— is available through Genentech BioOncologyTM Access Solutions®. Our Specialists can help you navigate the process.

To find out more, contact our Specialists at (888) 249-4918 or visit BioOncologyAccessSolutions.com/resources

Hem/Onc Pharmacy

Pharmacy Practice News • May 2012

In Focus

BEVACIZUMAB continued from page 30

administered over 90 minutes, the second infusion over 60 minutes (if tolerated), and the third and subsequent infusions over 30 minutes (if tolerated). In 2007, researchers from Memorial Sloan-Kettering Cancer Center, in New York City, reported that bevacizumab 5 mg/kg could be infused over 10 minutes, with only a 1.6% increase in events that were of minor clinical consequence (J Clin Oncol 2007;25:2691-2695). Since that time, many clinicians have switched to this protocol. According to Dr. Shah, however, because that study did not report the incidence of proteinuria or hypertension, other clinicians have been reluctant to switch over. To fill this knowledge gap, Dr. Shah and his colleagues gathered prospective data on 63 patients with colorectal cancer who were receiving their first dose of bevacizumab and were given a dose of less than 10 mg/kg infused

at a rate of 0.5 mg/kg per minute. A total of 392 shorter bevacizumab infusions were given during the study, which was conducted at the Veterans Affairs North Texas Health Care System, the University of Texas Southwestern Medical Center and Parkland Health and Hospital System, all in Dallas. Twenty-two patients received bevacizumab at a dose of 5 mg/kg and 41 patients received a dose of 7.5 mg/kg. The investigators measured blood pressure and urine protein prior to every other bevacizumab infusion. The researchers then compared results from this cohort with retrospective data of 120 patients who had similar baseline characteristics and received the standard dose (90, 60 and 30 minutes) at the three centers. The researchers

found similar rates of proteinuria in the two groups: 30.2% patients receiving the shortened infusion experienced proteinuria compared with 38% of those receiving the standard dose. Patients receiving the standard dose had higher rates of grade 2 (17.5% vs. 9.5%) and grade 3/4 (0.8% vs. 0) proteinuria, but the differences were not statistically significant. Overall, the incidence of new or worsening hypertension was similar between both groups (50.8% vs. 57%). “The incidence of proteinuria is not increased with a shorter infusion of bevacizumab,” said Dr. Shah. He thinks the study will help sway institutions that haven’t already adopted the shorter infusion, because the risks for proteinuria and hypertension were unknown. “The risk for proteinuria, hyperten-

sion and also infusion-related reactions could be the reason for some centers not transitioning to rapid infusion,” commented Sara Kim, PharmD, BCOP, oncology pharmacy clinical coordinator at the Mount Sinai Medical Center, in New York City. She said that based on the 2007 JCO study, her institution has standardized the bevacizumab infusion rate at 30 minutes for all doses (up to 15 mg/kg per dose) for both inpatients and ambulatory patients with all types of cancers. Dr. Kim agreed that the new study demonstrated that administering bevacizumab at 0.5 mg/kg per minute for doses less than 10 mg/kg per dose did not increase the risk for proteinuria and hypertension compared with that previously reported with the standard infusion rate, but she noted that the study included only colon cancer patients. —Kate O’Rourke Drs. Shah and Kim had no relevant financial conflicts of interest.

Vascular Disease

ADVANTAGES continued from page 1

The single-drug oral regimen raises the possibility of substantially reducing the hospital length of stay for patients receiving treatment for PE, said Dr. Buller, professor of vascular medicine at the Academic Medical Center, in Amsterdam, The Netherlands, during a press briefing at the ACC meeting. “Therefore, we wanted to make this regimen very simple,” he said. Treatment consisted of two pills daily in the first three weeks, with no monitoring or dose adjustment, followed by one pill daily for the remainder of treatment. The regimen could make it possible for patients to undergo only one day of hospital treatment rather than the five to 10 days typically required for standard treatment, Dr. Buller said. The study, called EINSTEIN-PE, which was simultaneously presented at the ACC meeting and published online in the March 26 issue of The New England Journal of Medicine (http://www.nejm. org/doi/full/10.1056/NEJMoa1113572), builds on a previous study by Dr. Buller and his colleagues (N Engl J Med 2010;363:2499-2510) demonstrating the safety and effectiveness of rivaroxaban for the treatment of deep venous thrombosis (DVT). (Both studies were sponsored by Bayer HealthCare and Janssen Pharmaceuticals.) “If we look at [the two studies] together, they are very consistent. I think they reassure us that for patients

with venous thromboembolism [VTE], we now can offer both physicians and patients an attractive alternative,” Dr. Buller said. The current open-label non-inferiority study randomized 4,832 patients with acute symptomatic PE with or without DVT at 263 sites in 38 countries to receive either rivaroxaban (15 mg twice daily for three weeks, followed by 20 mg once daily) or standard therapy (enoxaparin at 1 mg/kg twice daily for a minimum of five days and until the international normalized ratio [INR] reached 2.0 or more for two consecutive days, followed by a vitamin K antagonist [warfarin, or acenocoumarol outside the United States] doseadjusted to keep INR at 2.0 to 3.0) for three, six or 12 months. The primary efficacy outcome of recurrent VTE was statistically the same in both groups—50 patients (2.1%) in the rivaroxaban group versus 44 patients (1.8%) in the standard-therapy group (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.75-1.68; P=0.003). The primary safety outcome of clinically relevant bleeding also was statistically the same, occurring in 249 subjects

(10.3%) in the rivaroxaban group and in 274 (11.4%) in the standard-treatment group (HR, 0.90; CI, 0.76-1.07; P=0.23). However, major bleeding occurred in half as many patients receiving rivaroxaban as patients receiving standard treatment—26 (1.1%) versus 52 (2.2%) (HR, 0.49; CI, 0.31-0.79; P=0.003). The two groups experienced similar rates of clinically relevant bleeding during the first three weeks of twice-daily rivaroxaban treatment, Dr. Buller said. However, throughout the course of treatment, patients in the rivaroxaban group experienced fewer episodes of intracranial or other major bleeding than those receiving standard treatment. “We had the hope that we would see less bleeding ... and so we carefully followed these patients for major bleeding and for clinically relevant non-major bleeding. If you combine the two, they were actually the same rates,” Dr. Buller said. However, he added, “If you look carefully at the major bleeding, which is the ones we really hate—not only physicians but patients too—there was a statistically significant 50% reduction in major bleeding.” To address concerns regarding administering the same dose to all patients without laboratory monitoring, Dr. Buller and his colleagues performed multiple subgroup analyses for safety and efficacy and found that “rates of recurrent venous thromboembolism and bleeding were similar in the two study groups regardless of age, sex, presence or absence of obesity, level of renal function or extent

of pulmonary embolism.” Commenting on the results, Sarah A. Spinler, PharmD, professor of clinical pharmacy at the Philadelphia College of Pharmacy, University of the Sciences, said that the initial dose of 15 mg twice daily, which is titrated down to 20 mg once daily, underscores the importance of patient education. “You want to make sure that you have an excellent followup because you don’t want the patient to take 15 mg twice a day for any longer than three weeks,” she said. A special blister pack containing the correct supply of 15 mg twice-a-day medication for patients with VTE would be one way to address this, she said. Dr. Spinler said that dosing in patients with a creatinine clearance (CrCl) of 30 to 49 mL per minute also needs to be addressed. A previous study comparing rivaroxaban with warfarin in patients with atrial fibrillation (AF) (http:// www.nejm.org/doi/full/10.1056/NEJMoa1009638) used 15 mg rather than 20 mg as the daily dose in patients with CrCl of 30 to 49 mL per minute, but the EINSTEIN study did not apply a similar dose adjustment. “Pharmacists will need to know the indication for rivaroxaban to check the proper dosing,” she said. “What to do with a patient with AF plus VTE is anyone’s guess.” —Susan Birk Dr. Buller reported no relevant financial conflicts of interest. Dr. Spinler is a consultant to Bristol-Myers Squibb, Daiichi Sankyo and Janssen.

NOW YOU HAVE A CHOICE!

1/2 SECOND SPRAY is all it takes!

UNIT DOSE â&#x20AC;&#x201C; PATIENT SAFETY

SPRAY KIT â&#x20AC;&#x201C; MULTIPLE USE

An Innovative Non-Aerosol Unit Dose Topical Anesthetic Spray

20% Benzocaine Oral Anesthetic

t .FFUT +PJOU $PNNJTTJPO 4UBOEBSE GPS UIF NPTU SFBEZ UP BENJOJTUFS GPSN BWBJMBCMF

t 4IPSU EVSBUJPO NJOVUFT

t *OEJDBUFE GPS UFNQPSBSZ HBH SFÃ¸FY TVQQSFTTJPO EVSJOH VQQFS FOEPTDPQJD QSPDFEVSFT

t #FTU WBMVF BNPOH UPQJDBM BOFTUIFUJD TQSBZT

t &MJNJOBUFT QBJO BOE EJTDPNGPSU t 'BTU POTFU TFDPOET

t 4BGF o BWBJMBCMF PWFS UIF DPVOUFS t (SFBU 8JME $IFSSZ Ã¸BWPS

t 'BTU POTFU t 4IPSU EVSBUJPO t 7JSUVBMMZ OP TZTUFNJD BCTPSQUJPO t 6UJMJ[FT CBS DPEF NFEJDBUJPO BENJOJTUSBUJPO #$." UP BDDPNNPEBUF QPJOU PG DBSF TDBOOJOH t 7JSUVBMMZ FMJNJOBUFT BEWFSTF FWFOUT SFTVMUJOH GSPN QSFWFOUBCMF NFEJDBUJPO FSSPST FOTVSJOH UIF i 3JHIUTw BSF NFU â&#x2C6;&#x161; 3JHIU %SVH â&#x2C6;&#x161; 3JHIU 1BUJFOU â&#x2C6;&#x161; 3JHIU %PTF â&#x2C6;&#x161; 3JHIU 3PVUF â&#x2C6;&#x161; 3JHIU 5JNF t 4JOHMF VOJU PG VTF QBDLBHJOH FMJNJOBUFT UIF QPUFOUJBM GPS DSPTT DPOUBNJOBUJPO t *ODSFBTFT CJMMJOH BDDVSBDZ BOE JNQSPWFT TVQQMZ DIBJO DPTUT

Spray

t 3FDZDMBCMF

ORDERING INFORMATION NDC#

AMERISOURCE BERGEN

0283-0610-26

048-868

0283-0610-11

048-855

CARDINAL HEALTH CIN 4363370 CIN 4362547

ORDERING INFORMATION

MORRIS & DICKSON

PRODUCT

1411925

086629

HurriCaine ONE Unit Dose Non-Aerosol Spray Box of 25, 0.017 fl. oz. (0.5 ml) each

1410125

086611

HurriCaine ONE Unit Dose Non-Aerosol Spray Box of 2, 0.017 fl. oz. (0.5 ml) each

MCKESSON

4QSBZ ,JU o P[ TQSBZ DBO BOE EJTQPTBCMF FYUFOTJPO UVCFT /%$ 4QSBZ o P[ TQSBZ DBO BOE EJTQPTBCMF FYUFOTJPO UVCF /%$ &YUFOTJPO UVCFT o #PY PG EJTQPTBCMF FYUFOTJPO UVCFT 1SPEVDU OVNCFS

*G )VSSJ$BJOF 0/& JT OPU ZFU BWBJMBCMF UISPVHI ZPVS XIPMFTBMFS SFRVFTU JU CZ OBNF BOE /%$ /VNCFS +PJOU $PNNJTTJPO 4UBOEBSE .. &1

LLC

Extension Tubes

5P SFRVFTU B GSFF TBNQMF PS GPS NPSF JOGPSNBUJPO DBMM VT BU . ' B N o Q N $45 XXX IVSSJDBJOF POF DPN ] XXX CFVUMJDI DPN )VSSJ$BJOF 0/& BOE )VSSJ$BJOF BSF SFHJTUFSFE USBEFNBSLT PG #FVUMJDI 1IBSNBDFVUJDBMT --$ )047

34 Operations & Management

Pharmacy Practice News • May 2012

Finance

Strength in Numbers for Oncology Drug Reimbursement E

nsuring appropriate reimbursement for drugs can be a time-consuming and tedious process, especially if they are high-cost cancer medications. But all hospitals would be wise to have at least one pharmacy team member paying attention to continually changing drug codes and billable units, to ensure the hospital gets reimbursement and gets to keep that reimbursement, experts say. Because chemotherapy drugs are so expensive, Medicare has recovery audit contractors (RACs) who go back and try to identify drugs for which Medicare has overpaid and audit hospitals to regain that money, explained Gary Fong, PharmD, senior vice president and partner at the financial and compliance consultancy Panacea Healthcare Solutions, Inc., in Scottsdale, Ariz. In just a three-month period during 2011, the Office of Inspector General (OIG) recouped more than $500,000 in overpayments from 10 hospitals, according to Dr. Fong. At issue are claims submitted with outdated Healthcare Common Procedure Coding System (HCPCS) codes or billable units. “Many times the hospital pharmacy controls its own formulary, which then maps to the hospital billing system,” Dr. Fong said. “If the pharmacy formulary doesn’t stay up to date, you could be billing the wrong number of units, and the OIG will nail you.” To ensure proper billing, coding and pricing of chemotherapy and other medications, hospital finance leaders can conduct an internal audit to look for any inaccuracies related to national drug codes (NDCs), HCPCS codes, UB-04 revenue codes, billable units, wholesale acquisition costs and aver-

age wholesale prices. Dr. Fong said the four main steps pharmacists can take to ensure proper reimbursement are: 1. Pay attention to coding and billable units (e.g., ensure HCPCS are associated with a specific number of billable units). 2. Make sure formularies are accurate and up to date. 3. Make sure drug charges are within reason for the marketplace. 4. Verify that the calculations created by the pharmacy system are mapped correctly to the hospital billing system. At least yearly, and ideally quarterly, pharmacists should update their systems for costs and codes, he added. Companies such as his offer software tools and consulting services that pharmacies can use to help update their systems. Pharmacists also can stay on top of quarterly NDC changes online by searching fda.gov and HCPCS codes by searching CMS.gov.

MD Anderson Has Bolstered In-house Reimbursement Efforts Dina Patel, PharmD, clinical pharmacist at the University of Texas MD Anderson Cancer Center in Houston, said reimbursement for oncology medications “is becoming more and more of an issue, especially as drugs get more expensive and plans get more restrictive on coverage.” Drug coverage sometimes depends on the type of cancer, she said. The chemotherapy regimen for colorectal cancer often is recognized, but it’s tougher to get approvals for unknown primary tumors or rarer tumors, for which there are not

a lot of data to support specific regimens. Ensuring reimbursement tends to fall on the physician, mid-level practitioner or clinical pharmacist, Dr. Patel said, “but a lot of times it falls on the back burner, especially if the process is cumbersome and time-consuming.” Dr. Patel said she and her colleagues are fortunate to have a strong in-house

‘If the pharmacy formulary doesn’t stay up to date, you could be billing the wrong number of units, and the Office of Inspector General will nail you.’ —Gary Fong, PharmD resource. More than five years ago, the hospital established a Division of Pharmacy Finance, with staff dedicated to purchasing, reimbursement and helping patients enroll in patient assistance programs (PAPs). Its staff of 14 works regularly with 18 pharmaceutical companies representing 55 prescription drugs, said Lili Trevino, senior financial analyst with the division. “Our strategy is to offer as many programs as we can to patients to provide them assistance with their medications,” including counseling patients on available programs and providing complete documentation to support their case, said Florence McKelvey, CPA, MBA, MD Anderson’s director of pharmacy finance. Ms. McKelvey estimated that the division works with some 750 to 1,000 patients each year, saving them “tens of thousands of dollars.” Programs vary and provide services such as replacement drugs, copay assistance

‘I think it’s becoming more complex, but it’s an important part of our pharmacy mission. With looming health reforms, there’s a big uncertainty over what will happen to these programs, but there will always be people who do not have insurance, regardless of the model.’

and shipping medications directly to patients’ homes. There are a number of challenges working with these programs, Ms. McKelvey noted. Enrolling patients can require “quite a bit of documentation,” she said, including proof of residency, evidence the patient is not covered by Medicare and a list of the

—Florence McKelvey, CPA, MBA

patient’s assets. Most programs require that patients are U.S. citizens, so international patients coming for treatment are likely to be excluded. Programs can start and stop abruptly, so pharmacists and finance offices need to manage patients’ expectations, explaining that just because their medications are covered now, they may not always be covered. Many companies regularly send auditors to review patient records and make sure enrolled patients truly need assistance. And some programs require a patient to be denied coverage for medication at least twice before they will reimburse. “I think it’s becoming more complex, but it’s an important part of our pharmacy mission,” Ms. McKelvey said. With looming health reforms, “there’s a big uncertainty over what will happen to these programs, but there will always be people who do not have insurance, regardless of the model.” For pharmacies or medical centers looking to enroll patients in PAPs, Ms. McKelvey and Ms. Trevino recommend looking at the formulary’s most expensive drugs, then checking the Web sites for those drugs’ manufacturers to see if there are PAPs available. Asking neighboring hospitals how their pharmacies administer programs is another good way to glean information, they said. The Web site needymeds.org has a long list of PAPs and other resources pharmacists can share with their patients. For a free article by Dr. Fong and colleagues about uncovering pharmacy department risks and opportunities, see http://www.panaceahealthsolutions. com/ftpaccess/PHARMauditor/ hfm_ May_2011.pdf. —Karen Blum Dr. Fong, Dr. Patel, Ms. McKelvey and Ms. Trevino reported no relevant financial conflicts of interest.

36 Operations & Management

Pharmacy Practice News • May 2012

Leadership in Action

Leading From the Heart W

elcome to my last article in this short series on servant leadership. I trust that as you have considered this aspect of servant leadership, you have come to realize that servant leadership must come from the heart. When I serve you out of a caring heart, it is not to get anything in return. It is not something that can be contrived. People see through that in a heartbeat. In our health care industry, we are always looking for the scientific evidence. In health care, this is a good thing to pursue. But leading people oftentimes is not so scientific. We lead people based on who we are as individuals. Leaders have an intuitive sense that makes them trustworthy and dependable. We sense the needs and responses of people and adjust accordingly to intervene or persuade. Recently, I was speaking with one of our managers about leadership styles. We agreed that while we have a predominant leadership style, we also adjust our style based on the circumstances. For example, a participative management style, while it engenders a high level of autonomy and satisfaction, is not appropriate in a crisis situation, in which an autocratic style is usually most appropriate. If you have built a reputation as a servant leader, that will allow you to tap into some of the surplus in the emotional bank account and give directives that people will accept and follow in the crisis situation.

ference, either directly with a patient or indirectly through the caregivers whom we advise. As servant leaders, we should think about how we can create satisfying work environments for our employees, both pharmacists and other pharmacy personnel. How can we create opportunities with our pharmacy programs that allow our employees to make a difference in patient care and derive a sense

How can we best influence our employees, our colleagues and people in general? It is by subordinating our own desires, to serve others. of satisfaction that further encourages a commitment far above the attitude of ‘I only work to get that paycheck’? As leaders, we can “frame” a task to show our pharmacy technicians the impor-

tance of that task. I remember showing IV room technicians the neonates for whom they were preparing pediatric TPN [total parenteral nutrition] bags. That gave a whole new perspective to

Satisfaction of Work Work not only yields a product or a service, but it also provides satisfaction to the worker. Pharmacists are usually not 9-to-5 workers. We are part of a profession that prides itself on service to our patients. Our satisfaction comes from our ability to make a difference in patients’ lives, curing them of their diseases or at least controlling their illnesses or conditions. The times that we feel good about the day’s work are when we were able to make a dif-

Follow PPN on

INDICATION: Venofer ® (iron sucrose injection, USP) is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). IMPORTANT SAFETY INFORMATION: • Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been lifethreatening and fatal, have been reported in patients receiving Venofer ® (iron sucrose injection, USP). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer ® immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer ® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. • Venofer ® may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer ®. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered.

@PharmPracNews Leading anemia management.™

Pharmacy Practice News • May 2012

Operations & Mangement 37

Leadership in Action the task for those pharmacy technicians. They understood their value in keeping those preemies alive and helping to nourish them to health. The ASHP Pharmacy Practice Model Initiative (PPMI) and new health care models encourage pharmacists to be more involved in multidisciplinary teams in both inpatient and ambulatory settings across the care continuum. These direct care roles prove to be great motivators for pharmacists. These roles are satisfying for pharmacists because they are empowering. They allow phar-

macists to directly affect patients. That is very gratifying. It is incumbent on us as leaders in pharmacy to encourage these opportunities for pharmacists. Changes in financial incentives with bundled payments to the health care system provide new opportunities for pharmacist involvement to help reduce overall costs of patient care while improving quality. As medication experts, pharmacists are best qualified to help patients and the health system in these new health care models. As leaders, we have an opportunity to

The science behind the molecule behind the formulation... The efficacy behind the safety behind the trust A distinctive hydrogel core...a long history of clinical excellence... over 260 million units*1 prescribed...and counting

There’s CORE Experience in every drop ™

Millions prescribed. Millions treated.

• Venofer ® is contraindicated in patients with known hypersensitivity to Venofer ®. Do not administer to patients with evidence of iron overload. • In efficacy studies in non-dialysis dependent-CKD patients (N=139), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were nausea (8.6%), taste disturbance (7.9%), peripheral edema (7.2%), diarrhea (7.2%), dizziness (6.5%), hypertension (6.5%), infusion site pain or burning (5.8%), dyspnea (5.8%), and vomiting (5.0%). • In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the most frequent adverse events (>5%) whether or not related to Venofer® administration, were hypotension (39.4%), muscle cramps (29.4%), nausea (14.7%), headache (12.6%), graft complications (9.5%), vomiting (9.1%), dizziness (6.5%), hypertension (6.5%), chest pain (6.1%), and diarrhea (5.2%). In the study of peritoneal dialysis-CKD patients (N=75), the most frequent adverse events, whether or not related to Venofer ®, reported by 5% of these patients were infections and infestations (nasopharyngitis, sinusitis, upper respiratory tract, pharyngitis) (16.0%), diarrhea (8.0%), vomiting (8.0%), hypertension (8.0%), peripheral edema (5.3%), and nausea (5.3%). *100 mg vials and ampules worldwide from 1992 to February 2011. Reference: 1. Data on file. American Regent, Inc. Shirley, NY.

Please see brief Prescribing Information on adjacent page.

“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

be growing new leaders in changed health-care paradigm.

•

the

see FROM THE HEART, page 38

38 Operations & Management

Pharmacy Practice News • May 2012

Leadership in Action

FROM THE HEART continued from page 37

Power of Influence As I end this series on servant leadership, I am reminded that servant leaders always are concerned about influence. How can we best influence our employees, our colleagues and people in general? It is by subordinating our own desires, to serve others. This attitude of servant leadership stems from within. It comes from high moral standards and values that

are unshakable and not tossed about by the chaos of our times. I think of a picture of a lighthouse sitting high on the rocks while the ocean crashes around it. It is solid, immovable and a symbol of strength, warning of the impending dangers of the rocks upon which it sits. It is the epitome of influence, serving those around in an unwavering fashion. We often strive to change others, but change has to begin with us. We are truly the only ones we have the power to change. The paradox is that when we serve others,

(Table 1. Continued)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Adverse Reactions (Preferred Term)

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Venofer safely and effectively. See full prescribing information for Venofer. Initial U.S. Approval: 2000 RECENT MAJOR CHANGES Warnings and Precautions 6/2011 INDICATIONS AND USAGE Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). DOSAGE AND ADMINISTRATION Administer Venofer intravenously either by slow injection or by infusion. CKD patients on hemodialysis: 100 mg undiluted slow intravenous injection over 2 to 5 minutes or as an infusion of 100 mg, diluted in a maximum of 100 mL of 0.9% NaCl, over a period of at least 15 minutes. CKD patients not on dialysis: 200 mg undiluted slow IV injection over 2 to 5 minutes. • CKD patients receiving peritoneal dialysis: infuse 300 mg over 1.5 hours given on two occasions 14 days apart followed by a single infusion 14 days later of 400 mg given over 2.5 hours. Dilute each Venofer dose in a maximum volume of 250 mL of 0.9% NaCl. DOSAGE FORMS AND STRENGTHS • 10 mL single use vial / 200 mg elemental iron (20 mg/mL) • 5 mL single use vial / 100 mg elemental iron (20 mg/mL) • 2.5 mL single use vial / 50 mg elemental iron (20 mg/mL) CONTRAINDICATIONS • Known hypersensitivity to Venofer WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. • Hypotension:Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Venofer. • Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer to patients with iron overload. ADVERSE REACTIONS • The most common adverse reactions (≥ 2%) following the administration of Venofer are diarrhea, nausea, vomiting, headache, dizziness,hypotension,pruritus,pain in extremity,arthralgia,back pain,muscle cramp,injection site reactions,chest pain,and peripheral edema. To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION 2 DOSAGE AND ADMINISTRATION Venofer must only be administered intravenously either by slow injection or by infusion. The dosage of Venofer is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron. The usual total treatment course of Venofer is 1000 mg. Venofer treatment may be repeated if iron deficiency reoccurs. 2.1 Adult Patients with CKD on dialysis Administer Venofer 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session.Venofer should be administered early during the dialysis session. 2.2 Adult Patients CKD not on dialysis Administer Venofer 200 mg undiluted as a slow IV injection undiluted over 2 to 5 minutes on 5 different occasions over a 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 to 4 hours on day 1 and day 14. 2.3 Adult Patients with CKD receiving peritoneal dialysis Administer Venofer in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Venofer in a maximum of 250 mL of 0.9% NaCl. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion. 5.2 Hypotension Venofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer. Hypotension following administration of Venofer may be related to the rate of administration and/or total dose administered. 5.3 Iron Overload Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Patients receiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Venofer to patients with evidence of iron overload. Transferrin saturation values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing. 6 ADVERSE REACTIONS Venofer injection may cause serious hypersensitivity reactions and hypotension. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice. 6.1 Adverse Reactions in Clinical Studies The frequency of adverse reactions associated with the use of Venofer has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse events reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Venofer exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks. Table 1. Treatment-Emergent Adverse Reactions Reported in ≥ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate for Comparator Adverse Reactions (Preferred Term) Subjects with any adverse reaction Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain Diarrhea Dysgeusia Nausea Vomiting

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

PDD-CKD EPO* Only (N=46) %

78.8

76.3

73.4

72.0

65.2

2.2

0.7

0.4

2.7

2.9 10.1 0 12.2 8.6

4.0 8.0 0 5.3 8.0

6.5 4.3 0 4.3 2.2

3.5 5.2 0.9 14.7 9.1

1.4 7.2 7.9 8.6 5.0

people change of their own volition. As I have stated in these articles in the past, “being precedes doing. We do what we do because we are what we are.” Servant leadership is the key to building strong departments of motivated, empowered and committed individuals who make up a team. It says that I as a leader am committed to train, teach and serve others to make them into leaders. In this way, we leave our legacy and make our mark on our profession.

General Disorders and Administration Site Conditions Asthenia Chest pain Feeling abnormal Infusion site painor burning Injection site extravasation Peripheral edema Pyrexia Infections and Infestations Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis Injury, Poisoning and Procedural Complications Graft complication Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia Hypoglycemia Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Nasal congestion Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension Hypotension

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

PDD-CKD EPO* Only (N=46) %

2.2 6.1 3.0 0 0 2.6 3.0

0.7 1.4 0 5.8 2.2 7.2 0.7

2.2 0 0 0 0 5.0 0.7

2.7 2.7 0 0 0 5.3 1.3

0 0 0 0 0 10.9 0

2.6

2.2

4.3

16.0

4.3

9.5

1.4

3.0 0 0 0.4

1.4 2.9 2.9 0.7

0.7 1.4 0 0.7

1.3 0 0 4.0

0 0 2.2 0

3.5 2.2 29.4 0 5.6

1.4 2.2 0.7 3.6 4.3

2.2 3.6 0.7 0 0

4.0 1.3 2.7 1.3 2.7

4.3 4.3 0 0 6.5

6.5 12.6

6.5 2.9

1.4 0.7

1.3 4.0

4.3 0

3.0 3.5 0

2.2 5.8 1.4

0.7 1.4 2.2

1.3 1.3 1.3

0 2.2 0

3.9

2.2

4.3

2.7

6.5 39.4

6.5 2.2

4.3 0.7

8.0 2.7

6.5 2.2

Coming soon…

Conflict: The Destroyer or the Opportunity?

onflict is inevitable in life. If there are human beings interacting, there is bound to be conflict. It’s natural. What may not be natural is how we respond to conflict in a way that helps to restore relationships. Whether we’re talking about the workplace with your pharmacy team, dealing with an interdisciplinary hospital team or in your personal or family relationships, conflict happens. Starting with next month’s issue, I would like to give you some principles of conflict resolution based on a book by Ken Sande called “The Peace Maker” (Grand Rapids, MI: Baker Books 2004). As we think through some principles of conflict resolution, I trust that these principles will help you to develop teams that have a high level of trust and that can work cooperatively and smoothly because they have

*EPO=ERYTHROPOIETIN 6.2 Adverse Reactions from Post-Marketing Spontaneous Reports In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia. The following additional adverse reactions have been identified with the use of Venofer from postmarketing spontaneous reports: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia. 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. Symptoms associated with Venofer total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Symptoms may respond to IV fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms. 7 DRUG INTERACTIONS Drug interactions involving Venofer have not been studied. However, Venofer may reduce the absorption of concomitantly administered oral iron preparations. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Venofer should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether iron sucrose 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. 8.4 Pediatric Use Safety and effectiveness of Venofer in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of Venofer did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGE No data are available regarding overdosage of Venofer in humans. excessive dosages of Venofer may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. do not administer Venofer to patients with iron overload. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How supplied Venofer is supplied sterile in 10 mL, 5 mL, and 2.5 mL single use vials. Each 10 mL vial contains 200 mg elemental iron, each 5 mL vial contains 100 mg elemental iron, and each 2.5 mL vial contains 50 mg elemental iron (20 mg/mL). 16.2 Stability and storage Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Do not freeze. Do not dilute to concentrations below 1 mg/mL. Do not mix Venofer with other medications or add to parenteral nutrition solutions for intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion. 17 PATIENT COUNSELING INFORMATION Prior to Venofer administration: • Question patients regarding any prior history of reactions to parenteral iron products. • Advise patients of the risks associated with Venofer • Advise patients to report any symptoms of hypersensitivity that may develop during and following Venofer administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems.

AMERICAN REGENT, INC. SHIRLEY, NY 11967 Venofer is manufactured under license from Vifor (International) Inc., Switzerland.

IN2340BS, Rev. 6/2011

learned how to resolve conflict and not run away from it when it occurs. Effective teams build hightrust relationships, conversation proceeds effortlessly, and the workplace is dynamically positive. This only can occur when people learn to work together through all the uncertainty that exists in health care today and in life in general. Many of the crises we face are due to strained relationships. Wouldn’t the resolution of strained relationships bring productivity and peace in your life? As we walk down this path together, I am a learner as well. I look forward to this discovery process over the coming months. —E.A.

Pharmacy Practice News • May 2012

Q & A 39

CareFusion

PHACTS® Is Now Part of CareFusion

The following advertorial is provided by CareFusion. It is designed to support the advertisement presented below.

Q: How does the PHACTS product portfolio integrate with that of Pyxis?

Q: What are CareFusion and PHACTS? A: CareFusion, a global medical device company, delivers proven products and services that help measurably improve the safety and cost of health care. Used in more than 120 countries, the CareFusion family of products and services includes some of the most widely recognized brand names in the industry, including Pyxis® medication and supply management. The PHACTS mission is to identify and create technologically advanced pharmacy systems that increase accuracy, simplify workflow processes, improve productivity, reduce costs and deliver information. In effect, hospitals and health systems can efficiently manage their business while providing high-quality customer service and operating profitably.

The easy-to-use software solution can generate labels to meet the bar-code needs of bar code medication administration and health information technology systems.

A: PHACTS and Pyxis products integrate to streamline the medication management process from pharmacy to nursing. Pharmogistics automatically receives Pyxis MedStation® system refill, critically low and stock-out information, enabling users to process station requests quickly and efficiently and providing inventory oversight for management. And because Pharmogistics is

an enterprise system, Pyxis MedStation system inventory can be handled centrally if desired.

Q: How do I learn more information about the PHACTS and Pyxis product portfolio from CareFusion? A: To learn how our customers have successfully used PHACTS and Pyxis products to better manage pharmacy inventory, visit carefusion.com/ PHACTSmethodiststudy or contact us at communications@carefusion.com.

Q: Why did CareFusion acquire PHACTS? A: The acquisition advances the CareFusion strategy to offer hospitals safe and efficient systems to manage medication throughout their facilities—from the loading dock, to the patient bedside, to waste segregation. By adding the PHACTS portfolio of products to the core Pyxis dispensing technologies portfolio, CareFusion can increase visibility to drug inventories, helping hospitals reduce on-hand inventory, streamline staff workflow, manage drug shortages and improve financial performance.

Q: What is the PHACTS portfolio of products? A: The PHACTS portfolio includes three main products: 1. Pharmogistics® operates as an enterprise-wide inventory management software with a workflow process administrator. The easy-touse solution helps hospitals reduce medication waste throughout the health system and hospital using package-sharing and centralized distribution methods. Pharmogistics improves accuracy and productivity within the pharmacy during order fulfillment and restocking by using bar-code verification at all steps. The flexibility of pharmogistics allows it to be combined with carousels to manage inventory at larger institutions or used in a software-only configuration to control inventory at smaller facilities. 2. PharmoPack provides an automated medication bar-code packaging and labeling system for oral solids. PharmoPack is simple to use, compact enough to fit in any size pharmacy and flexible enough to provide multidose or unit-dose packaging safely, accurately and quickly. PharmoPack can operate as a stand alone or in conjunction with Pharmogistics software to streamline packaging and bar-coding workflow. 3. PharmoCode enables bar-code labeling for non-oral solid medications such as ampoules, syringes, creams, ointments and inhalers.

Help me cut costs and improve efficiency. The Methodist Hospital System yielded system-wide savings using PHACTS ® solutions, recently acquired by CareFusion. Pharmogistics ® software helps The Methodist maintain a perpetual inventory, consolidate Pyxis MedStation® system replenishment and share medication inventory between pharmacies—ultimately, centralizing inventory management. The result—achieving economies of scale through shared services, personnel, technology and medication inventory. That’s the CareFusion difference. Visit carefusion.com/PHACTSmethodiststudy to learn more, or email communications@carefusion.com.

carefusion.com © 2012 CareFusion Corporation or one of its subsidiaries. All rights reserved. Pyxis MedStation, Pyxis, PHACTS and Pharmogistics are trademarks or registered trademarks of CareFusion Corporation or one of its subsidiaries. DI3781 (0511)

40 Policy

Pharmacy Practice News • May 2012

Medication Safety

Prescription Drug Monitoring Programs May Share Data

o combat prescription drug abuse, prescription drug monitoring programs (PDMPs) have been authorized in 48 states. PDMPs collect and analyze prescribing and dispensing data within a state for enforcement and abuse prevention as well as research and education, according to the Alliance of States with Prescription Monitoring Programs. Now, recently introduced legislation takes the concept a

‘Our bill would strengthen states’ ability to monitor and track prescription drug dispersion ... a big step forward in the fight to prevent abuse.’ —Sen. Rob Portman (R-Ohio) step further. The Interstate Drug Monitoring Efficiency and Data Sharing Act of 2012 (ID MEDS; H.R. 4292, S.

2254) would establish uniform national standards for exchange of information among PDMPs. Unless states can share information, they can miss individuals who cross state lines to obtain prescription drugs for illicit purposes. “Sharing information across state lines can help physicians identify doctor shoppers [who] may travel to several states to obtain multiple

No Needles. No Spills. No Exposure. No Problem. Why put yourself at risk when mixing oncology drugs? Choose ChemoClave™, the world’s only needlefree Closed System Transfer Device for the safe handling of hazardous drugs. The toxicity of hazardous drugs and the dangers of prolonged exposure to them has been proven to cause hair loss, skin rashes, infertility, miscarriages, birth defects, and even leukemia and other forms of cancer in healthcare workers. Using the ChemoClave closed system transfer device in conjunction with other safety precautions can significantly minimize the chance of accidental exposure and keep you in compliance with OSHA, NIOSH, ASHP, ISOPP, ONS, APHON, and USP <797>. ChemoClave is the simple, safe, and secure way to help improve pharmacist, nurse, and patient safety throughout the entire hazardous drug delivery process. Contact us to find out how to keep yourself safe today.

Needlefree > Easy to Use > Less Waste > Lower Cost Pre

paration

Disposal

sportatio n ran

m in istratio n

800.824.7890 | www.icumed.com

Fentanyl Patches Cited in Deaths Of 10 Children

he FDA is again warning consumers about the potentially life-threatening dangers of fentanyl patches falling into the hands of young children. The agency recently released information on 26 cases of accidental poisoning of children who obtained improperly stored or discarded patches reported since 1997. Twelve of the cases resulted in hospitalization and 10 resulted in death. Sixteen of the cases occurred in children aged 2 years or younger. Fentanyl, a Schedule II opioid, has a high risk for fatal overdose caused by respiratory depression and hypoventilation, according to the FDA. Young children are at particularly high risk for accidental exposure to fentanyl patches because of their curiosity and mobility around the house, officials said. Children who obtain patches that have not been stored or discarded properly may place them in their mouths or adhere them to their bodies. However, officials stressed that adults also are at risk from the products if not used as directed. Physicians should read the package labeling and advise patients about how to use and dispose of the patches, the FDA said. The safest way to dispose of a spent patch is to press the sticky side together and flush it down the toilet, according to the agency. The alert marks the fourth time since 2005 that the FDA has issued a warning about fentanyl patches. For more information, go to http:// www.fda.gov/Drugs/DrugSafety/ ucm300747.htm —Gabrielle Rosen

Pharmacy Practice News • May 2012

Policy 41

Medication Safety prescriptions for a controlled substance,” Sarah Kelsey, legislative attorney, National Alliance for Model State Drug Laws, Santa Fe, N.M., said in an interview. ID MEDS was introduced by Sens. Rob Portman (R-Ohio) and Sheldon Whitehouse (D-R.I.) and Reps. Harold Rogers (R-Ky.) and Frank Wolf (R-Va.). “Our bill would strengthen states’ ability to monitor and track prescription drug dispersion, which is a big step forward in the fight to prevent abuse,” said Mr. Portman in a statement. Brian M. Meyer, MBA, director, Government Affairs Division, American Society of Health-System Pharmacists (ASHP), noted in an email that the ASHP House of Delegates passed a policy in 2011 supporting interoperability among state PDMPs, as provided for in the new legislation.

Outpatient Pharmacies Affected Laws regarding PDMPs vary among states, but in many cases they do not affect the administration of medications to inpatients in hospitals, according to Ms. Kelsey. Mr. Meyer added, “Model legislation from NABP [National Association of Boards of Pharmacy] exempts licensed hospitals for the purpose of inpatient care or the dispensing of a prescription at time of discharge.” The PDMP in New York “primarily impacts us in our outpatient pharmacy where we comply with [New York state law] just as any pharmacy does,” said Timothy Lesar, PharmD, director of clinical pharmacy services, Albany Medical Center, in Albany, N.Y. “This does not really impact inpatient services.” Other sources, however, pointed to several potential areas that PDMPs could have a broader impact on hospitals. Jennifer Fass, PharmD, CPh, clinical assistant professor, College of Pharmacy, Nova Southeastern University, in Ft. Lauderdale, Fla., noted that PDMPs can be used by clinicians “to conduct patient searches for those individuals whose care they are directly involved in.” Karl F. Gumpper, RPh, BCPS, FASHP, director, Section of Pharmacy Informatics & Technology, ASHP, said by email that there are several areas in which hospitals could make use of PDMP information, including medication reconciliation, emergency room visits and data access in the case of hospitals with retail pharmacies. Ms. Kelsey cited another potential inhospital application of PDMPs: “In an [emergency room] situation, where the doctor likely would not know a patient’s history, a [PDMP] can be a useful tool to assist in determining whether a particular individual may be seeking drugs for a non-legitimate purpose,” she said. A paper by Dr. Fass and Patrick C. Hardigan, PhD (J Manag Care Pharm 2011;17:430-438) found that both hospital and community pharmacists in Florida

were in favor of implementing a PDMP in Florida. Among hospital pharmacists, 74.2% agreed or strongly agreed with the statements that a PDMP “should be implemented in Florida”; similar numbers were reported for chain (84.0%), independent (77.9%) and other (71.1%) pharmacists.

Other Tools for Fighting Abuse Health-system pharmacies are not limited to the use of PDMPs when it comes to combating prescription drug abuse. “There is usually a sign-off

sheet that pharmacy and nursing complete,” Dr. Fass said. “Many of these substances are contained in computer systems … where individuals must log in to administer these substances. Hospitals usually have policies in place to monitor and prevent diversion among health care professionals.” Dr. Lesar added, “We use required chain-ofpossession documentation, review of all discrepancies, and statistical data monitoring for unit-based cabinet withdrawal rates.” Not all states are waiting for legisla-

tion to permit information exchange. Two existing platforms allow states to exchange PDMP data: the Prescription Monitoring Information Exchange (PMIX) and the NABP PMP InterConnect. According to Ms. Kelsey, “Some states are already sharing their [PDMP] data and others are working toward doing so.” —George Ochoa Mr. Gumpper, Ms. Kelsey, Dr. Lesar and Mr. Meyer reported no relevant financial conflicts of interest. Dr. Fass reported a grant from Nova Southeastern University.

Sound alike, yes. Look alike, NEVER!

Look-alike, sound-alike drugs are an ongoing challenge for healthcare providers. SAGENT’s response is PreventIV MeasuresSM, our unique approach to packaging and labeling that considers every person handling the product, to help make accurate drug selection an easy and obvious choice. As an added safety feature, SAGENT is also the only manufacturer that consistently provides full-color, differentiated cartons that match the labeling on the vials. In these highly visible and tangible ways, we’re striving every day to help customers reduce the risk of medication errors. You’ll ﬁnd SAGENT’s PreventIV Measures Packaging and Labeling on every SAGENT product. Find out more at www.SagentPharma.com.

Packaging and Labeling All trademarks herein are the property of Sagent Pharmaceuticals, Inc. ©2012 Sagent Pharmaceuticals, Inc. Printed in USA 1523 PreventIV Measures is a service mark of Sagent Pharmaceuticals, Inc.

www.SagentPharma.com

Listening. Responding. Delivering. That’s Injectables Excellence.™ That’s SAGENT Pharmaceuticals.

42 Policy

Pharmacy Practice News • May 2012

Ethics

Journals Urging More Inquiry in Fujii Case Japanese university cites lack of ethics review in scandal, but editors fear sweeping fraud

leading Japanese anesthesiologist has been fired by his university for ethics violations in his clinical trials, and journal editors fear that he has been publishing fraudulent data for decades. The researcher, Yoshitaka Fujii, MD, was released from Toho University in Tokyo in late February. Announcing its decision in early March, the institution released a list of eight published articles of studies for which Dr. Fujii had failed to obtain proper ethics approval. In a statement posted online, Masaru Kuroda, MD, PhD, dean of the Toho University Faculty of Medicine, declared that an internal investigation revealed that eight of Dr. Fujii’s papers “should be retracted since they did not

conform to the global standard of ethics for clinical studies.” Dr. Kuroda also noted that those studies, and one other trial by Dr. Fujii, took place at Ushiku Aiwa General Hospital—“which has no relation to his research activity in Toho University.” However, editors of several anesthesia journals believe Dr. Fujii’s misconduct goes much deeper, and could involve roughly 170 papers he had published during the past two decades. Many of Dr. Fujii’s papers involved trials of drugs to treat postoperative nausea and vomiting (PONV), specifically the antiemetic granisetron. The bulk of Dr. Fujii’s papers appeared in the anesthesia literature, and in particular the Canadian Jour-

‘The conclusion of the investigation was that the studies were conducted without ethical approval, not that they were fabricated. I’d have liked to have seen a statement about the investigating committee’s conclusions as to whether these studies took place at all or whether they took place but without approval.’ —Steve Yentis, MD

Toho University, which fired Yoshitaka Fujii, MD, in late February.

nal of Anesthesia (CJA), which published at least 39 of his articles. The investigation was triggered last summer when Dr. Fujii submitted a manuscript to that journal containing what appeared to be borrowed text and fabricated data. Although the scope of the deception might prove to be shocking, it likely will come as no surprise to some in the anesthesia community. In 2000, researchers led by Peter Kranke, MD, PhD, MBA, of the Department of Anaesthesia and Critical Care at University of Würzburg Hospital, in Germany, challenged the veracity of Dr. Fujii’s studies in a letter to the journal Anesthesia & Analgesia. Its title:

“Reported data on granisetron and postoperative nausea and vomiting by Fujii et al. are incredibly nice!” Dr. Kranke and his colleagues analyzed 47 of Dr. Fujii’s papers, published between 1994 and 1999, on the treatment of PONV with granisetron. “With increasing amazement, we noticed that the results reported by Fujii et al. are incredibly nice and we became skeptical when we realized that side effects were almost always identical in all groups,” Dr. Kranke’s group wrote. They closed their letter with the conclusion that “there must be an underlying influence causing such incredibly nice data.”

•

see INQUIRY, page 44

Legacies of Deception Scott Reuben, MD

Joachim Boldt, MD, PhD

Yoshitaka Fujii, MD

n February 2009, anesthesiology journals announced that they would be retracting nearly 20 of Dr. Reuben’s published studies after the pain specialist acknowledged fabricating data. The eventual toll of retractions reached 22. Dr. Reuben was convicted of health care fraud and spent six months in federal prison. He also was forced to pay more than $360,000 in fines to drug companies that had funded his research.

uspicions about Dr. Boldt’s work surfaced in late 2010, when a reader questioned the validity of a figure in a recently published study in Anesthesia & Analgesia. Subsequently, it was learned that Dr. Boldt had failed to obtain proper ethics approval for dozens of studies—of which approximately 90 have been retracted so far. An investigation into whether Dr. Boldt also committed research misconduct is ongoing.

lthough Dr. Fujii’s former institution, Toho University, limited its statement to the researcher’s failure to obtain proper ethics approval in some trials, editors of several anesthesiology journals strongly suspect that the misconduct runs much deeper. With some 170 published studies potentially implicated in the scandal, the number of potential retractions has a chance to nearly double Dr. Boldt’s tally.

THERE’S JUST NO SUBSTITUTE

- Unit-of-Use Omeprazole and

Lansoprazole Oral Suspension Compounding Kits are now available. NEW Omeprazole Oral Suspension Kits

10 OZ NDC# 65628-070-10 5 OZ NDC# 65628-070-05 3 OZ NDC# 65628-070-03

NEW Lansoprazole Oral Suspension Kits

- Unit-of-Use Compounding Kits will change the way you view prescription compounding. Now there is every reason to take advantage of this highly profitable business - Unit-of-Use Compounding because Kits are:

FAST: Compound while the patient waits.

Each kit contains everything you need and all ingredients are pre-weighed/pre-measured. Save prep, compounding and cleanup time.

PROFITABLE: One NDC number for all

components facilitates reimbursement.

ACCURATE: Standardized procedures

deliver consistent quality script after script. Every dispensing container is bar coded.

10 OZ NDC# 65628-080-10 5 OZ NDC# 65628-080-05 3 OZ NDC# 65628-080-03 CutisPharma, Inc., 68 Cummings Park, Woburn MA 01801 Telephone: 781-935-8141, Fax: 781-935-8395

CP C

Learn more at www.cutispharma.com or call 1-800-461-7449

UTIS PHARMA, INC.

SMART PRODUCTS FOR SMART

PEOPLE ®

Scan this code to learn more about these kits.

44 Policy

Pharmacy Practice News • May 2012

Ethics

INQUIRY continued from page 42

Dr. Fujii, who at that time was affiliated with the University of Tsukuba Institute of Clinical Medicine, in Ibaraki, had dismissed the implied accusation in a response that the journal published alongside Dr. Kranke’s letter. He wrote that in many of his trials, “we found that several patients who had received granisetron experienced mild headache and that an incidence of headache was approximately 10%. Consequently, an incidence of head-

ache seems to be identical, but it was true. How much evidence is required to provide adequate proof about antiemetics’ adverse events introduced recently by several investigators?” Christian C. Apfel, MD, PhD, an expert on PONV and a co-author of the letter by Dr. Kranke, said he has been disappointed that the anesthesiology journals did not retract any of the papers his critique cited, and that other journals continued to publish Dr. Fujii’s studies, despite what he considered to be clear evidence of fabrication. “The

likelihood that the data are true, as we calculated, is something like less than seven in a billion,” said Dr. Apfel, of the University of California, San Francisco Medical Center. In a follow-up study published in 2001 in Acta Anaesthesiologica Scandinavica (45:659-670), Drs. Apfel, Kranke and colleagues conducted a meta-analysis of Dr. Fujii’s studies of granisetron and showed that his trials demonstrated efficacy for the drug that was well outside what other groups were finding.

Does your unit dose packaging offer all this?

does.

Simple to Use–No Extensive Training Needed 1 and 2-dimensional barcoding–including NDC, Lot Numbers and Expiration Dating Tall Man Lettering and Dynamic Formatting Options Packaging Logs and Error Reporting 6-month and 1-year Beyond-Use Dating UV and Moisture Resistance Tamper-Evidence 4 Sizes of Blisters to accommodate virtually all meds No machinery or Space Requirements Inexpensive

Unit dose packaging the way it should be: Smart. Simple. Reliable.

Our MILT® software maintains packaging logs and lets you design and print your Lid-Label® Covers...In Color! With Tall Man Lettering! In Bold! With optional Bar Codes! Directly from your own computer and printer! Medi-Dose works well in any pharmacy operation and can be used with all classifications of drugs (chemo meds, compounded drugs, controlled substances, etc.) And it’s affordably priced for all pharmacy budgets. For the best in manual unit dose packaging, check out Medi-Dose!

Signs of Plagiarism Steven L. Shafer, MD, current editorin-chief of Anesthesia & Analgesia, said the case revived in earnest last spring after Dr. Fujii submitted a manuscript to the CJA.

in Your Inbox

Since 1971, hospital and community pharmacies around the world have relied on the proven Medi-Dose® system for the quick, simple and inexpensive method to manually package solid oral unit dose. Medi-Dose provides Tamper-Evidence as well as UV & Moisture Resistance for One-Year beyond-use dating.

Although the recommended dose of granisetron is 1 mg, Dr. Fujii’s papers said that amount was ineffective. Instead, the papers said, 3 mg worked—and remarkably well. On average, Dr. Apfel said, Dr. Fujii’s studies indicated that the drug was three times as effective as any other antiemetic. “The data for effectiveness are off the charts,” he said. However, Dr. Apfel noted, Dr. Fujii’s findings likely did not affect patient care in the United States. “If Fujii’s data had an impact, people would have used 3 mg. But people didn’t.” Dr. Apfel even wrote to the FDA, its Japanese counterpart and the Japanese Society of Anesthesiologists to warn them about Dr. Fujii’s results—but received either no reply or a cursory acknowledgment of his concerns. The FDA could not confirm that it had received the letter. Ronald Miller, MD, former editor-inchief of Anesthesia & Analgesia, which published 24 of Dr. Fujii’s papers, said he had largely forgotten the details of the letters regarding Dr. Fujii’s studies. However, he said in an interview that his decision to print the correspondence was an effort to promote a public vetting of the competing claims. “I felt publishing those two letters might shake out whether there was any more to it,” he said.

... to receive the monthly e-newsletter from

EPS®, INC. Extra Personal Service in supplying pharmacy packaging needs around the world

Milton Building, 70 Industrial Drive Ivyland, PA 18974 800-523-8966 Fax: 800-323-8966 215-396-8600 Fax: 215-396-6662 E-mail: info@medidose.com

www.medidose.com

Please see us at Booth #607 at the ASHP Show in Baltimore

at www.pharmacypracticenews.com

Get the latest news delivered directly to your computer and PDA.

Pharmacy Practice News • May 2012

Policy 45

Ethics Donald Miller, MD, editor-in-chief of the CJA, said he first had suspicions about Dr. Fujii’s 2011 submission when a plagiarism screening turned up the possibility of lifted text from an earlier article. When he looked at that paper, he noticed “a similarity in the nature of experiments.” Dr. Miller corresponded with Dr. Fujii, asking for a copy of the ethics approval form for the study. What he received “was translated and the form did not match the experiment. The number of animals was different,” as were other details, he said. “At that point, I informed Dr. Fujii that I had substantial concerns and would be contacting his institution.” When the CJA contacted Dr. Fujii’s clinical institution, they were informed that not only were the data fabricated, but that Dr. Fujii had not obtained approval to conduct such a study. Although the CJA has published more of Dr. Fujii’s papers than any other journal—“regrettably,” Dr. Miller said—it will not be retracting any just yet. Retractions may come after the journal has had the opportunity to communicate with the other institutions where Dr. Fujii worked. In the meantime, Dr. Miller said he would “definitely issue an expression of concern” for all of Dr. Fujii’s articles published in the CJA. “There’s a cloud of suspicion over everything he has published.”

been looking into Dr. Fujii’s research record, has posted four articles and editorials about the case and related issues on its Web site. Like Dr. Shafer, Steve Yentis, MD, editor-in-chief of Anaesthesia, expressed disappointment in the direction of the Toho University investigation. “As far as the head of the hospital knows, there was only one clinical study listed by Dr. Fujii as having been conducted at the hospital–but the conclusion of the investigation was that the studies were conducted without ethics

approval, not that they were fabricated,” Dr. Yentis said. “I’d have liked to have seen a statement about the investigating committee’s conclusions as to whether these studies took place at all or whether they took place but without approval.” This case is the latest in a string of recent misconduct scandals involving anesthesiologists, in the United States and abroad (See box). In 2009, journals were forced to retract nearly two dozen papers by Scott Reuben, MD, a Massachusetts pain specialist, who

fabricated data and eventually spent six months in federal prison for health care fraud. That was followed last year by revelations that Joachim Boldt, MD, PhD, a critical care specialist in Germany, had failed to receive ethics approval for many of his clinical trials. To date, journals have retracted nearly 90 of his papers. Dr. Boldt also may have fabricated data in at least one study, a 2010 article in Anesthesia & Analgesia. —Adam Marcus

Multiple Allegations of Fraud In a letter to readers that will be posted online, Dr. Shafer apologized for what he called his journal’s “inadequate response” to the 2000 letter challenging Dr. Fujii’s results. “Publication of the letter was appropriate, but the lack of institutional follow-up was not appropriate,” the letter stated. “It was similarly inappropriate to publish additional manuscripts by Dr. Fujii when the allegations of fraud were unresolved.” Anesthesia & Analgesia published 11 articles by Dr. Fujii after the 2000 letter that alleged improprieties in his data, Dr. Shafer noted. Dr. Shafer said he would issue expressions of concern for all of Dr. Fuji’s papers in his journal. “There are multiple allegations of research fraud involving Dr. Fujii, dating at least to the April 2000 Letter to the Editor in Anesthesia & Analgesia,” said Dr. Shafer. “Although Toho University does not mention fraud in their announcement of his dismissal, I have grave concerns about the possibility of manipulation or fabrication in Dr. Fujii’s published research. This will be investigated, and compromised papers in Anesthesia & Analgesia will be retracted.” The journal Anaesthesia, which has

*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

46 Policy

Pharmacy Practice News • May 2012

FDA Watch

U.S. Prepares Groundwork for Biosimilar Approval With the recent release of FDA draft guidelines, launch of the first oncology biosimilars is looming

s biosimilar drugs make their way to American soil, clinicians, regulators, pharmaceutical executives and patients alike are asking: How long will it take for the first biosimilars to reach the U.S. market? How much lower will their prices be than the original molecules they mimic? How quickly will they be accepted by clinicians and patients?

Biosimilar medications—also known as follow-on biologics—are virtually identical or highly similar versions of large and intricate biologic molecules like monoclonal antibodies. Brandname biologics are already essential for the treatment of breast, colorectal, esophageal, gastric, head and neck, kidney and non-small cell lung cancers;

and Hodgkin’s and non-Hodgkin’s lymphoma. They also are vital in the treatment of cancer- and chemotherapyinduced anemia and neutropenia. The hope is that biosimilars will significantly improve the affordability of, and access to, cancer medications. The clock is already ticking toward the entry of biosimilars into the American

market. This is because the 12-year patent-protection period will soon end for some brand-name products (Table 1, page 48). For the epoetin-alfa products Epogen (Amgen) and Procrit (Janssen Products), as well as Aranesp (darbepoetin alfa, Amgen) and Neupogen (filgrastim, Amgen), protection will run out in 2013. Some monoclonal antibody products, such as Rituxan (rituximab, Genentech/Biogen Idec), will likely lose their exclusivity protection as soon as the fourth quarter of 2015 and early 2016. And critically, on Feb. 9, 2012, the FDA released its draft guidance outlining the regulatory pathway required for the development and licensing of biosimilars. Several companies have already started to move proposed biosimilar products toward approval, and as of midFebruary the FDA had received requests to discuss drug approval of biosimilars for at least 11 different biologic drugs. In fact, a few started immediately after President Barack Obama signed the Biologics Price Competition and Innovation (BPCI) Act of 2009 into law on March 23, 2010, as part of the Affordable Care Act. Like the Drug Price Competition and Patent Term Restoration Act of 1984 for biologics, known colloquially as the “Hatch-Waxman Act,” the BPCI provides a legal framework for the approval of biosimilars in the United States.

Cost Savings From Biosimilars In no other field are biologics as important as in oncology and biosimilars are expected to be equally dominant players. Six of the 10 top-selling biologics in the United States are used in oncology, according to a 2011 review of biosimilars by Bradford Hirsch, MD, and Gary Lyman, MD, MPH (J Natl Compr Canc Netw 2011;9:934-942). And they are very expensive: The No. 1 money-earner in 2009 was bevacizumab (Avastin, Genentech), with sales of $5.8 billion. It was followed closely by rituximab at $5.7 billion. At $5 billion and $4.9 billion respectively, the markets for epoetin alfa and trastuzumab (Herceptin, Genentech) were not far behind. In Europe, draft biosimilar development guidelines were released in 2004. The first product—epoetin alfa Hexal (Hexal)—was approved in August 2007 and now more than a dozen biosimilars are on the market. Erythropoiesis-stimulating agent biosimilars such as epoetin alfa account for 35% of the market (NCCN Biosimilars White Paper. J Natl Compr Canc Netw 2011;9:S1-S22) and are marketed at a 25% to 30% discount from the “originator” or “reference” product, according to Drs. Hirsch

Pharmacy Practice News • May 2012

Policy 47

FDA Watch and Lyman. This also has led to price reductions of the reference products themselves. The European Generic Medicines Agency estimated in a “Vision 2015” document that the European Union (EU) saved 1.4 billion euros (US$1.8 billion) from biosimilar use in 2009. Another analysis projects the total savings to exceed 8 billion euros (US$10.6 billion) by 2020. Most experts believe that overall, biosimilars will cost 20% to 30% less than reference products. Some project that in the United States, this will result in $25 billion in savings per decade. Others peg the windfall as high as $108 billion in the first 10 years and $378 billion over 20 years (Targ Oncol 2012 Jan. 17. [Epub ahead of print]). Biosimilar versions of simple, unmodified biologics may well be approved and accepted relatively quickly in the United States because companies have gained experience with biosimilar approval in Europe. Thus, it is possible that they will be marketed for less than their European equivalents. However, the price reductions with biosimilars will never be in the same ballpark as generics. Generics can be accompanied by price tags that are as much as 90% lower than their brandname counterparts. Biosimilars are made in living systems and are much more complex, and the steps regulators require for product testing and approval are concomitantly more onerous in both the United States and Europe. The estimated cost to bring a biosimilar to market is $10 million to $40 million and the time frame is six to nine years, compared with $1 million to $2 million and three years for generics.

Biologic drugs are 40 to 180 times the size of small-molecule generic drugs and are vastly more complex.

switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” On Feb. 9, 2012, the FDA released three draft guidance documents on the pathway for biosimilar development based on the framework set out by the BPCI Act and on feedback received in 2010 at public meetings. The FDA emphasized that it “intends to consider the totality of the evidence” and use a “stepwise approach”

•

see BIOSIMILARS, page 48

New FDA Draft Guidance On Biosimilars The American biosimilar regulatory bar has been set high. The BPCI Act requires biosimilars to be “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and have “no clinically meaningful differences” from the reference product in terms of “safety, purity and potency.” The biosimilars also must have “the same mechanism or mechanisms of action” for the approved indications and the same route of administration, dosage form and strength. The BPCI Act also deems that biosimilars may be determined to be interchangeable with the reference product based on several criteria, including a demonstration “that the biological product can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once in an individual, the risk in terms of safety or diminished efficacy of alternating or

48 Policy

FDA Watch

BIOSIMILARS continued from page 47

to determine the safety, efficacy, purity and potency of each proposed biosimilar. The regulations allow “bridging”—that is, companies can use offshore data for compounds that have been tested or marketed as biosimilars in other countries. Firms can apply to have the compounds designated as being interchangeable—in other words, suitable for substitution for the original or “reference” product— although this will be subject to go ahead on a state-by-state basis. They also can apply for a period of exclusivity during which no other interchangeable version of a reference product can be launched into the U.S. market.

At a glance Cost and time of bringing follow-on products to market Small molecule generic: 3 years, $1 million to $2 million Biosimilar: 6 to 9 years, $10 million to $40 million

First Guidance Document: The Science of Demonstrating Biosimilarity The first draft guidance document summarizes the scientific requirements for a biosimilar to reach the market. These range from analyses of its structure and function to manufacturing process considerations, and animal and human studies that may be required, including evaluating clinical immunogenicity. It also describes the framework for postmarketing safety monitoring that companies must set up for every product. “That is the document that lays out our expectations that a sponsor will, if you will, squeeze out every bit of knowledge they can from the structure of their molecule, then come and talk to the agency … so we give the right good advice on the extent and scope of the necessary animal and clinical testing,” Rachel Sherman, MD, director of the FDA’s Office of Medical Policy, said in a news teleconference on the day the documents were released. “The law requires three, if you will, buckets of information: the physical-chemical testing, the animal studies and then the human studies, although it does permit us to waive any of the above.” She added that although the overall process is “not ‘one size fits all,’…

Pharmacy Practice News • May 2012

Table 1. FDA Approval Dates of Some Oncology Biologics Reference Product

Approved

Guaranteed Data Exclusivity

Bevacizumab (Avastin)

Feb. 6, 2004

2016

Cetuximab (Erbitux)

Feb. 12, 2004

2016

Darbepoetin (Aranesp)

Sept. 17, 2001

2013

Epoetin alfa (Epogen/Procrit)

June 1, 1989

Filgrastim (Neupogen)

Feb. 20, 1991

2003

Pegfilgrastim (Neulasta)

Jan. 31, 2002

2014

Rituximab (Rituxan)

Nov. 26, 1997

2009

Trastuzumab (Herceptin)

Sept. 25, 1998

2010

‘[Europeans] are a number of years ahead of us and have a lot of clinical data.’ —FDA Office of Medical Policy Director Rachel Sherman, MD it’s not conceivable to me that we can make an interchangeability determination without clinical data.” Dr. Sherman noted, in response to a question from a European journalist, that the FDA “would like to be able to bridge the European data. That would be product-specific, but we would try very hard to make that bridge, because you guys are a number of years ahead of us and have a lot of clinical data.” Robert Bell, PhD, who has occupied senior drug development positions in sev-

Biologic

$4679.36

55%

eral companies, supports this approach. “Data [from biosimilars that have been approved in other countries] is very relevant here, and would accelerate the approval process,” said Dr. Bell, president of Drug & Biotechnology Development, LLC, in Clearwater, Fla., in an interview with Pharmacy Practice News. “Specifically, data accumulated from the epoetin and myeloid growth factor biosimilars that have been approved in Europe potentially could be used to meet the FDA requirements. Because … while typically the FDA likes to see data from clinical trials in the U.S., if there are data avail-

Nonbiologic

$3848.21

45%

Figure 1. Biologics vs. nonbiologics distribution of drug expenditures of the top 20 antineoplastic drugs in outpatient clinics (in millions of dollars). Data from Doloresco F, Fominaya C, Schumock GT, et al. Projecting future drug expenditures—2011. Am J Health Syst Pharm. 2011;68:921–932..

able from comparable populations, in Europe or other countries, that should suffice.”

Second Guidance Document: Quality Considerations for Demonstrating Biosimilarity The second document provides details about the “extensive, robust comparative physicochemical and functional studies” required to show that the proposed biosimilar and the reference product are virtually identical in structure and function. The tests may include bioassays, biological assays, binding assays and enzyme kinetics. “If you use current modern analytical technologies and the resulting data from the biosimilar can be superimposed on data from the reference compound—showing for example that they are highly similar—you will have fewer issues demonstrating clinical comparability,” Dr. Bell said, citing the evolution of mass spectrometry, which can now detect differences between monoclonal antibodies as small as 32 Da or about 5 µ 10-26 kg. “But as the proteins become more complex, the analytical methodology may not be able to detect all relevant structural and functional differences between the proteins so the sponsor, in a stepwise approach, will have to further rely on preclinical and clinical studies to demonstrate comparability.” He gave a practical example of the importance of these analyses: the debacle with Eprex in Europe (erythropoietin alpha, Johnson & Johnson). In 1998, the company began to use rubber stoppers for the product’s prefilled syringes. This led to more than 200 reported cases of pure red cell aplasia in patients with chronic kidney disease over the next five years. Many experts believe this is what spurred European—and later, U.S.—regulators to create their very rigorous biosimilar approval criteria. A team eventually found the source of the problem: Using high-pressure liquid chromatography of Eprex batches they detected a contaminant, a leachate, originating from the rubber stoppers (Nephrol Dial Transplant 2005;20:iii33-iii40).

Third Guidance Document: Implementing the BPCI The third draft document is a 15-page Q&A. It covers everything from when company officials should ask the FDA for a first meeting to whether applicants can extrapolate clinical data supporting a biosimilar application to one or more additional indications. The Q&A summarizes many of the most important issues expanded on in the previous two guidance documents, while also defining several ways in which biosimilars may be different from their reference products

•

see BIOSIMILARS, page 50

QUALITY ALITY CONVENIENCE When You Need It Most Pharmacy Sterile Compounding Services for Peripheral Nerve Block, Epidural and Wound Inﬁltration

Examples of Services

CHRONIC

INTRATHECAL

NERVE BLOCK

CONTINUOUS

ACUTE

www.pharmedium.com

PCA

IV PUSH

EPIDURAL

SERVICES FOR THE ENTIRE PAIN MANAGEMENT CONTINUUM P10148 Rev 1.

50 Policy

Pharmacy Practice News • May 2012

FDA Watch

Not at all familiar

High interest

36%

Slightly familiar

Moderate interest

19%

Somewhat familiar

10%

Need more information to make a decision

No interest

15%

Extremely familiar

35%

Low interest

23%

Moderately familiar

27%

15%

20%

25%

30%

35%

40%

26%

Percentage of Respondents

10%

15%

20%

25%

30%

35%

40%

Percentage of Respondents

Figure 2. Familiarity among physicians, nurses and pharmacists with biosimilars.a,b

Figure 3. Interest in prescribing FDA-approved biosimilars in clinical practice.a,b a

N=277.

From NCCN Trends Survey conducted March 10-11, 2011, at the 16th Annual NCCN Conference in Hollywood, Fla.

BIOSIMILARS continued from page 48

(e.g., differences in formulation or delivery device).

Going Down the Regulatory Pathway For all the detail contained in the FDA’s draft guidance, nobody knows what the entire regulatory process will entail and how long it will take for any product to be approved as a biosimilar. “It’s relatively difficult to foresee the complete development path because companies have to go step by step and don’t know ahead of time what will be required,” said Bernd Meibohm, PhD, a professor of pharmaceutical sciences at the University of Tennessee Health Sciences Center in Memphis. “So I think this is going to be a learning experience on both sides. The FDA and the companies will go hand in hand and walk down the path set down by the draft guidance and try to make something out of it.” He believes that it will be a couple of years until the first biosimilar appears on the U.S. market, and that it will take much longer for the first one to be deemed interchangeable. “In Europe if you’re a biosimilar, you’re a biosimilar—they don’t have a system for determining interchangeability. Here it’s built into the legislation, and I think the scary part [for companies] is this is a different hurdle, and a much higher hurdle.” Some companies have already sprinted ahead in the biosimilar approval marathon. Dr. Sherman said at the Feb. 9 news conference that agency officials had received 35 pre-Investigational New

Drug (IND) inquiries and were reviewing nine INDs. An IND is the first step toward approval of a product. The agency’s goals for 2013 are to “review and act on 70% of original biosimilar biological product application submissions within 10 months of receipt, and to review and act on 70% of resubmitted original biosimilar biological product applications within six months of receipt.” These percentages will be increased to 90% by 2017. None of the information submitted by companies in the approval pathway is publicly accessible except studies that have been published in peer-reviewed

journals or presented at conferences. Companies are very likely following a similar sequence as in Europe, submitting applications first for smaller molecule biosimilars and later for monoclonal antibody biosimilars. Teva Pharmaceuticals anticipates that Phase II trials of its proposed rituximab biosimilar will be completed this year—putting it in a good position for application for biosimilarity status in Europe, where the patent-protection period for the reference product, Rituxan (Biogen Idec), expires in 2013.

‘The landscape is going to change very rapidly in the U.S.—in Europe it’s already changed.’ —Arnold G. Vulto, PharmD, PhD Table 2. Fundamental Differences Between Small Molecule and Biologic Drugsa

Small Molecule Drugs

Biologic Drugs

Synthesis

Chemical

Made in living cells

Structure

Well defined

Heterogeneous, mixtures of related molecules

Size

<800 Da

30,000-150,000 Da

Characterization

Easy

Difficult

Stability

Relatively stable

Variable, sensitive to environmental conditions (e.g., light and temperature)

Immunogenicity

Not an issue

Can be a problem

rom “Development of biosimilars is not an easy matter.” Generics and Biosimilars Initiative. F http://gabionline.net/Biosimilars/Research/Development-of-biosimilars-is-not-an-easy-matter.

Since Rituxan’s patent protection ended in the United States in 2009, a biosimilar application by Teva to the FDA may also be in the foreseeable future.

Big Pharma Preparing To Go To Battle Over Biosimilars Small companies for the most part will not participate in this potentially very lucrative market. This is because the regulations are onerous. Alternately, firms that already market or will soon market biosimilars in Europe or other countries such as Canada and Japan have a huge head start. In fact, a number of large pharma and biotech companies are lining up to start the march toward manufacturing and selling biosimilars in the United States. Many are doing this by making linkages with muscular generic firms. For example, in December 2011 the large biotechnology company Amgen and U.S. generic manufacturer Watson Pharmaceuticals announced a worldwide collaboration for the development and commercialization of several as-yetunspecified cancer antibody biosimilars. Biogen Idec and Samsung made a similar announcement that month. Pfizer, Merck and Novartis also intend to plunge into making biosimilars in the United States and elsewhere. This shift first took place in Europe. “I see now that almost every company [that makes reference products] has its own subsidiary producing biosimilars [for the European market],” said Arnold G. Vulto, PharmD, PhD, deputy head of

•

see BIOSIMILARS, page 54

Spotlight On Our Very Best As 2011 drew to a close, the McMahon Group bestowed honors on several employees within its talented workforce. Throughout the year, McMahon’s portfolio of clinical news magazines maintained readership numbers that solidiﬁed their best-read status, and sales revenues increased despite a challenging economic climate. The diverse talents and collaborations among McMahon’s staff allowed the company to maintain its position as a trusted source of news and educational initiatives. McMahon’s publishing success was on display both in print and on the Web sites of its publications and custom media platforms.

2011

Here is a look at those recognized for their unique contributions during 2011.

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR:

GRAPHIC DESIGNER OF THE YEAR:

Employees were asked to select the two most outstanding members from these departments. The ﬁrst winner was JOHN CAbA, software developer, for his tireless devotion toward improving the company’s digital platforms.

The second winner was ROSA DIMICCO, accounting associate, for diligently ensuring that freelance writers and key opinion leaders are paid in a timely manner for their exceptional work.

JEANETTE MOONEy won the award in recognition of her creative talents as art director for Pain Medicine News, along with her superb layout designs for a host of Special Reports and custom newsletters.

MOST IMPROVED SALESPERSON OF THE YEAR:

SPECIAL PROJECTS EDITOR OF THE YEAR:

NEWSMAGAZINE EDITOR OF THE YEAR:

Each member of the sales staff seeks to improve throughout the year; however, one inevitably displays accelerated growth. DAVID NATHANSON, account manager, managed to do just that across several publications in 2011.

SETH KANDEL was voted best projects editor for his exemplary work on numerous custom media programs for medical industry clients as well as his management of the editorial in Infectious Disease Special Edition.

DONALD PIZZI, managing editor of Pain Medicine News, was recognized for the excellence of his news coverage throughout 2011. Under Don’s discerning eye, the magazine offers a comprehensive resource for clinicians involved in the management of pain.

SALES ACHIEVEMENT AWARD:

SALESPERSON OF THE YEAR:

DAVE KAPLAN, publication director of Pharmacy Practice News, was the 2011 winner in this category. Dave has proven himself to be an innovator among his peers by championing exciting new platforms and marketing opportunities for his many clients.

Whereas the other awards are decided by a jury of one’s peers, this honor is bestowed on the one salesperson who brings in the most revenue. For a record-breaking sixth year in a row, the winner was RICHARD TUORTO, senior group publication director for Anesthesiology News and Pain Medicine News. Richard’s dedication to his clients’ marketing needs and intimate knowledge of their products enable him to reach the zenith of sales proﬁciency year after year.

PERSON OF THE YEAR

PARTNERS AWARD

PERSON OF THE YEAR 2011:

PARTNERS SPECIAL RECOGNITION AWARD 2011:

This award recognizes the cream of the crop, and MARy LOU CAMPANELLA, chief financial officer, was the 2011 Person of the Year. Mary Lou has been able to streamline the company’s finances by thwarting inefficiencies and highlighting excess expenditures. Her constant professionalism, hard work and keen eye for detail have proven to be invaluable commodities that are greatly appreciated by her peers.

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 URbAN S. MULVEHILL, who has provided legal services to the company since 1983. He became a partner at his law ﬁrm, O’Neill DiManno and Kelly, in 1980 after having served as a trial lawyer for several years at the U.S. Department of Justice. Urban’s relaxed demeanor and sage advice over the past three decades have been greatly appreciated.

52 Policy

Pharmacy Practice News • May 2012

Quality Improvement

READMISSIONS

‘We focus on acute care while looking ahead to what

continued from page 1

sponsored by the Institute for Safe Medication Practices (ISMP). Medication-related factors are believed to be a major cause of readmissions, although the phenomenon is lightly studied, and precise numbers are hard to come by. In one study of 400 consecutively discharged patients, 19% experienced postdischarge adverse events (AEs). Of those, adverse drug events (ADEs) accounted for 66% and were the most common type

the discharge regimen will be, including promoting adherence, decreasing pill burden, or helping financially troubled patients obtain post-discharge drugs.’

—Meghan Davlin, PharmD, MBA

of AE (Ann Intern Med 2003;138:161-167), Stacy Carson, PharmD, BCPS, ISMP safe medication management fellow, noted during the webinar.

Medications commonly associated with readmission, Dr. Carson pointed out, include analgesics/opioids, anticancer drugs, oral anticoagulants, anti-

Focus on Inhaled Anesthesia Podcast Series Providing support and information for anesthesiologists and health-system pharmacists

NE W

Podcast 2: Recovery From Inhaled Anesthesia Delivered by LMA™ Mask Chris Cardone, MD Chairman, Department of Anesthesiology Miami Valley Hospital Dayton, Ohio

Learning Objectives: • Discuss potential benefits of using short-acting anesthetic agents with an LMA™ (laryngeal mask airway). • Discuss the potential clinical benefits and risks that SUPRANE (desflurane, USP) may provide when used with an LMA™ mask in adult patients. • Outline anesthetic technique when using SUPRANE (desflurane, USP) with an LMA™ mask in adult patients. The Inhaled Anesthesia Podcast Series is supported by Baxter Healthcare Corporation. Baxter and Suprane are trademarks of Baxter International Inc. LMA is a trademark of The Laryngeal Mask Company Limited.

Listen @ 742967C 3/12

www.anesthesiologynews.com/podcast www.pharmacypracticenews.com/podcast

platelets, digoxin, diuretics/antihypertensives and glucocorticoids (Eur J Clin Pharmacol 2008;64:715-722; J Am Geriatr Soc 2011;59:948-949). “The reasons medications can lead to readmission include incomplete medication reconciliation either upon admission or during transitions of care within a hospital,” Dr. Carson said. “It could be due to poor discharge planning or patient education. It could be due to low patient or caregiver health literacy, medication noncompliance—including the inability to pay for prescriptions after discharge—and no follow-up with the physician after discharge.” Several studies, she added, demonstrate that multidisciplinary collaboration involving pharmacists can reduce drug-related readmissions. Such a multidisciplinary initiative designed to stem readmissions is active on three units of The Johns Hopkins Hospital in Baltimore: one hospitalist unit and two step-down surgical units, according to Meghan Davlin, PharmD, MBA, division director of ambulatory and care transitions at the hospital. Three more units are scheduled to go live this spring. The process begins at admission, when patients are screened and stratified by readmission risk. All patients, regardless of risk status, receive multidisciplinary care. Daily rounds set the direction for subsequent treatment decisions, are attended by all relevant clinicians and address both acute care and discharge planning. “Everyone is together in the same room, including the physician, pharmacist, bedside nurse, nurse manager, physical therapist, social worker and nutritionist— whoever is applicable,” said Dr. Davlin. The scheduled time for rounds was set a couple of hours later in the day than is typical, which allows adequate time for important information, such as lab results, to flow in. Rounds usually last 30 to 45 minutes on the hospitalist unit, whose average census is 16 patients. “We focus on acute care while looking ahead to what the discharge regimen will be, including promoting adherence, decreasing pill burden, or helping financially troubled patients obtain postdischarge drugs,” said Dr. Davlin. “Our reformatted, multidisciplinary rounds have been a huge success.” Pharmacy-specific elements of the care plan include medication reconciliation, patient education, optional discharge prescription delivery and home-based pharmacy care. Medication reconciliation remains primarily the physician’s responsibility, with the option to consult a pharmacist when the job of compiling a comprehensive list of home medications proves difficult, and for patients with poor health literacy, a history of nonadherence, or

•

see READMISSIONS, page 54

The bookstore division of

mcmahoNmedicalbooks.com an online bookstore

order books oNliNe

The book Page

Visit our site to get a FREE financial planning audio CD!

Publisher’s ToP Picks of The moNTh oN mcmahoNmedicalbooks.com These books and thousands more...

2012/2013 Top 300 Pharmacy Drug Cards

Jill M. Kolesar; Lee Vermeulen McGraw-Hill, January 12, 2012 These cards are a fun, fast way to learn essential information about the top 300 drugs. They are essential for pharmacy school courses and NAPLEX® preparation.

Scan here for our complete catalog of medical books.

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.

Apha’s Immunization Handbook, Second Edition

Lauren B. Angelo APhA, March 31, 2012 Pharmacists and student pharmacists are strongly encouraged to participate in immunization-related activities. This book provides numerous guidelines, tips and resources for building and sustaining a successful immunization practice. Written in a concise and quick-look-up format, this handy resource is an essential tool for the busy pharmacist.

Applied Biopharmaceutics & Pharmacokinetics, Sixth Edition

Leon Shargel; Andrew Yu; Susanna Wu-Pong McGraw-Hill, January 6, 2012 This book provides a basic understanding of the principles of biopharmaceutics and pharmacokinetics and applies these principles to drug product development, drug product performance and drug therapy. The revised and updated sixth edition is unique in teaching basic concepts that relate to understanding the complex issues associated with safe and efficacious drug therapy.

Fundamentals of Pharmacognosy and Phytotherapy, Second Edition

Michael Heinrich Elsevier/Churchill Livingstone, April 11, 2012 This textbook provides useful and fascinating insights into the history, botany, chemistry, phytotherapy and importance of medicinal plants in some of today’s health care systems. It brings together relevant data from numerous sources and provides cutting-edge information that is relevant to pharmacists, doctors and nurses alike.

Heroes of Pharmacy: Professional Leadership in Times of Change

Dennis Worthen APhA, February 27, 2012 This book presents the highlights of the professional lives of 52 American pharmacists—including founders of the American Pharmaceutical Association—who helped change the way we use medicines and the profession of pharmacy, not only in the United States but also worldwide.

Interpreting Laboratory Data: A Point-of-Care Guide

Justin Schmidt; Jeffrey Wieczorkiewicz ASHP, November 22, 2011 The pharmacists you trust for quality and clarity have transformed ASHP’s best-selling laboratory data textbook into the convenient portable reference that pharmacy clinicians and students have been waiting for.

Mosby’s Drug Reference for Health Professions, Third Edition

Mosby Elsevier/Mosby, April 20, 2011 From Abilify to Zyrtec and nearly every drug in between, this is the must-have guide for every current or aspiring health professional in the field today. Filled with the details you need to know about your clients’ or patients’ medications, this updated edition features concise, reliable information that is easy to navigate and simple to follow.

PharmPrep: ASHP’s NAPLEx Review, Fourth Edition

Lea S. Eiland; Diane B. Ginsburg ASHP, May 10, 2011 Using real patient cases accompanied by questions that address all NAPLEX® competency statements, the new fully updated fourth edition of PharmPrep: ASHP’s NAPLEX® Review 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. PPN0512

54 Policy

FDA Watch

BIOSIMILARS

Pharmacy Practice News • May 2012

At a glance Interchangeability

continued from page 50

hospital pharmacy at Erasmus University Medical Center in Rotterdam, The Netherlands. “So I think the landscape is going to change very rapidly in the U.S.— in Europe it’s already changed.” Dr. Vulto is co-creator of the Generics and Biosimilars Initiative (GaBI) and the Web site www.GaBIonline.net where he and other experts monitor biosimilarrelated developments around the world. Another observer of the biosimilarity field, Kristie C. Kuhl, JD, senior vice president at Makovsky + Company in New York City, also sees this as a significant sea change. “This is an interesting transformation for the industry,” said Ms. Kuhl. “Before, there were generics and there were innovators. And now we’re seeing more of a confluence of the two. The large companies are pursuing both innovation and intellectual property that’s in the public domain and seeing what they can do with that.”

Survey: Interest in Biosimiliars Is High, but Understanding Is Lacking Meanwhile, clinicians and members

Generic is biosimilar to the reference product Produces the same clinical result as the reference product in any given patient Safety and efficacy are not affected by alternating or switching between reference product and biosimilar Biosimilar may be substituted for the reference product without the authorization of the health care provider

of the public are anticipating that biosimilars will cut the cost of cancer care considerably. A survey of 277 health care professionals conducted by the National Comprehensive Cancer Network (NCCN) Work Group and presented at the NCCN’s 2011 annual conference indicated 66% had a high or moderate interest in biosimilars (Figures 1-3). Between 17% and 23% said they would use a biosimilar as soon as it was available, depending on the

product, and 55% to 60% said they would require review and discussion before using a biosimilar. However, more than half were either not at all familiar or only slightly familiar with recent developments surrounding biosimilars, a fact that points to the necessity of education about these medications, according to the investigators. The NCCN Work Group also queried patients about their views of biosimilars. Clinicians can expect to hear from patients who want to be sure biosimilars are safe and effective and that the therapy they provide is as high quality as that of the reference products. Another survey by the pharmaceutical and biotech consulting firm Decision Resources showed that more than 50% of surveyed U.S. physicians would begin prescribing a biosimilar epoetin within six months of its launch and 88% would start using it within a year. Ultimately, there are both similarities and differences between the European biosimilar market and the one unfolding in the United States. There are many unsettled regulatory questions; nevertheless large shifts already are occurring as a result of the imminent arrival of biosimilars.

READMISSIONS continued from page 52

a drug-related readmission. Dr. Davlin also urges starting patient education about post-discharge drug regimens as early as possible. “We found that patients can’t focus when you load them up with information about their medications a few hours before discharge, because there’s so much activity occurring,” she said. After discharge, patients classified as moderate or high risk for readmission (or whose length of stay exceeds expectations) receive follow-up phone calls from a clinician who checks on patient compliance with drug regimens and assists with post-acute care referrals and appointments. High-risk patients also are assigned a care transition guide—a nurse who coordinates care with pharmacists and home-based care nurses for four to six weeks after discharge. “We want to ensure a good handoff to primary care providers,” said Dr. Davlin. The home-based care component— which is geared to the most complex polypharmacy patients—allows ambulatory care pharmacists to work directly with home care nurses to promote and monitor adherence and make sure that each patient’s prescriptions are filled on schedule. The service also includes a pilot program in which pharmacists visit patients’ homes. “Some patients

may have many changes made to their drug regimen during their admission. It can be very confusing for the patient,” Dr. Davlin said. According to preliminary data, readmission rates have fallen on the units where the new care plan is in effect, although Dr. Davlin cautioned that more thorough data collection and analysis are needed to verify the trend.

Einstein Medical Center Focuses on Cardiac Patients A program along similar lines was established at the Einstein Medical Center, in Philadelphia, which serves a large underprivileged population and where readmission rates for patients with AMI and HF were running well above national averages. In fall 2010, the hospital implemented Medication REACH (validate medication Reconciliation; Deliver patient-centered Education; Resolve medication Access issues during transition; Coordinate a comprehensive Counseling approach; Healthy,

compliant patient at home). Its primary objective is to create a smooth transition for patients between the hospital and home, with an emphasis on safe medication management. Ultimately, this comprehensive approach to care is intended to reduce ADEs and hospital readmissions, explained Deborah Hauser, RPh, MHA, network pharmacy director, Einstein Healthcare Network. Pharmacist interventions play a central role in REACH, because they have been shown to increase patient compliance with prescriptions and reduce ADEs. “I can’t emphasize enough the importance of using pharmacists in the discharge process,” Ms. Hauser said. Interventions might consist of dose optimization, deleting unnecessary therapy or adding new ones. Face-toface patient education also is stressed. Patients receive a “toolkit” that includes pictorial medication cards and medication organizers. When possible, the program also addresses access-of-care issues—for example, verifying insurance,

“I would think that the biggest thing we can ‘take to the bank’ is that biosimilar regulatory review and approval processes will be dramatically different from anything we’ve been accustomed to with generic drugs here in the U.S.,” said Dwight Kloth, PharmD, the director of pharmacy at Fox Chase Cancer Center in Philadelphia. “With generics, the issue is documenting that it is the same molecule, has the same purity, if it’s a tablet that dissolution rates are the same, the bioavailability of the compound is the same, and so forth. But if you’re talking about a delicate monoclonal antibody that’s produced by recombinant DNA technology and which can be denatured if it’s subjected to temperature extremes and where the biologic activity may be altered by seemingly minor differences in the manufacturing process, it’s a much more complicated question. Uncertainty always tends to make regulators worry and I think that’s a good thing.” —Rosemary Frei, MSc

Drs. Bell, Kloth, Meibohn and Vulto, and Ms. Kuhl reported no relevant financial conflicts of interest.

formulary conversions to less expensive drugs and helping uninsured patients obtain post-discharge medications. To evaluate the program’s efficacy, Ms. Hauser and her colleagues conducted a randomized controlled study covering the first nine months after Medication REACH was rolled out on a limited basis. All subjects in the study were taking at least five medications, had at least one chronic condition and were hospitalized for a minimum of 48 hours before discharge to their home. Of the 45 patients in the control group, 29.5% were readmitted, compared with just 17% of the 47 patients in the REACH group. The lower readmission rate among REACH patients was sustained over an additional six months of monitoring. Ms. Hauser said she was a bit surprised to find that the number of pharmacist interventions (59) exceeded the number of patients in the REACH group, pointing to the high level of engagement by—and the great need for—pharmacists in the drug therapy management process. In fact, 25% of the pharmacist interventions documented in the study involved initiation of drug therapy. “There’s a tremendous opportunity for pharmacists to have an impact,” Ms. Hauser said. “For example, the validation of medication reconciliation at discharge by a pharmacist can identify a missed medication.” —Steve Frandzel

SAMSCAÂ® (tolvaptan) tablets for oral use %ULHI 6XPPDU\ RI 3UHVFULELQJ ,QIRUPDWLRQ )RU FRPSOHWH SUHVFULELQJ LQIRUPDWLRQ FRQVXOW RIÂ¿FLDO SDFNDJH LQVHUW WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM 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. INDICATIONS AND USAGE: 6$06&$ LV LQGLFDWHG IRU WKH WUHDWPHQW RI FOLQLFDOO\ VLJQLÂ¿FDQW K\SHUYROHPLF DQG HXYROHPLF K\SRQDWUHPLD VHUXP VRGLXP P(T / RU OHVV PDUNHG K\SRQDWUHPLD WKDW LV V\PSWRPDWLF DQG KDV UHVLVWHG FRUUHFWLRQ ZLWK Ã&#x20AC;XLG UHVWULFWLRQ LQFOXGLQJ SDWLHQWV ZLWK KHDUW IDLOXUH FLUUKRVLV DQG 6\QGURPH RI ,QDSSURSULDWH $QWLGLXUHWLF +RUPRQH 6,$'+ Important Limitations 3DWLHQWV UHTXLULQJ LQWHUYHQWLRQ WR UDLVH VHUXP VRGLXP XUJHQWO\ WR SUHYHQW RU WR WUHDW VHULRXV QHXURORJLFDO V\PSWRPV VKRXOG QRW EH WUHDWHG ZLWK 6$06&$ ,W KDV QRW EHHQ HVWDEOLVKHG WKDW UDLVLQJ VHUXP VRGLXP ZLWK 6$06&$ SURYLGHV D V\PSWRPDWLF EHQHÂ¿W WR SDWLHQWV CONTRAINDICATIONS: 6$06&$ LV FRQWUDLQGLFDWHG LQ WKH IROORZLQJ FRQGLWLRQV Urgent need to raise serum sodium acutely: SAMSCA has not been studied in a setting of urgent need to raise serum sodium acutely. Inability of the patient to sense or appropriately respond to thirst: 3DWLHQWV ZKR DUH XQDEOH WR DXWR UHJXODWH Ã&#x20AC;XLG EDODQFH DUH DW VXEVWDQWLDOO\ LQFUHDVHG ULVN RI LQFXUULQJ DQ RYHUO\ UDSLG FRUUHFWLRQ RI VHUXP VRGLXP K\SHUQDWUHPLD DQG K\SRYROHPLD Hypovolemic hyponatremia: 5LVNV DVVRFLDWHG ZLWK ZRUVHQLQJ K\SRYROHPLD LQFOXGLQJ FRPSOLFDWLRQV VXFK DV K\SRWHQVLRQ DQG UHQDO IDLOXUH RXWZHLJK SRVVLEOH EHQHÂ¿WV Concomitant use of strong CYP 3A inhibitors: .HWRFRQD]ROH PJ DGPLQLVWHUHG ZLWK WROYDSWDQ LQFUHDVHG WROYDSWDQ H[SRVXUH E\ IROG /DUJHU GRVHV ZRXOG EH H[SHFWHG WR SURGXFH ODUJHU LQFUHDVHV LQ WROYDSWDQ H[SRVXUH 7KHUH LV QRW DGHTXDWH H[SHULHQFH WR GHÂ¿QH WKH GRVH DGMXVWPHQW WKDW ZRXOG EH QHHGHG WR DOORZ VDIH XVH RI WROYDSWDQ ZLWK VWURQJ &<3 $ LQKLELWRUV VXFK DV FODULWKURP\FLQ NHWRFRQD]ROH LWUDFRQD]ROH ULWRQDYLU LQGLQDYLU QHOÂ¿QDYLU VDTXLQDYLU QHID]RGRQH DQG WHOLWKURP\FLQ Anuric patients: ,Q SDWLHQWV XQDEOH WR PDNH XULQH QR FOLQLFDO EHQHÂ¿W FDQ EH H[SHFWHG WARNINGS AND PRECAUTIONS: Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae (see BOXED WARNING): Osmotic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Ã&#x20AC;XLG )OXLG UHVWULFWLRQ GXULQJ WKH Â¿UVW KRXUV RI WKHUDS\ ZLWK 6$06&$ PD\ LQFUHDVH WKH OLNHOLKRRG RI RYHUO\ UDSLG FRUUHFWLRQ RI VHUXP VRGLXP DQG VKRXOG JHQHUDOO\ EH DYRLGHG Gastrointestinal Bleeding in Patients with Cirrhosis: ,Q SDWLHQWV ZLWK FLUUKRVLV WUHDWHG ZLWK WROYDSWDQ LQ K\SRQDWUHPLD WULDOV JDVWURLQWHVWLQDO EOHHGLQJ ZDV UHSRUWHG LQ RXW RI WROYDSWDQ WUHDWHG SDWLHQWV DQG RXW RI SODFHER WUHDWHG SDWLHQWV 6$06&$ VKRXOG EH XVHG LQ FLUUKRWLF SDWLHQWV RQO\ ZKHQ WKH QHHG WR WUHDW RXWZHLJKV WKLV ULVN Dehydration and Hypovolemia: 6$06&$ WKHUDS\ LQGXFHV FRSLRXV DTXDUHVLV ZKLFK LV QRUPDOO\ SDUWLDOO\ RIIVHW E\ Ã&#x20AC;XLG LQWDNH 'HK\GUDWLRQ DQG K\SRYROHPLD FDQ RFFXU HVSHFLDOO\ LQ SRWHQWLDOO\ YROXPH GHSOHWHG SDWLHQWV UHFHLYLQJ GLXUHWLFV RU WKRVH ZKR DUH Ã&#x20AC;XLG UHVWULFWHG ,Q PXOWLSOH GRVH SODFHER FRQWUROOHG WULDOV LQ ZKLFK K\SRQDWUHPLF SDWLHQWV ZHUH WUHDWHG ZLWK WROYDSWDQ WKH LQFLGHQFH RI GHK\GUDWLRQ ZDV IRU WROYDSWDQ DQG IRU SODFHER WUHDWHG SDWLHQWV ,Q SDWLHQWV UHFHLYLQJ 6$06&$ ZKR GHYHORS PHGLFDOO\ VLJQLÂ¿FDQW VLJQV RU V\PSWRPV RI K\SRYROHPLD LQWHUUXSW RU GLVFRQWLQXH 6$06&$ WKHUDS\ DQG SURYLGH VXSSRUWLYH FDUH ZLWK FDUHIXO PDQDJHPHQW RI YLWDO VLJQV Ã&#x20AC;XLG EDODQFH DQG HOHFWURO\WHV )OXLG UHVWULFWLRQ GXULQJ WKHUDS\ ZLWK 6$06&$ PD\ LQFUHDVH WKH ULVN RI GHK\GUDWLRQ DQG K\SRYROHPLD 3DWLHQWV UHFHLYLQJ 6$06&$ VKRXOG FRQWLQXH LQJHVWLRQ RI Ã&#x20AC;XLG in response to thirst. Co-administration with Hypertonic Saline: 7KHUH LV QR H[SHULHQFH ZLWK FRQFRPLWDQW XVH RI 6$06&$ DQG K\SHUWRQLF VDOLQH &RQFRPLWDQW XVH ZLWK K\SHUWRQLF VDOLQH LV QRW UHFRPPHQGHG Drug Interactions: Other Drugs Affecting Exposure to Tolvaptan: CYP 3A Inhibitors: 7ROYDSWDQ LV D VXEVWUDWH RI &<3 $ &<3 $ LQKLELWRUV FDQ OHDG WR D PDUNHG LQFUHDVH LQ WROYDSWDQ concentrations [see Dosage and Administration (2.3), Drug Interactions (7.1)] 'R QRW XVH 6$06&$ ZLWK VWURQJ LQKLELWRUV RI &<3 $ [see Contraindications (4.4)] DQG DYRLG FRQFRPLWDQW XVH ZLWK PRGHUDWH &<3 $ LQKLELWRUV CYP 3A Inducers: $YRLG FR DGPLQLVWUDWLRQ RI &<3 $ LQGXFHUV H J ULIDPSLQ ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH 6W -RKQÂ¶V :RUW ZLWK 6$06&$ DV WKLV FDQ OHDG WR D UHGXFWLRQ LQ WKH SODVPD FRQFHQWUDWLRQ RI WROYDSWDQ DQG GHFUHDVHG HIIHFWLYHQHVV RI 6$06&$ WUHDWPHQW ,I FR DGPLQLVWHUHG ZLWK &<3 $ LQGXFHUV WKH GRVH RI 6$06&$ PD\ QHHG WR EH increased [see Dosage and Administration (2.3), Drug Interactions (7.1)]. P-gp Inhibitors: 7KH GRVH RI 6$06&$ PD\ KDYH WR EH UHGXFHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK 3 JS LQKLELWRUV H J cyclosporine [see Dosage and Administration (2.3), Drug Interactions (7.1)]. Hyperkalemia or Drugs that Increase Serum Potassium: 7UHDWPHQW ZLWK WROYDSWDQ LV DVVRFLDWHG ZLWK DQ DFXWH UHGXFWLRQ RI WKH H[WUDFHOOXODU Ã&#x20AC;XLG YROXPH ZKLFK FRXOG UHVXOW LQ LQFUHDVHG VHUXP SRWDVVLXP 6HUXP SRWDVVLXP OHYHOV VKRXOG EH PRQLWRUHG DIWHU LQLWLDWLRQ RI WROYDSWDQ WUHDWPHQW LQ SDWLHQWV ZLWK D VHUXP SRWDVVLXP ! P(T / DV ZHOO DV WKRVH ZKR DUH UHFHLYLQJ GUXJV NQRZQ WR LQFUHDVH VHUXP SRWDVVLXP OHYHOV ADVERSE REACTIONS: Clinical Trials Experience: %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQV UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHÃ&#x20AC;HFW WKH UDWHV REVHUYHG LQ SUDFWLFH 7KH DGYHUVH HYHQW LQIRUPDWLRQ IURP FOLQLFDO WULDOV GRHV KRZHYHU SURYLGH D EDVLV IRU LGHQWLI\LQJ WKH DGYHUVH HYHQWV WKDW DSSHDU WR EH UHODWHG WR GUXJ XVH DQG IRU DSSUR[LPDWLQJ UDWHV ,Q PXOWLSOH GRVH SODFHER FRQWUROOHG WULDOV K\SRQDWUHPLF SDWLHQWV VHUXP VRGLXP P(T / ZHUH WUHDWHG ZLWK 6$06&$ 7KH PHDQ DJH RI WKHVH SDWLHQWV ZDV \HDUV RI SDWLHQWV ZHUH PDOH DQG ZHUH &DXFDVLDQ 2QH KXQGUHG HLJKW\ QLQH WROYDSWDQ WUHDWHG SDWLHQWV KDG D VHUXP VRGLXP P(T / DQG SDWLHQWV KDG D VHUXP VRGLXP P(T / +\SRQDWUHPLD ZDV DWWULEXWHG WR FLUUKRVLV LQ RI SDWLHQWV KHDUW IDLOXUH LQ DQG 6,$'+ RWKHU LQ 2I WKHVH SDWLHQWV ZHUH WUHDWHG ZLWK WKH UHFRPPHQGHG GRVH WLWUDWLRQ PJ WLWUDWHG WR PJ DV QHHGHG WR UDLVH VHUXP VRGLXP 2YHUDOO RYHU SDWLHQWV KDYH EHHQ WUHDWHG ZLWK RUDO GRVHV RI WROYDSWDQ LQ RSHQ ODEHO RU SODFHER FRQWUROOHG FOLQLFDO WULDOV $SSUR[LPDWHO\ RI WKHVH SDWLHQWV KDG K\SRQDWUHPLD DSSUR[LPDWHO\ RI WKHVH K\SRQDWUHPLF SDWLHQWV ZHUH WUHDWHG ZLWK WROYDSWDQ IRU PRQWKV RU PRUH 7KH PRVW FRPPRQ DGYHUVH UHDFWLRQV LQFLGHQFH Â&#x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able 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term

Tolvaptan 15 mg/day-60 mg/day (N = 223) n (%)

Placebo (N = 220) n (%)

Gastrointestinal Disorders 'U\ PRXWK

Constipation

General Disorders and Administration Site Conditions a 7KLUVW

Asthenia

Pyrexia

Metabolism and Nutrition Disorders b +\SHUJO\FHPLD

Anorexia c

Renal and Urinary Disorders

3ROODNLXULD RU SRO\XULD d 7KH IROORZLQJ WHUPV DUH VXEVXPHG XQGHU WKH UHIHUHQFHG $'5 LQ 7DEOH a b c d SRO\GLSVLD GLDEHWHV PHOOLWXV GHFUHDVHG DSSHWLWH XULQH RXWSXW LQFUHDVHG PLFWXULWLRQ XUJHQF\ QRFWXULD ,Q D VXEJURXS RI SDWLHQWV ZLWK K\SRQDWUHPLD 1 VHUXP VRGLXP P(T / HQUROOHG LQ D GRXEOH EOLQG SODFHER FRQWUROOHG WULDO PHDQ GXUDWLRQ RI WUHDWPHQW ZDV PRQWKV RI SDWLHQWV ZLWK ZRUVHQLQJ KHDUW IDLOXUH WKH IROORZLQJ DGYHUVH reactions RFFXUUHG LQ WROYDSWDQ WUHDWHG SDWLHQWV DW D UDWH DW OHDVW JUHDWHU WKDQ SODFHER PRUWDOLW\ WROYDSWDQ SODFHER QDXVHD WROYDSWDQ SODFHER WKLUVW WROYDSWDQ SODFHER GU\ PRXWK WROYDSWDQ SODFHER DQG SRO\XULD

SAMSCAÂ® (tolvaptan) RU SROODNLXULD WROYDSWDQ SODFHER 7KH IROORZLQJ DGYHUVH UHDFWLRQV RFFXUUHG LQ RI K\SRQDWUHPLF SDWLHQWV WUHDWHG ZLWK 6$06&$ DQG DW D UDWH JUHDWHU WKDQ SODFHER LQ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV 1 WROYDSWDQ 1 SODFHER RU LQ RI SDWLHQWV LQ DQ XQFRQWUROOHG WULDO RI SDWLHQWV ZLWK K\SRQDWUHPLD 1 DQG DUH QRW PHQWLRQHG HOVHZKHUH LQ WKH ODEHO Blood and Lymphatic System 'LVRUGHUV 'LVVHPLQDWHG LQWUDYDVFXODU FRDJXODWLRQ &DUGLDF 'LVRUGHUV ,QWUDFDUGLDF WKURPEXV YHQWULFXODU Â¿EULOODWLRQ Investigations: Prothrombin time prolonged; Gastrointestinal Disorders: Ischemic colitis; Metabolism and Nutrition Disorders: Diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis; Nervous System: Cerebrovascular accident; Renal and Urinary Disorders: Urethral hemorrhage; Reproductive System and Breast Disorders (female): Vaginal hemorrhage; Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure; Vascular disorder: Deep vein thrombosis. DRUG INTERACTIONS: Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP 3A Inhibitors: 6$06&$ LV PHWDEROL]HG SULPDULO\ E\ &<3 $ .HWRFRQD]ROH LV D VWURQJ LQKLELWRU RI &<3 $ DQG DOVR DQ LQKLELWRU RI 3 JS &R DGPLQLVWUDWLRQ RI 6$06&$ DQG NHWRFRQD]ROH PJ GDLO\ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PJ NHWRFRQD]ROH GDLO\ RU ZLWK RWKHU VWURQJ &<3 $ LQKLELWRUV H J FODULWKURP\FLQ LWUDFRQD]ROH WHOLWKURP\FLQ VDTXLQDYLU QHOÂ¿QDYLU ULWRQDYLU DQG QHID]RGRQH DW WKH KLJKHVW ODEHOHG GRVH ZRXOG EH H[SHFWHG WR FDXVH DQ HYHQ JUHDWHU LQFUHDVH LQ WROYDSWDQ H[SRVXUH 7KXV 6$06&$ DQG VWURQJ &<3 $ LQKLELWRUV VKRXOG QRW EH FR DGPLQLVWHUHG [see Dosage and Administration (2.3) and Contraindications (4.4)]. Moderate CYP 3A Inhibitors: 7KH LPSDFW RI PRGHUDWH &<3 $ LQKLELWRUV H J HU\WKURP\FLQ Ã&#x20AC;XFRQD]ROH DSUHSLWDQW GLOWLD]HP DQG YHUDSDPLO RQ WKH H[SRVXUH WR FR DGPLQLVWHUHG WROYDSWDQ KDV QRW EHHQ DVVHVVHG $ VXEVWDQWLDO LQFUHDVH LQ WKH H[SRVXUH WR WROYDSWDQ ZRXOG EH H[SHFWHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK PRGHUDWH &<3 $ LQKLELWRUV &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PRGHUDWH &<3 $ LQKLELWRUV VKRXOG WKHUHIRUH JHQHUDOO\ EH DYRLGHG [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Grapefruit Juice: &R DGPLQLVWUDWLRQ RI JUDSHIUXLW MXLFH DQG 6$06&$ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. P-gp Inhibitors: 5HGXFWLRQ LQ WKH GRVH RI 6$06&$ PD\ EH UHTXLUHG LQ SDWLHQWV FRQFRPLWDQWO\ WUHDWHG ZLWK 3 JS LQKLELWRUV VXFK DV H J F\FORVSRULQH EDVHG RQ FOLQLFDO UHVSRQVH [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. Rifampin and Other CYP 3A Inducers: 5LIDPSLQ LV DQ LQGXFHU RI &<3 $ DQG 3 JS &R DGPLQLVWUDWLRQ RI ULIDPSLQ DQG 6$06&$ UHGXFHV H[SRVXUH WR WROYDSWDQ E\ 7KHUHIRUH WKH H[SHFWHG FOLQLFDO HIIHFWV RI 6$06&$ LQ WKH SUHVHQFH RI ULIDPSLQ DQG RWKHU LQGXFHUV H J ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH DQG 6W -RKQÂ¶V :RUW PD\ QRW EH REVHUYHG DW WKH XVXDO GRVH OHYHOV RI 6$06&$ 7KH GRVH RI 6$06&$ PD\ KDYH WR EH LQFUHDVHG [Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide: &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ GLJR[LQ IXURVHPLGH DQG K\GURFKORURWKLD]LGH ZLWK 6$06&$ KDV QR FOLQLFDOO\ UHOHYDQW LPSDFW RQ WKH H[SRVXUH WR WROYDSWDQ Effects of Tolvaptan on Other Drugs: Digoxin: 'LJR[LQ LV D 3 JS VXEVWUDWH DQG 6$06&$ LV D 3 JS LQKLELWRU &R DGPLQLVWUDWLRQ RI 6$06&$ DQG GLJR[LQ UHVXOWV LQ D IROG LQFUHDVH LQ WKH H[SRVXUH WR GLJR[LQ Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide: &R DGPLQLVWUDWLRQ RI WROYDSWDQ GRHV QRW DSSHDU WR DOWHU WKH SKDUPDFRNLQHWLFV RI ZDUIDULQ IXURVHPLGH K\GURFKORURWKLD]LGH RU DPLRGDURQH RU LWV DFWLYH PHWDEROLWH GHVHWK\ODPLRGDURQH WR D FOLQLFDOO\ VLJQLÂ¿FDQW GHJUHH Lovastatin: 6$06&$ LV D ZHDN LQKLELWRU RI &<3 $ &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ DQG 6$06&$ LQFUHDVHV WKH H[SRVXUH WR ORYDVWDWLQ DQG LWV DFWLYH PHWDEROLWH ORYDVWDWLQ È&#x2022; K\GUR[\DFLG E\ IDFWRUV RI DQG UHVSHFWLYHO\ 7KLV LV QRW D FOLQLFDOO\ UHOHYDQW change. Pharmacodynamic Interactions: 7ROYDSWDQ SURGXFHV D JUHDWHU KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDQ GRHV IXURVHPLGH RU K\GURFKORURWKLD]LGH &RQFRPLWDQW DGPLQLVWUDWLRQ RI WROYDSWDQ ZLWK IXURVHPLGH RU K\GURFKORURWKLD]LGH UHVXOWV LQ D KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDW LV VLPLODU WR WKH UDWH DIWHU WROYDSWDQ DGPLQLVWUDWLRQ DORQH $OWKRXJK VSHFLÂ¿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see Clinical Pharmacology (12.3)]. Pregnancy: Pregnancy Category C. 7KHUH DUH QR DGHTXDWH DQG ZHOO FRQWUROOHG VWXGLHV RI 6$06&$ XVH LQ SUHJQDQW ZRPHQ ,Q DQLPDO VWXGLHV FOHIW SDODWH EUDFK\PHOLD PLFURSKWKDOPLD VNHOHWDO PDOIRUPDWLRQV GHFUHDVHG IHWDO ZHLJKW GHOD\HG IHWDO RVVLÂ¿FDWLRQ DQG HPEU\R IHWDO GHDWK RFFXUUHG 6$06&$ VKRXOG EH XVHG GXULQJ SUHJQDQF\ RQO\ LI WKH SRWHQWLDO EHQHÂ¿W MXVWLÂ¿HV WKH SRWHQWLDO ULVN WR WKH IHWXV ,Q HPEU\R IHWDO GHYHORSPHQW VWXGLHV SUHJQDQW UDWV DQG UDEELWV UHFHLYHG RUDO WROYDSWDQ GXULQJ RUJDQRJHQHVLV 5DWV UHFHLYHG WR WLPHV WKH PD[LPXP UHFRPPHQGHG KXPDQ GRVH 05+' RI WROYDSWDQ RQ D ERG\ VXUIDFH DUHD EDVLV 5HGXFHG IHWDO ZHLJKWV DQG GHOD\HG IHWDO RVVLÂ¿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see Nonclinical Toxicology (13.3)]. Labor and Delivery: 7KH HIIHFW RI 6$06&$ RQ ODERU DQG GHOLYHU\ LQ KXPDQV LV XQNQRZQ Nursing Mothers: ,W LV QRW NQRZQ ZKHWKHU 6$06&$ LV H[FUHWHG LQWR KXPDQ PLON 7ROYDSWDQ LV H[FUHWHG LQWR WKH PLON RI ODFWDWLQJ UDWV %HFDXVH PDQ\ GUXJV DUH H[FUHWHG LQWR KXPDQ PLON DQG EHFDXVH RI WKH SRWHQWLDO IRU VHULRXV DGYHUVH UHDFWLRQV LQ QXUVLQJ LQIDQWV IURP 6$06&$ D GHFLVLRQ VKRXOG EH PDGH WR GLVFRQWLQXH QXUVLQJ RU 6$06&$ WDNLQJ LQWR FRQVLGHUDWLRQ WKH LPSRUWDQFH of SAMSCA to the mother. Pediatric Use: 6DIHW\ DQG HIIHFWLYHQHVV RI 6$06&$ LQ SHGLDWULF SDWLHQWV KDYH QRW EHHQ HVWDEOLVKHG Geriatric Use: 2I WKH WRWDO QXPEHU RI K\SRQDWUHPLF VXEMHFWV WUHDWHG ZLWK 6$06&$ LQ FOLQLFDO VWXGLHV ZHUH DQG RYHU ZKLOH ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV LQ VDIHW\ RU HIIHFWLYHQHVV ZHUH REVHUYHG EHWZHHQ WKHVH VXEMHFWV DQG \RXQJHU VXEMHFWV DQG RWKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂ¿HG GLIIHUHQFHV LQ UHVSRQVHV EHWZHHQ WKH HOGHUO\ DQG \RXQJHU SDWLHQWV EXW JUHDWHU VHQVLWLYLW\ RI VRPH ROGHU LQGLYLGXDOV FDQQRW EH UXOHG RXW ,QFUHDVLQJ DJH KDV QR HIIHFW RQ WROYDSWDQ plasma concentrations. Use in Patients with Hepatic Impairment: 0RGHUDWH DQG VHYHUH KHSDWLF LPSDLUPHQW GR QRW DIIHFW H[SRVXUH WR WROYDSWDQ WR D FOLQLFDOO\ UHOHYDQW H[WHQW 1R GRVH DGMXVWPHQW RI WROYDSWDQ LV QHFHVVDU\ Use in Patients with Renal Impairment: 1R GRVH DGMXVWPHQW LV QHFHVVDU\ EDVHG RQ UHQDO IXQFWLRQ 7KHUH DUH QR FOLQLFDO WULDO GDWD LQ SDWLHQWV ZLWK &U&O P/ PLQ DQG EHFDXVH GUXJ HIIHFWV RQ VHUXP VRGLXP OHYHOV DUH OLNHO\ ORVW DW YHU\ ORZ OHYHOV RI UHQDO IXQFWLRQ XVH LQ SDWLHQWV ZLWK D &U&O P/ PLQ LV QRW UHFRPPHQGHG 1R EHQHÂ¿W FDQ EH H[SHFWHG LQ SDWLHQWV ZKR DUH DQXULF [see Contraindications 4.5) and Clinical Pharmacology (12.3)]. Use in Patients with Congestive Heart Failure: 7KH H[SRVXUH WR WROYDSWDQ LQ SDWLHQWV ZLWK FRQJHVWLYH KHDUW IDLOXUH LV QRW FOLQLFDOO\ UHOHYDQWO\ LQFUHDVHG 1R GRVH DGMXVWPHQW LV QHFHVVDU\ OVERDOSAGE: 6LQJOH RUDO GRVHV XS WR PJ DQG PXOWLSOH GRVHV XS WR PJ RQFH GDLO\ IRU GD\V KDYH EHHQ ZHOO WROHUDWHG LQ VWXGLHV LQ KHDOWK\ VXEMHFWV 7KHUH LV QR VSHFLÂ¿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Â¿UVW VWHS $ WKRURXJK KLVWRU\ DQG GHWDLOV RI RYHUGRVH VKRXOG EH REWDLQHG DQG D SK\VLFDO H[DPLQDWLRQ VKRXOG EH SHUIRUPHG 7KH SRVVLELOLW\ RI PXOWLSOH GUXJ LQYROYHPHQW VKRXOG EH considered. 7UHDWPHQW VKRXOG LQYROYH V\PSWRPDWLF DQG VXSSRUWLYH FDUH ZLWK UHVSLUDWRU\ (&* DQG EORRG SUHVVXUH PRQLWRULQJ DQG ZDWHU à¯&#x2DC;HOHFWURO\WH VXSSOHPHQWV DV QHHGHG $ SURIXVH DQG SURORQJHG DTXDUHVLV VKRXOG EH DQWLFLSDWHG ZKLFK LI QRW PDWFKHG E\ RUDO Ã&#x20AC;XLG LQJHVWLRQ VKRXOG EH UHSODFHG ZLWK LQWUDYHQRXV K\SRWRQLF Ã&#x20AC;XLGV ZKLOH FORVHO\ PRQLWRULQJ HOHFWURO\WHV DQG Ã&#x20AC;XLG EDODQFH (&* PRQLWRULQJ VKRXOG EHJLQ LPPHGLDWHO\ DQG FRQWLQXH XQWLO (&* SDUDPHWHUV DUH ZLWKLQ QRUPDO UDQJHV 'LDO\VLV PD\ QRW EH HIIHFWLYH LQ UHPRYLQJ WROYDSWDQ EHFDXVH RI LWV KLJK ELQGLQJ DIÂ¿QLW\ IRU KXPDQ SODVPD SURWHLQ ! &ORVH PHGLFDO VXSHUYLVLRQ DQG PRQLWRULQJ VKRXOG FRQWLQXH XQWLO WKH SDWLHQW UHFRYHUV PATIENT COUNSELING INFORMATION: $V D SDUW RI SDWLHQW FRXQVHOLQJ KHDOWKFDUH SURYLGHUV PXVW UHYLHZ WKH 6$06&$ 0HGLFDWLRQ *XLGH ZLWK HYHU\ SDWLHQW [see FDA-Approved Medication Guide (17.3)]. Concomitant Medication: $GYLVH SDWLHQWV WR LQIRUP WKHLU SK\VLFLDQ LI WKH\ DUH WDNLQJ RU SODQ WR WDNH DQ\ SUHVFULSWLRQ RU RYHU WKH counter drugs since there is a potential for interactions. Strong and Moderate CYP 3A inhibitors and Pg-p inhibitors: $GYLVH SDWLHQWV WR LQIRUP WKHLU SK\VLFLDQ LI WKH\ XVH VWURQJ H J NHWRFRQD]ROH LWUDFRQD]ROH FODULWKURP\FLQ WHOLWKURP\FLQ QHOÂ¿QDYLU VDTXLQDYLU LQGLQDYLU ULWRQDYLU RU PRGHUDWH &<3 $ LQKLELWRUV H J DSUHSLWDQW HU\WKURP\FLQ GLOWLD]HP YHUDSDPLO Ã&#x20AC;XFRQD]RO RU 3 JS LQKLELWRUV H J F\FORVSRULQH [see Dosage and Administration (2.3), Contraindications (4.4), Warnings and Precautions (5.5) and Drug Interactions (7.1)]. Nursing: $GYLVH SDWLHQWV QRW WR EUHDVWIHHG DQ LQIDQW LI WKH\ DUH WDNLQJ 6$06&$ >VHH 8VH ,Q 6SHFLÂ¿F 3RSXODWLRQV @ )RU PRUH LQIRUPDWLRQ DERXW 6$06&$ FDOO RU JR WR ZZZ VDPVFD FRP 0DQXIDFWXUHG E\ 2WVXND 3KDUPDFHXWLFDO &R /WG 7RN\R -DSDQ 'LVWULEXWHG DQG PDUNHWHG E\ 2WVXND $PHULFD 3KDUPDFHXWLFDO ,QF 5RFNYLOOH 0' SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

86 / % 5HY

UNMET NEED. FILL IT.

FREE VVATER V2

CLEARANCE

Order SAMSCA® (tolvaptan)

15 mg

30 mg

NDC: 59148-020-50

NDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic and euvolemic hyponatremia

100 %

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 the following page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. Samsca is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

March 2012

0712A-4220K

A M at

ee bo

tin

ď ś

The Pharmacistâ&#x20AC;&#x2122;s News Source

pharmacypracticenews.com

Volume 39 â&#x20AC;˘ Number 5 â&#x20AC;˘ May 2012

ď ś

Printer-friendly versions available online

Changes Are Coming For Stress Ulcer Prevention Therapy

in this issue Up Front

In Brief Another reason for your patients to quit smoking.

Experts preview pending guidelines Houstonâ&#x20AC;&#x201D;Health care professionals anxiously awaiting the updated stress ulcer prophylaxis guidelines will have to wait until the end of 2012, but they should be aware that a wealth of new data has turned the previous guideline document on its head. During a session at the recent annual meeting of the Society of Critical Care Medicine, speakers involved in the development of the guidelines offered a quick preview. The new guidelines touch on areas including preferred therapy choice, patient selection factors and when to start and stop therapy. Clinicians in doubt as to whether to initiate therapy should go ahead and start, said presenter Douglas Naylor Jr., MD, staff intensivist

â&#x20AC;˘

see STRESS, page 7

With CMS Pay Cuts Looming, Hospitals Eye Readmissions

Clinical

Critical Care Weight-based dosing in ER still taken too lightly. Medication errors and C. difficile infections pose big risks in ICUs.

9 20

Hem/Onc Pharmacy Ipilimumab dose rounding and fixed dosing of rasburicase yield major cost savings.

Operations & Mgmt

Reimbursement A team approach to surviving RAC audits, maximizing reimbursement.

Policy

early 18% of all Medicare patients who Ethics are admitted to hospitals are readmitted Yet another retraction of published studies within 30 days after discharge, at a cost of $15 shines spotlight on billion annuallyâ&#x20AC;&#x201D;about $7,200 per caseâ&#x20AC;&#x201D;accordresearch ethics. 42 ing to the Medicare Payment Advisory Commission (MedPac). The commission also asserts that FDA Watch two-thirds of those readmissions are avoidable. New proposed rule on Starting in 2013, the Center for Medicare & biosimilars inches the Medicaid Services (CMS) will reduce payments market closer to generic biologics. to hospitals that log excessive readmissions relat46 ed to heart failure (HF), acute myocardial infarction (AMI) and pneumonia. Private insurers are likely to follow suit, and the prospect has hospiEducational Review tals scrambling to reduce readmission rates. CatheterFortunately, there are several strategies that hospitals can follow to keep patients at home. related One effective approachâ&#x20AC;&#x201D;leveraging multidisBloodstream DROP-BY-DROP. VIAL-BY-VIAL. A VITAL FOCUS ON SAFETY AND SUPPLY. ciplinary care and pharmacy services to help Infections patients avoid drug-related adverse eventsâ&#x20AC;&#x201D; ÂŽ APP registered trademarks of APP Pharmaceuticals, See page 11 wasandthe focusareof a recent Web-based seminarLLC. ÂŠ2012, APP Pharmaceuticals, LLC. All Rights Reserved. 0374-APPF-05-04/12

â&#x20AC;˘

see READMISSIONS, page 52

Drug Shortages Continue To Chip Away at Patient Care At HOPA annual meeting, pharmacists, FDA share coping strategies Orlando, Fla.â&#x20AC;&#x201D;If the start of this year is any indication, the drug shortage crisis is likely to escalate in 2012. â&#x20AC;&#x153;By about the second week of February, we already had exceeded 40 new drug shortages,â&#x20AC;? said Dan Sageser, PharmD, BCOP, clinical pharmacy supervisor at the Huntsman Cancer Institute, Salt Lake City. That placed the hospital on track to exceed the 267 drug shortages it dealt with in 2011, Dr. Sageser said during a session on drug shortages at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). APPÂŽalthough increased By early April, theoncolytics number ofsupply new up to 45% ONCOLOGY shortages atto the Institute has remained stable at 40, â&#x20AC;&#x153;we currently have 263 active 2 meet this vital need shortages we are dealing withâ&#x20AC;&#x201D;most of which are holdovers from last year. So thereâ&#x20AC;&#x2122;s not much relief in sight,â&#x20AC;? he noted via email after the HOPA meeting. t 1SPWJEJOH B CSPBE TQFDUSVN PG NVMUJTPVSDF PODPMPHZ UIFSBQFVUJDT

â&#x20AC;˘

see SUPPLY CHAIN, page 28

t "11 T DBQBCJMJUJFT TVQQPSU DPOTJTUFOU TVQQMZ JODMVEJOH o5PQPUFDBO )ZESPDIMPSJEF GPS *OKFDUJPO o(FNDJUBCJOF GPS *OKFDUJPO 641

Rivaroxaban Edges Standard Therapy for Pulmonary Embolism Regimen References: allows substantial reductions in hospital LOS 1. " NFSJDBO )PTQJUBM "TTPDJBUJPO ")" TVSWFZ PO ESVH TIPSUBHFT +VMZ

Chicagoâ&#x20AC;&#x201D;The factor Xa inhibitor rivaThe fixed-dose oral regimen could 2. %BUB PO mMF "11 1IBSNBDFVUJDBMT --$ +VOF roxaban was as effective as standard offer a viable alternative to subcutanetherapy in the treatment of pulmonary ous injections of enoxaparin and vitaembolism (PE) but yielded a 50% reduc- min K antagonist, which is complex tion in the incidence of major bleeding and requires very close monitoring, and allowed for a simplified regimen reported investigator Harry R. Buller, that enabled patients to spend less time MD, PhD, at the annual meeting of the in the hospital, according to the results American College of Cardiology (ACC). NO SHORTAGE OF COMMITMENT. of a large, multinational study. see ADVANTAGES, page 32

â&#x20AC;˘

Featured Service

GlobalHealth Education offers graduate credential in management program. See page 24.

New Product American Health Packaging introduces new unit-dose products. See page 25.

NO SHORTAGE OF COMMITMENT.