July 2015 by McMahon Group

The Pharmacist’s News Source

pharmacypracticenews.com

UP FRONT

Reader comments, tweets trending online.

CLINICAL

6 10 12 24

At ASCO, resistant lymphoma study called practice-changing. Smoldering myeloma deemed hot enough to warrant earlier Rx. Which fatty acids are best for feeding critically ill patients? IVIG treatment tips for two challenging conditions.

TECHNOLOGY

A molecular-based approach to managing drug waste.

POLICY

28 35 36

Profile: Salud embraces community care. ASHP says it’s time to get serious about provider status. Three things to know to maximize reimbursement.

OPERATIONS & MGMT

Ernie Anderson Jr. on ‘Leader Shock.’

Volume 42 • Number 7 • July 2015

Gene Sequencing Poised for Wide Use—with Limits

Switch to Bedside Drug Prep Slashes Time to Stroke Lysis

Boston—Human genome sequencing is poised to transform medical care, but it also creates new challenges for clinicians, experts said at the recent Bio-IT World Conference and Expo. What to do with incidental findings tops the list, said Robert C. Green, MD, MPH, the director of the G2P Research Program in Translational Genomics and Health Outcomes at Brigham and Women’s Hospital and Harvard Medical School, in Boston. Last summer, Dr. Green and his colleagues wrote about diagnostic clinical genome and exome sequencing ((N Engl J Med d 2014;370[25]:24182425). “This article was framed as an announcement to the [clinicians] of the world, saying, ‘Hey, [genetic] sequencing is here, and you too can use it. We think that it is something that everybody is going to be applying in their day-to-day practice.’” When this happens, clinicians will have to understand and communicate incidental findings.

Denver—Before revamping their acute stroke response process in June 2014, emergency department providers at Lutheran Medical Center in Wheat Ridge, Colo., were averaging a 59-minute door-to-needle time for alteplase use—just shy of the American Heart Association’s recommended 60 minutes. After the revamp, the center reduced median door-to-needle times by 32%, to an awardwinning 40 minutes—and even nine minutes in one instance, according to data presented at the American Society of Health-System Pharmacists 2015 Summer Meeting (poster 40-T).

see GENE SEQUENCING, page 16

see STROKE, page 3

Report From ASCO:

Rate of liver damage from supplements quadruples

Combo Therapy A New Standard For Melanoma

Patients, Clinicians Face ‘Growing Challenge’ of Harmful Diet Aids

Chicago—In previously untreated patients with metastatic melanoma, an ipilimumab/nivolumab combination provided a nearly 60% increase in progression-free survival (PFS) relative to ipilimumab alone. Drawn from a Phase III trial called CheckMate 067, the data were characterized as setting a new treatment standard. “Based on the results of nivolumab alone and nivolumab plus ipilimumab arms relative to ipilimumab and see MELANOMA, page 8

Bethesda, Md.—A decade ago, roughly 5% of liver injuries were attributable to herb and dietary supplements. Since then, that figure has quadrupled, health officials say. As concern over the surging caseload mounts, a related danger is surfacing: There is a significant knowledge gap regarding how best to diagnose and track these adverse reactions. In fact, assessing liver injury related to supplements remains vexing for clinicians around the world, according to researchers who spoke about the problem at a workshop sponsored by the National Institute of

New Product

Teva launches generic version of Lomedia 24 Fe Tablets. See page 9

Diabetes and Digestive and Kidney Diseases (NIDDK) and the American Association for the Study of Liver Diseases. “It’s a growing challenge,” said Jay Hoofnagle, MD, director of the liver disease research branch at NIDDK. Dietary supplements often contain multiple ingredients and can vary from batch to batch, experts note. Product labels do not always accurately reflect the contents. Moreover, many patients take multiple supplements and don’t always report this to see LIVER INJURY, page 21

Get the App

Kcentra

WHEN PATIENTS NEED URGENT WARFARIN REVERSAL…

plex m o C n i hromb l t o r P r ersa -Facto v 4 e R y l n n i arfar and O W t s t r i n F e a—the -PCC) for Urg r t n e c K (4F e t a r t n Kcentra—Ready When You Need It Conce Important Safety Information Kcentra is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA—eg, warfarin) therapy in adult patients with acute major bleeding or the need for urgent surgery or other invasive procedure. Kcentra is for intravenous use only. WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the risk of thromboembolic events, especially in patients with history of such events. Resumption of anticoagulation therapy should be carefully considered once the risk of thromboembolic events outweighs the risk of acute bleeding. Both fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance. Monitor patients receiving Kcentra, and inform them of signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra might not be suitable for patients with thromboembolic events in the prior 3 months. Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any of its components (including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin). Kcentra is also contraindicated in patients with disseminated intravascular coagulation. Because Kcentra contains heparin, it is contraindicated in patients with heparin-induced thrombocytopenia (HIT). Hypersensitivity reactions to Kcentra may occur. If patient experiences severe allergic or anaphylactic type reactions, discontinue administration and institute appropriate treatment. In clinical trials, the most frequent (≥2.8%) adverse reactions observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia. The most serious adverse reactions were thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis. Kcentra 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. The safety and efficacy of Kcentra in pediatric use have not been studied, and Kcentra should be used in women who are pregnant or nursing only if clearly needed. Please see brief summary of full prescribing information on reverse.

The ﬁrst and only non-activated 4F-PCC for urgent warfarin reversal in adult patients with: – Acute major bleeding or – Need for an urgent surgery/invasive procedure Mean infusion time ~7x faster than plasma Room temperature storage for 36 months

Kcentra has over 15 years of clinical experience as Beriplex® outside the US. www.Kcentra.com Kcentra Hotline: 1-855-4KCENTRA (1-855-452-3687)

Urgent Warfarin Reversal Kcentra is manufactured by CSL Behring GmbH and distributed by CSL Behring LLC. Kcentra® and Beriplex® are registered trademarks of CSL Behring GmbH. ©2015 CSL Behring LLC 1020 First Avenue, PO Box 61501, King of Prussia, PA 19406-0901 USA www.CSLBehring-us.com www.Kcentra.com KCT15-01-0006 3/2015

Up Front 3

Pharmacy Practice News • July 2015

Clinical

STROKE continued from page 1

Maury Otterstetter, RPh, a clinical pharmacist at Lutheran Medical Center, worked with a neurologist, a stroke care coordinator, an emergency department representative and a computed tomography (CT) technician to revise their acute ischemic stroke response process. “We used Lean methodology to pick the process apart, and we found two unnecessary steps that we could avoid,” he said. The first process change they made

was to immediately administer CT, rather than take stroke patients to a room, change beds and move on to CT, as they had been doing, Mr. Otterstetter said. “The one thing we identified from a pharmacy standpoint was that we could probably administer the drug faster by preparing the alteplase at the bedside,” he added. To accommodate this second change, the emergency department now has a “stroke emergency box” containing alteplase and pharmacy supplies to prepare the agent (photo). Bedside pharmacist attendance also

KCENTRA® (Prothrombin Complex Concentrate [Human]) For Intravenous Use, Lyophilized Powder for Reconstitution Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Kcentra safely and effectively. See full prescribing information for Kcentra. WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thromboembolic events. Potential beneﬁts of reversing VKA should be weighed against the potential risks of thromboembolic events, especially in patients with the history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding. • Both fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. • Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. ---------------------------------INDICATIONS AND USAGE-----------------------------------Kcentra, Prothrombin Complex Concentrate (Human), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deﬁciency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with: • acute major bleeding or • need for an urgent surgery/invasive procedure. -----------------------------DOSAGE AND ADMINISTRATION--------------------------------For intravenous use only • Kcentra dosing should be individualized based on the patient’s baseline International Normalized Ratio (INR) value, and body weight. • Administer Vitamin K concurrently to patients receiving Kcentra to maintain factor levels once the effects of Kcentra have diminished. • The safety and effectiveness of repeat dosing have not been established and it is not recommended. • Administer reconstituted Kcentra at a rate of 0.12 mL/kg/min (~3 units/kg/min) up to a maximum rate of 8.4 mL/min (~210 units/min.).

Pre-treatment INR

improves the safety of alteplase administration, Mr. Otterstetter explained. Now, they record the patient’s weight, blood pressure and blood sugar, his or her medication history and identify any contraindications to alteplase use, such as recent use of anticoagulants or recent surgeries. “We also have one final check-in with the neurologist to confirm the drug is being given to the right patient at the right dose and that there are no contraindications,” he said. According to data collected between January and December 2014, the new

2–<4

4–6

Dose* of Kcentra (units† of Factor IX) / kg body weight

Maximum dose‡ (units of Factor IX)

Not to exceed 2500

Not to exceed 3500

Not to exceed 5000

* Dosing is based on body weight. Dose based on actual potency as stated on the carton, which will vary from 20-31 Factor IX units/mL after reconstitution. Nominal potency is 500 or 1000 units per vial, approximately 25 units per mL after reconstitution. † Units refer to International Units. ‡ Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded.

--------------------------------DOSAGE FORMS AND STRENGTHS-------------------------• Kcentra is available as a single-use vial containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S as a lyophilized concentrate. -------------------------------------CONTRAINDICATIONS ------------------------------------Kcentra is contraindicated in patients with: • Known anaphylactic or severe systemic reactions to Kcentra or any components in Kcentra including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin. • Disseminated intravascular coagulation. • Known heparin-induced thrombocytopenia. Kcentra contains heparin. --------------------------------WARNINGS AND PRECAUTIONS-----------------------------• Hypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment. • Arterial and venous thromboembolic complications have been reported in patients receiving Kcentra. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thrombotic or thromboembolic (TE) event within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. • Kcentra is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. ------------------------------------ADVERSE REACTIONS--------------------------------------• The most common adverse reactions (ARs) (frequency *2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia. • The most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis. To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-9156958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------------USE IN SPECIFIC POPULATIONS---------------------------------Pregnancy: No human or animal data. Use only if clearly needed. Based on March 2014R version.

process led to an immediate drop in median door-to-needle times, Mr. Otterstetter reported. In the case where alteplase was administered within nine minutes of presentation, he noted, teamwork was key. “In this and a couple of other exceptionally fast cases, we had our neurologist onsite rather than on camera, which eliminated delays in communication, and we also gave the medication while the patient was undergoing CT,” he explained. The initiative has won the team an American Heart Association Gold Plus Quality Award, which recognizes institutions that administer thrombolytic therapy within 45 minutes of presentation in at least 50% of their acute ischemic stroke patients. The team did not collect data on clinical outcomes, but Dr. Daley pointed out that earlier thrombolytic therapy is associated with better patient outcomes. He cited, as an example, a large registry study ((JAMA 2013;309:2480-2488) that showed that each 15-minute interval

A “stroke emergency box” containing alteplase and pharmacy supplies to prepare the agent can help speed drug delivery to patients at the bedside.

reduction in onset to thrombolytic treatment was associated with reduced inhospital mortality (odds ratio [OR], 0.96; 95% CI, 0.95-0.98; P<0.001) and symptomatic intracranial hemorrhage (OR, 0.96; 95% CI, 0.95-0.98; P<0.001) while increasing patients’ ability to ambulate independently at discharge (OR, 1.04; 95% CI, 1.03-1.05; P<0.001) and be discharged home (OR, 1.03; 95% CI, 1.021.04; P<0.001). “Results like these can be used to justify maintaining existing pharmacist roles and expanding them to other roles in the emergency department,” commented Mitchell Daley, PharmD, a network clinical pharmacy specialist in critical care at the University Medical Center Brackenridge in Austin, Texas, who was not involved in the research. “The results are not only clinically significant, but also meaningful for hospital administrators focused on ensuring compliance with Joint Commission core measures, such as the timing for thrombolytic administration in ischemic stroke.” —David Wild Mr. Otterstetter and Dr. Daley reported no relevant ﬁnancial conﬂicts of interest.

4 Up Front

Pharmacy Practice News • July 2015

Digital

Online www.pharmacypracticenews.com Only on the Web!

Reader Comments

Visit us online for Web-exclusive content. Links to the articles below can be found at pharmacypracticenews.com/webex0715 or by scanning the adjacent 2D barcode. Be sure to check the Pharmacy Practice News site every day for late-breaking news!

Re: Founding Dean Makes the Case for New Pharmacy School (May 2015)

othing said here is any different than what the existing 134 schools are trying to do, at a higher cost of $67,000. To say we could use another pharmacy school is disingenuous at best and one has to consider whether they would want to attend a program that insists there is a need for another school. Of course, no other pharmacy school will come out and say we don’t need anymore for the sake of their own programs, but anyone can look at the numbers and see the forming cliff for the profession.

New Tool May Help Reduce Prescription Misuse, Abuse

—tcwch... posted: 5/20/2015

he Alliance for Balanced Pain Management has launched a new educational tool, entitled “Are You the Only One Taking Your Medicine?” that consumers and health care providers can use to assess whether a home is at risk for medication misuse, abuse or diversion.

Sandoz Launches Glatopa In the United States

andoz announced the U.S. launch of Glatopa, the first generic version of Teva’s Copaxone (glatiramer acetate injection) 20 mg/mL once-daily medication for multiple sclerosis (MS). The FDA approved Glatopa for the treatment of patients with relapsing forms of MS, including those who have experienced a first clinical episode and have features consistent with MS on magnetic resonance imaging.

Re: Making Medication Reconciliation More Exact (May 2015)

ore studies and still no tools to do the job! We already know that our patients are taking too many medications that are often in conflict with their condition and age. In an era where your phone can predict what you are going to type next, you’d think that systems could be designed by now which recognize problems within a medication profile, including those related to disease states and physiologic parameters. And it’s not as if there is more money for another Candy Crush app iteration versus a useful medication management tool; we just seem unable to dive in and create useful, cross-platform programs that recognize and prevent medication errors. By the way, blindly following the Beers Criteria as a guide for steering clear of problematic medication in the elderly is a recipe for unnecessary effort and failed interventions. The National Comprehensive Cancer Network has yet to provide a clear and evidence-based guideline for preventing venous thromboembolisms in patients with a wide variety of solid and hematologic malignancies. So I am not holding my breath for this area of research to affect care in the next decade.

—tmccl... posted: 5/19/2015

Tweets of Interest #PharmPracNews

Proton Pump Inhibitors Linked To Heart Attack

roton pump inhibitors, commonly prescribed for gastroesophageal reflux, erosive esophagitis and other causes of pyrosis, have been associated with an increased risk for myocardial infarction, according to investigators at Stanford University, in California.

EDITORIAL BOARD

ART/PRODUCTION STAFF Michele McMahon Velle, MAX Graphics/Creative Director

ADMINISTRATION

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

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

Volume 42 • Number 7 • July 2015 • pharmacypracticenews.com

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

INTERNAL MEDICINE

EDITORIAL STAFF

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

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

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

NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

BIOTECHNOLOGY

Jeffrey Norenberg, PharmD, Albuquerque, NM

Indu Lew, PharmD, Livingston, NJ

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

CARDIOLOGY C. Michael White, PharmD, Storrs, s CT CNS/PSYCHIATRY

Robert Ignoffo, PharmD, San Francisco, CA

Kevin Horty, Don Pizzi, Adam Marcus, Contributing Editors

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

James Prudden, Group Editorial Director

Cindy O’Bryant, PharmD, Aurora, CO

Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, Texas Larry Ereshefsky, PharmD, San Antonio, T Texas

Marie Rosenthal, MS, Senior Editor mrosenthal@mcmahonmed.com

COMPLEMENTARY AND ALTERNATIVE MEDICINE

ORGAN TRANSPLANT PHARMACY

Cathy Rosenbaum, PharmD, Cincinnati, OH

Eric Tichy, PharmD, BCPS, New Haven, CT

CRITICAL CARE

PEDIATRICS

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

INFECTIOUS DISEASES

REIMBURSEMENT

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH

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

McMAHON PUBLISHING Raymond E. McMahon, Publisher and 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

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 06896

David Kaplan, Group Publication Director dkaplan@mcmahonmed.com Matt Spoto, Senior Account Manager mspoto@mcmahonmed.com Lillie Onday, Account Manager londay@mcmahonmed.com

David P. Nicolau, PharmD, Hartford, CT

TECHNOLOGY

Robert P. Rapp, PharmD, Lexington, KY

Thomas Van Hassel, RPh, Yuma, AZ

Craig Wilson, Sales Associate, Classified Advertising cwilson@mcmahonmed.com

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 Publishing, 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 42-year-old, first-generation, family-owned publishing company dedicated to providing medical professionals with essential, up-to-date news. As

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

Marty Barbieri, Production Manager Brandy Wilson, Circulation Coordinator

Elizabeth Zhong, Associate Copy Chief

Ali McBride, PharmD, MS, BCPS, St. Louis, MO Sara S. Kim, PharmD, BCOP, New York, NY

James O’Neill, Senior Systems Manager Dan Radebaugh, Director of Production and Technical Operations

Copyright © 2015 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.

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 and Specialty Pharmacy Continuum.

6 Clinical

Pharmacy Practice News • July 2015

Oncology

GADOLIN Called Practice-Changing Trial for Indolent NHL Chicago—Results from the international Phase III GADOLIN trial show that obinutuzumab plus bendamustine followed by obinutuzumab maintenance is an effective treatment option for patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL) who do not respond to rituximab. The combination therapy at least doubles progression-free survival (PFS) compared with bendamustine monotherapy. “This represents the first randomized controlled trial data that demonstrates the utility of a novel anti-CD20 monoclonal antibody in patients with rituximab-refractory lymphoma,” said Laurie Sehn, MD, MPH, a medical oncologist at the BC Cancer Agency, in Vancouver, Canada. She presented the findings at the 2015 annual meeting of the American Society of Clinical Oncology (abstract LBA8502). Grzegorz Nowakowski, MD, a hematologist/oncologist at Mayo Clinic in Rochester, Minn., who was not involved with the research, called GADOLIN “a practice-changing study for patients with rituximab-refractory disease.” He added that the obinutuzumab (Gazyva, Genentech) regimen used in the trial “provides significant [PFS] benefit, and it doesn’t do it at increased toxicity.” In the GADOLIN trial, 413 patients with rituximab (Rituxan, Genentech)-refrac-

tory CD20+ iNHL were randomized to receive obinutuzumab—a monoclonal antibody already approved for use in combination with chemotherapy for chronic lymphocytic leukemia—plus bendamustine (Treanda, Cephalon) (n=194), or bendamustine alone (n=202). Patients in the obinutuzumab arm who achieved a complete response, partial response or stable disease (n=143) received maintenance therapy with obinutuzumab for two years or until disease progression. The investigators assessed response by computed tomography scan postinduction, every three months for two years, and then every six months. At the primary interim analysis, 46 of the 143 patients who had started maintenance therapy were still on it and 35 had completed maintenance. The primary end point was PFS, as assessed by an independent radiology facility. The facility-assessed median PFS was 14.9 months in the monotherapy arm and, with a median follow-up of 21 months, had not been reached in patients receiving obinutuzumab plus bendamustine (hazard ratio, 0.55; P=0.0001). The median PFS was significantly higher among patients receiving obinutuzumab (29.2 vs. 14 months; P<0.0001). There were no differences in response rates between the two arms. Rates of adverse events (AEs), serious

Table. Common Grade 3/4 Adverse Events AE, %

Obinutuzumab + Bendamustine

Bendamustine

Grade 3/4 neutropenia

Grade 3/4 thrombocytopenia

Anemia

Infusion-related reactions

≥1 serious AE

≥1 grade 3/4 AE

≥1 AE leading to dose modification

AE,, adve adverse se eve eventt

AEs, grade ≥3 AEs, deaths and withdrawals from therapy were similar in both arms (Table). Dr. Nowakowski said the fact that there were no differences in response rates raises the question of how much of the improvement is caused by the maintenance therapy versus the induction therapy, especially since the PFS survival curves begin to separate at the end of induction therapy. He also pointed out that, based on Medicare average sales price, the experimental arm would cost about $95,000 more than the bendamustine-alone arm ($157,608 vs. $65,677). However, this

does not consider the cost of subsequent therapy in patients who relapse in the bendamustine arm. “You need an analysis of the whole cost of caring for the patient, because it is very likely that patients who relapse early require subsequent, and sometimes more aggressive, therapies, such as transplant, etc.,” he noted. “The costs of treating with bendamustine alone could be much higher.” —Kate O’Rourke Dr. Sehn reported a ﬁnancial relationship with Genentech. Dr. Nowakowski reported ﬁnancial relationships with Celgene and MorphoSys.

Adding Ibrutinib Is Beneficial in Previously Treated CLL Chicago—The addition of ibrutinib reduces the risk for death or disease progression over that provided by bendamustine and rituximab (BR) alone in previously treated chronic lymphocytic leukemia (CLL) and small mall lymphocytic lymphoma (SLL), accorrding to results of a Phase III trial. “These results dem-onstrate that ibrutinib plus BR is superior to o the current standard of o care, which is BR alone, in previously treated CLL L/SLL patients,” reported Asheer ChananKhan, MD, the chair of hematology/ oncology at Mayo Clinic in Jacksonville, Fla., who presented the results of this study, called HELIOS, at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA7005). Ibrutinib (Imbruvica, Pharmacyclics/ Janssen), a Bruton tyrosine kinase (Btk) inhibitor, has demonstrated promise in previous CLL/SLL studies, but HELIOS is the first randomized, placebo-controlled trial in which the addition of ibrutinib was compared directly with chemotherapy alone. In this study, which

involved centers in 21 countries, 578 previously treated patients with CLL or SLL were randomized to receive a conventional regimen of BR with 420 mg of ibrutinib or placebo. Patients remained on ibrutinib or pla placebo after completing six cycles of BR until disease progression. The primary eend point was progreession-free survival (PFS S). Fo or PFS, which was valid dated by an independ dent review committee (IRC), the hazard ratio (HR) of 0.201 ((P<0.0001) represented an 80% reduction relative to BR alone. At 18 months, PFS rates for the ibrutinib and placebo groups were 79% and 24%, respectively. “The advantage of ibrutinib was noticeable as early as four months into the assessment of disease response,” Dr. Chanan-Khan reported. Ibrutinib also produced significantly higher objective response rates (ORR), whether assessed by the investigators or the IRC. On IRC evaluation, these

rates were 82.7% and 67.8% ((P<0.0001) for ibrutinib and placebo, respectively. The median overall survival (OS) has not been reached in either treatment arm after a median follow-up of 17 months, but the more than 35% improvement in survival has produced a trend favoring ibrutinib (HR, 0.63; P=0.0598). This trend was observed even though 90 of the placebo patients (31%) crossed over to ibrutinib after disease progression. Also notably, minimal residual disease (MRD) was achieved in 12.8% of patients receiving ibrutinib versus 4.8% of those receiving placebo ((P=0.0011). Of patients who achieved a complete response (CR) on either therapy, about half achieved MRD. Most adverse events (AEs) overall and most grade 3 or higher AEs were related to BR. Any differences in which grade 3 or higher events were more common with ibrutinib were modest; these included diarrhea (2.1% vs. 1.4%), pyrexia (3.5% vs. 1.7%) and headache (1.7% vs. 0%). There were, however, two AEs specifically linked to ibrutinib. Bleeding of any grade occurred in 31% of ibrutinibtreated patients versus 14.6% of placebo patients, but the difference in major

hemorrhage was more modest (3.8% vs. 1.7%). Atrial fibrillation (AF) occurred in 7.3% of patients taking ibrutinib versus 2.8% of those in the placebo group. Grade 3 or higher AF occurred in 2.8% and 0.7% of the patients in the ibrutinib and placebo groups, respectively. Dr. Chanan-Khan noted that a previous history of AF was not a predictor of AF with ibrutinib. The ASCO-invited discussant, Lloyd E. Damon, MD, the director of hematologic malignancies and bone marrow transplant, at the University of California, San Francisco, said he considered the HELIOS data useful for deciding treatment strategies for patients with advanced CLL. As for future research on treatment options for these challenging patients, Dr. Damon said he is looking forward to studies evaluating whether immunochemotherapy can be omitted altogether. —Ted Bosworth Dr. Chanan-Khan reported no relevant financial relationships. Dr. Damon reported financial relationships with Actelion, Boston Scientific, Gilead and Sunesis.

ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY ONE UNIT ONE DOSE ONE AND ONLY

0.5 mL each

An Innovative Non-Aerosol Unit Dose Topical Anesthetic Spray t .FFUT +PJOU $PNNJTTJPO 4UBOEBSE GPS UIF NPTU SFBEZ UP BENJOJTUFS GPSN BWBJMBCMF t 'BTU POTFU 4IPSU EVSBUJPO 7JSUVBMMZ OP TZTUFNJD BCTPSQUJPO t 6UJMJ[FT CBS DPEF NFEJDBUJPO BENJOJTUSBUJPO #$." UP BDDPNNPEBUF QPJOU PG DBSF TDBOOJOH t 7JSUVBMMZ FMJNJOBUFT BEWFSTF FWFOUT SFTVMUJOH GSPN QSFWFOUBCMF NFEJDBUJPO FSSPST FOTVSJOH UIF i 3JHIUTw BSF NFU √ 3JHIU %SVH √ 3JHIU 1BUJFOU √ 3JHIU %PTF √ 3JHIU 3PVUF √ 3JHIU 5JNF t 4JOHMF VOJU PG VTF QBDLBHJOH FMJNJOBUFT UIF QPUFOUJBM GPS DSPTT DPOUBNJOBUJPO t *ODSFBTFT CJMMJOH BDDVSBDZ BOE JNQSPWFT TVQQMZ DIBJO DPTUT ORDERING INFORMATION NDC#

AMERISOURCE BERGEN

CARDINAL HEALTH

MCKESSON

MORRIS & DICKSON

PRODUCT

$*/

)VSSJ$BJOF 0/& 6OJU %PTF /PO "FSPTPM 4QSBZ #PY PG þ P[ N- FBDI

$*/

)VSSJ$BJOF 0/& 6OJU %PTF /PO "FSPTPM 4QSBZ #PY PG þ P[ N- FBDI

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

MAKE THE SWITCH TODAY.

LLC

$BMM UP QMBDF ZPVS PSEFS PS SFRVFTU NPSF JOGPSNBUJPO XXX CFVUMJDI DPN )VSSJ$BJOF 0/& JT B SFHJTUFSFE USBEFNBSL PG #FVUMJDI® 1IBSNBDFVUJDBMT --$ )$0"

8 Clinical

Pharmacy Practice News • July 2015

Oncology

MELANOMA continued from page 1

the prior study comparing pembrolizumab to ipilimumab, it is my opinion that ipilimumab alone can no longer be considered a standard first-line immunotherapy for patients with advanced melanoma,” asserted Michael B. Atkins, MD, the deputy director of Georgetown University’s Lombardi Comprehensive Cancer Center, in Washington, D.C., who was the invited discussant for this trial at the 2015 annual meeting of the Ameri-

minimum size maximum performance

can Society of Clinical Oncology (ASCO), where the data were presented during the plenary session (abstract LBA1). The study, which was published simultaneously in The New England Journal of Medicine (2015 May 31. [Epub ahead of print]), was supported by Bristol-Myers Squibb. In this trial, presented by Jedd D. Wolchok, MD, the chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan-Kettering Cancer Center, in New York City, 945 previously untreated patients with unresectable stage III or IV melanoma were randomized to the CTLA-4 checkpoint inhibitor ipilimumab (Yervoy, BristolMyers Squibb) alone, the PD-1 checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) alone, or a combination of the two. Both medications have indications for melanoma, but they had not been evaluated in combination in a Phase III trial.

KEY

Findings 12-month PFS (in months)

Refrigeration performance you need in a space-saving footprint you want y

forced-air cooling for high performance temperature control 1 and 2 cubic foot models for smaller storage needs intuitive user interface for ease of use

See the new compact freezer models at follettice.com/freezer or call 800.523.9361 for more information

Pharmacy | Patient care | Clinic | Surgery center

2.9 | Ipilimumab 6.9 | Nivolumab 11.5 | Combination therapy Biggest gainers:

14% PFS in patients with greater than 5% PD-L1 expression, treated with either nivolumab alone or combination therapy.

After a median follow-up of slightly more than a year, the PFS rates were highest in the combination arm (box). The PFS advantage of the combination treatment was consistent across a large number of subgroups, including BRAF F mutation status and PD-L1 expression. However, greater than 5% PD-L1 expression was a factor in relative PFS rates. In patients whose tumors had greater than 5% PD-L1 expression, the median PFS was 3.9 months in the ipilimumab-alone group but 14 months in both the combination group and the nivolumab-alone group. In patients with tumors with less than 5% PD-L1 expression, the median PFS was 2.8 months with ipilimumab alone, 5.3 months with nivolumab alone and 11.2 months with the combination. Investigator-assessed objective response rates (57.6%) and complete response rates (11.5%) were also higher with the combination treatment relative

Clinical 9

Pharmacy Practice News • July 2015

Oncology These results are ‘the latest in a series of breakthroughs’ that have dramatically changed the prognosis of a cancer for which the median survival just five years ago was six to nine months. —Michael B. Atkins, MD work needs to be done on biomarkers to predict response and to explore whether alternative ipilimumab schedules or substitution of other immunotherapies for ipilimumab could improve

the therapeutic effectiveness of this combination. However, he considered these results to be “the latest in a series of breakthroughs” that have dramatically changed the prognosis of a cancer

”

” < IO @M J J H

B DI B DI 03 4 R %0

IV solutions that fit.

G < R IO GJ J A DU M <M ? J J C HDI J C G<

™

eva Pharmaceutical Industries Ltd. announced the launch of the generic equivalent of Lomedia 24 Fe (norethindrone acetate and ethinyl estradiol tablets USP, 1 mg/20 mcg and ferrous fumarate tablets, 75 mg) as part of its extensive line of Women’s Health products. The product was launched under the name Junel Fe 24 (norethindrone acetate and ethinyl estradiol tablets USP and ferrous fumarate tablets) and is now available in the United States. “Teva recognizes that women’s needs change over time and the portfolio of Women’s Health products is positioned to support women through many stages of life,” the company stated in a press release. “With the addition of Junel Fe 24, Teva can offer women a comprehensive line of nearly 30 generic contraceptive products.” Junel Fe 24 is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Dr. Wolchuk reported financial relationships with Bristol-Myers Squibb, EMD Serono, GlaxoSmithKline, Janssen, Jounce Therapeutics, Medimmune, Merck, Polaris, Polynoma Potenza Therapeutics, Vesuvius and Ziopharm Oncology. Dr. Atkins reported financial relationships with Alkermes, Amgen, Bristol-Myers Squibb, C-Cam, Costim, Genentech, GlaxoSmithKline, Infinity, Lilly, Merck, Neostem, Novartis, Pfizer and X4.

Teva Launches Generic Version of Lomedia 24 Fe

—Ted Bosworth

TI TA

NEW PRODUCT

for which the median survival just five years ago was six to nine months.

.S i.v

to nivolumab alone (43.7% and 8.9%) and ipilimumab alone (19% and 2.2%). The combination was less well tolerated than either immunotherapy alone. Discontinuations due to adverse events (AEs) occurred in 36.4% of patients in the combination arm versus 7.7% of those receiving nivolumab alone and 14.8% of those receiving ipilimumab alone. The grade 3 or higher AEs that occurred more commonly with the combination relative to nivolumab alone and ipilimumab alone, respectively, included diarrhea (9.3% vs. 2.2% and 6.1%), rash (4.8% vs. 0.6% and 1.9%), fatigue (4.2% vs. 1.3% and 1.0%), vomiting (2.6% vs. 0.3% and 0.3%) and liver enzyme abnormalities (6.1% vs. 1.0% and 0.6%). However, immune-modulatory agents— used in nearly half of patients receiving nivolumab alone, more than half of those receiving ipilimumab alone and nearly 85% of those receiving both agents— were effective in modifying the intensity of these AEs, according to Dr. Wolchok. Overall survival data from this trial are pending, but, as noted by Dr. Atkins, the data are already sufficiently compelling to suggest a new standard of care. According to Dr. Atkins, more

Fit your space With the smallest footprint, you’ll minimize renovation expenses and maximize scalability.

Fit your budget Lower cost puts advanced technology within your reach.

Fit your goals Integrated solutions enable you to enhance patient safety across your pharmacy.

Call 724-741-6780 or visit www.aesynt.com/ivsolutionsﬁt to learn more.

For more information, visit http://www.tevapharm.com.

i.v.STATION™

i.v.STATION ONCO™

i.v.SOFT®

10 Clinical

Pharmacy Practice News • July 2015

PPN: The Conversation

Smoldering Myeloma Patients Getting Attention

hile attending the Hematology/Oncology Pharmacy Association meeting, senior editor Marie Rosenthal, MS, sat down with Ashley E. Glode, PharmD, BCOP, assistant professor in the Department of Clinical Pharmacy at Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of Colorado, to talk about the new criteria for diagnosing multiple myeloma and what that will mean for pharmacists and the patients in their care. Q: The International Myeloma Working Group updated its criteria for multiple myeloma (MM) and it has been called a paradigm shift. How will these new guidelines change the management of MM? Dr. Glode: This is definitely an exciting change because the criteria have not been updated in several years. The biggest change is that patients who previously would have been diagnosed as having smoldering or asymptomatic disease are now going to be classified as having myeloma and will receive treatment. [The guidelines] have incorporated the use of MRI [magnetic resonance imaging scan] in the diagnosis, so patients need to have at least one focal lesion, detected

on an MRI of the bone, to be diagnosed. [Patients] also can be diagnosed by having a free light chain ratio present of 100 mg/L or greater, or a clonal bone marrow plasma cell percentage of 60% or higher. Q: Will there still be instances where you still will do watchful waiting? Dr. Glode: Yes, the patients who do not meet the high-risk criteria will still be in a smoldering category and won’t receive treatment. In the clinical trials, looking only at the plasma percentage, only 3% to 5% met the new diagnostic criteria and progressed to symptomatic myeloma within two years. Q: Several new treatments have been developed for MM, which is

encouraging for patients, but that means a larger population are now candidates for therapy. Will this pose any practice challenges? Dr. Glode: You are talking about patients who will undergo therapy for years longer than before. Long-term toxicities of these therapies as well as supportive therapies will be a big issue, and there will be a role for pharmacists in helping to manage these toxicities. Q: Now that MRI is being included for diagnosis, and patients are going to be in treatment for two years or so longer than before, won’t this increase the cost of managing MM? Dr. Glode: Definitely, some of these new regimens are also oral therapies and we are dealing with REMS [Risk Evaluation and Mitigation Strategies] and patient assistance programs to help individuals get these treatments and help them stay on them for maintenance if that is indicated. Oral chemotherapy counseling will be important. We have to help patients manage their medications at home and

Exclusive Video

Watch Ashley E. Glode, PharmD, from the University of Colorado, discuss the changing paradigm for multiple myeloma treatment. To access, visit www.specialtypharmacy continuum.com/GlodeVideo.

follow up with them on a regular basis. We also have to start thinking about the long-term quality of life for these patients. What is the role for transplant? Should they also undergo an autologous stem cell transplant, as traditional MM patients are treated? This is an exciting time, and I hope we can improve patients’ overall survival and quality of life.

New Dx Criteria From Myeloma Working Group Change Practice

recent redefinition of multiple myeloma (MM) allows patients to be diagbegin,” Dr. Rajkumar said. nosed and treated before they show signs of the disease’s most problematic With the redefinition of MM, the definition of smoldering MM (SMM) also characteristics. has changed. An SMM classification is now a patient having 10% to 60% clonal The guidelines, created by members of the International Myeloma Working plasma cells without evidence of CRAB or other MM-defining characteristics. Group (IMWG), represent a paradigm shift away from an earlier era in which The rationale for this update in definitions arose from the fact that MM patients were required to show end-organ damage, hypercalcemia, anemia and remained unique among cancers in that it required patients to develop endbone lesions (CRAB features; see box) before their condition was considered a organ damage before they could be diagnosed and treated. “Part of the reacancer and treated as such (Lancet Oncoll 2014;15[12]:e538-e548). son myeloma lagged behind was the thought that many patients with SMM “The criteria now allow early diagnosis, prior to symptoms,” said could go years without needing therapy,” Dr. Rajkumar said. “Another concern S. Vincent Rajkumar, MD, a professor of medicine at was over the toxicity of the treatment.” Mayo Clinic, in Rochester, Minn., and the lead author Today, however, both concerns are mitigated of the guidelines. because researchers have identified biomarkers to The new guidelines add three new criteria to the more accurately pinpoint the patients with SMM that existing definition of MM. These new myeloma-defining are likely to progress. In addition, current therapies events are the presence of 60% or more bone marrow are well tolerated and can more than double the surplasma cells, abnormal free light change ratio of 100 or vival rate of MM patients. greater, and more than one focal lesion found on mag“Also, we had a randomized trial in high-risk SMM netic resonance imaging. patients that showed early therapy can improve surThe presence of these three new MM-defining vival, further alleviating concerns about overtreatevents is associated with an ultra-high risk for develment,” Dr. Rajkumar said, referring to a Spanish trial oping end-organ damage from the malignancy, that compared lenalidomide with observation (N approximately 80% within two years, according to Dr. Engl J Med d 2013;369[5]:438-447). Rajkumar, who added that there is no reason to delay With the bar lowered for diagnosing MM, some of therapy. “Treating such patients would prevent serious the controversy over what to do for SMM patients end-organ damage,” he said. has abated. “The highest-risk SMM patients are now The IMWG also clarified that bone disease in MM considered multiple myeloma patients,” Dr. Rajkualcium elevation in the blood: can be determined not just by skeletal survey but mar said. “The extension of the multiple myeloma serum calcium >11.5 mg/dL also by magnetic resonance imaging (MRI), computed diagnostic criteria takes the pressure off treatment tomography (CT) or positron emission tomography decisions for patients with SMM, but there will still (PET) scans, and that renal disease can be identified be some patients for whom we are nervous about enal insufficiency: serum not only by serum creatinine levels but also by creatiwaiting and watching,” Dr. Rajkumar said. creatinine >2 mg/dL nine clearance. —Monica J. Smith “As a result of all these changes, we believe that myeloma will be diagnosed in a timely manner and nemia: hemoglobin <10 g/dL that patients will be spared the trauma of having to Dr. Rajkumar reported no relevant or 2 g/dL below normal wait until organ damage happens before therapy can ﬁnancial conﬂicts of interest.

Defining CRAB

one: (lytic) lesions or osteoporosis

www.equashield.com

Shouldnâ&#x20AC;&#x2122;t using the safest Closed System be this simple?

Safe. Simple. Closed. The Leading Closed System Transfer Device for Healthcare Professionals

12 Clinical

Pharmacy Practice News • July 2015

Nutrition

Choosing the Right Fatty Acid for Critical Care Feeding Long Beach, Calif.—When a patient with a soy allergy came to her hospital for a bone marrow transplant in 2002, Kathleen Gura, PharmD, couldn’t just reach for her go-to IV fat emulsion. The long-time standard is based on soybean oil. So, instead, she opted to treat her patient with pure fish oil. “It worked,” recalled Dr. Gura, a clinical pharmacist with the Gastroenterology and Clinical Nutrition Service and

the team leader for surgical programs at Boston Children’s Hospital. Furthermore, fish oil emulsions seemed to benefit subsequent patients she treated—in some cases, even correcting liver malfunction. It soon appeared to Dr. Gura that substitute emulsions might be ideal for more than just patients who couldn’t tolerate soy. She, along with surgeon Mark Puder, MD, PhD, decided to investigate further.

“Because nothing is perfect, I looked into other oil sources like olive oil, too,” she said. In February, at the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) annual conference, Dr. Gura was among several researchers who discussed evolving knowledge about how certain nutrient choices—from alternative oil sources in IV fat emulsions to immune-modulating high-protein

Medfusion® 4000 Wireless Syringe Infusion Pump and PharmGuard® Infusion Management Software

Divergent Data?

Advanced infusion integration elevating quality of care across the hospital network Medfusion® 4000 wireless syringe infusion pumps are now interoperable, allowing auto-charting of infusion data into a hospital’s electronic medical record (EMR). Infusion therapy data is sent wirelessly from a Medfusion® 4000 pump to a hospital’s server via PharmGuard® Server software. The new PharmGuard® Interoperability software add-on module for the PharmGuard® Server software now takes that information one step further by automatically charting it directly into patient records on the hospital’s EMR system via Integrating the Healthcare Enterprise (IHE) Integration Profiles.

enteral nutrition—may significantly alter outcomes in hospitalized patients. Still, the evidence so far leaves many questions unanswered and optimal protocols far from clear. Soybean oil, an omega-6 fatty acid, has been in use since the 1960s as a lipid emulsion for patients needing IV nutrition. How clinicians use the emulsion has evolved over decades, Dr. Gura said. Although its initial primary use was to prevent fatty acid deficiency, clinicians now also enlist it to decrease the amount of carbohydrates administered to a patient. Not only are doses today higher, she added, but the emulsion is often used for longer periods. However, evidence has been accumulating that the oil provides an “unbalanced fatty acid composition,” predisposing some patients to poor outcomes, according to Philip Calder, PhD, a professor of nutritional immunology at the University of Southampton, in England. Soybean oil may trigger inflammation more readily than fish oil and other omega-3s, as well as alter immunosuppression and coagulation, Dr. Calder said. “Finding evidence for this is hard. But finding evidence that there [are] better outcomes when soybean oil is replaced with emulsions containing olive oil and, more especially, fish oil, is a bit easier,” he added, pointing to numerous studies supporting the benefits of alternative emulsions (Crit Care 2015;19[1]:167).

Now Supports Interoperability!

Some studies, however, shed a different light on the use of fish oil. Arthur van Zanten, MD, PhD, an internist and a medical manager at Gelderse Vallei Hospital in the Netherlands, shared with A.S.P.E.N. attendees findings from the MetaPlus trial, which so far suggests that immune-modulating nutrients enriched with fish oil, as well as antioxidants and glutamine, result in poorer outcomes than standard high-protein enteral nutrition—a concoction containing no fish oil and lower levels of the other supplements. “This intervention was not beneficial and did harm,” said Dr. van Zanten, noting a hazard ratio between the immune-modulating and standard nutrition groups of 1.57 (95% CI, 1.032.39; P=0.04) for six-month mortality ( (JAMA 2014;312[5]:514-524). “As the first dictum in medicine is to do no harm, we recommend not to use these immune-modulating ingredients in ICU patients until more data are present,” he added. Of course, the studies by Drs. Gura and van Zanten addressed two different types of nutrition: IV and enteral. Todd Rice, MD, an associate professor

Clinical 13

Pharmacy Practice News • July 2015

Nutrition ‘As the first dictum in medicine is to do no harm, we recommend not to use … immune-modulating ingredients in ICU patients until more data are present.’

Using a fish oil emulsion in many of these cases, she added, would be “much cheaper” than having someone “undergo a liver transplant and then face lifelong immunosuppressants and follow-up care. “As these products become available in the U.S., practitioners—and pharmacists—will need to understand the differences,” Dr. Gura said. “Which populations benefit from different types of oils? We can’t assume it’s one-size-fits-all.”

—Arthur van Zanten, MD, PhD of medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt University School of Medicine, in Nashville, Tenn., offered suggestions as to why the effects of omega-3s may have differed between the studies. Variation in nutrient absorption between IV and enteral pathways may be a factor, Dr. Rice noted. Increases in dose may be less tolerable via enteral nutrition than IV. The timing may also differ, he explained, because the inflammatory cascade caused by a critical illness may already be underway by the time enteral nutrition is begun or actual delivery is accomplished. “We’re a little late by the time they present to us,” he said. “IV is probably started earlier. That might get the omega3s on board before the injury—surgery— and, therefore, before that cascade starts.” Prior to the MetaPlus trial, Dr. Rice led a study on the use of enteral fish oil in patients with acute respiratory distress syndrome, which resulted in similar findings. “The end points were significantly worse in the fish oil group,” he said. “This was the first signal that maybe we should have some caution with these [formulations].” Dr. Rice noted that enteral fish oil might still benefit a subset of the population, such as preoperative inpatients undergoing major surgeries if it can be given before injury. As for the IV preparations, he added, “the jury is still out.”

Product Availability an Issue For patients in the United States, fish oil emulsions aren’t an option anyway. “Critical care nutrition guidelines coming out at the end of this year will specifically say that we make no recommendation for or against IV omega-3 fatty acids because they are not available in the U.S.,” said Dr. Rice, also a co-author on the upcoming guidelines. The situation is different outside the United States. “Americans have lagged behind Europeans in product development. They’ve had access to many products that we’re only just now seeing in the U.S.,” said Dr. Gura, highlighting an olive oil and soybean product that was approved by the FDA in 2013 but is still not readily available. Dr. Calder added that although cost may be an issue with the new oils, this hasn’t proven prohibitory in Europe. He highlighted a study that found omega-3 fatty acid emulsions to be cost-effective in U.K., Italian, French and German hospitals (Clin Nutrr 2014;33[5]:785-792).

“For most people who require short courses, they can tolerate soybean oil just fine,” Dr. Gura said. “But with premature babies, or critically ill, septic patients, there are sources of oils now available that may be better tolerated.”

Dr. Gura reported that Boston Children’s Hospital has filed for a use patent on behalf of herself and Dr. Puter. She also reported participation on advisory bureaus for B. Braun and Fresenius Kabi, and a licensing agreement between Boston Children’s Hospital and Fresenius Kabi. Dr. Calder reported that he has received speaking honoraria from Fresenius Kabi, B. Braun and Baxter Healthcare. Dr. van Zanten reported that he has received honoraria for advisory board meetings, lectures and travel expenses from Abbott, Baxter, B. Braun, Danone, Fresenius Kabi, Nestle, Novartis and Nutricia. Dr. Rice reported no relevant financial conflicts of interest.

—Lynne Peeples

Why Compromise? Choose NAROPIN Labor & Delivery Acute Pain Management Surgical Anesthesia

Fresenius Kabi’s NAROPIN sets the standard with an extensive portfolio, proven clinical results, and innovative packaging—all of which make it the brand you and your patients can count on.

Important Safety Information Using NAROPIN beyond recommended doses to increase motor block or duration of sensory block may negate its favorable cardiovascular advantages, in the event that an inadvertent intravascular injection occurs. NAROPIN may be associated with adverse reactions

Experience our latest versatile delivery system, the freeflex® bag—an innovative container designed for premixed solutions.

which are characteristic of those associated with other amide-type local anesthetics.1 In clinical trials, side effects were mild and transient and may reflect the procedures, patient health status, and/or other medications used. Adverse events reported at a rate

We offer product options in 4 strengths: 0. 2 %

0. 5 %

0.75 %

of *5%: hypotension, nausea, vomiting, bradycardia, fever, pain, postoperative complications, anemia, paresthesia, headache, pruritus, and back pain. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. NAROPIN is not approved for this use.

Reference 1. NAROPIN Prescribing Information.

NAROPIN-US.com

0793-NAR- 05-1/ 15

14 Clinical

Pharmacy Practice News • July 2015

Bleeding Disorders

4F-PCC Bests Plasma in Vitamin K Antagonist Reversal

randomized study of nearly 170 patients has provided the strongest evidence yet that the 4-factor prothrombin complex concentrate (4F-PCC), Kcentra (CSL Behring), reverses the anticoagulation effects of vitamin K antagonists (VKA) at a faster rate than plasma in patients requiring emergency invasive procedures. The findings ((Lancet 2015;385:20772087) are consistent with previous studies, including one other randomized trial (Vox Sang 2010;99:251-260), noted Edith Nutescu, PharmD, an expert in anticoagulation who was not involved in the study. However, that randomized study included only 20 patients, which limited the findings, she said.

A First-Line Agent “These results have the potential to impact clinical practice and guide adoption of 4F-PCC as a first-line agent in patients needing emergent reversal of VKA-related anticoagulation in a way that prior results were not able to, because of their study design limitations,” commented Dr. Nutescu, who is an associate professor and a co-director of the Center for Pharmacoepidemiology and Pharmacoeconomic Research, Department of Pharmacy Systems, Outcomes and Policy, in the College of Pharmacy at The University of Illinois at Chicago. Joshua Goldstein, MD, PhD, who is an attending physician in the Department of Emergency Medicine at Massachusetts General Hospital, and an associate professor of surgery at Harvard Medical School, both in Boston, and a team at 33 hospitals in the United States, Europe and Asia, analyzed data from 168 patients who underwent an urgent surgical or invasive procedure and were randomized to receive either 4F-PCC or plasma in an open-label fashion for rapid VKA reversal. Both treatments were dosed according to the patients’ international normalized ratio (INR) and weight, and patients in both arms also received vitamin K.

Rapid Infusions The infusion rate of 4F-PCC was 3 IU/kg per minute or slower. There was no standard infusion protocol; instead, the agent was infused “as rapidly as possible and at the discretion of the ... clinical team,” according to the researchers. Emergency procedures included general surgeries, cranial, cardiothoracic, orthopedic, urologic, gynecologic, cardiovascular and spinal surgeries, and some invasive but nonsurgical procedures. Mean INR at baseline was 2.9 in both groups. Vitamin K was administered a median of 13 to 15 minutes before 4F-PCC and plasma infusions, respectively. Dr. Goldstein and his team found

‘These results have the potential to impact clinical practice and guide adoption of 4F-PCC as a firstline agent in patients needing emergent reversal.’ —Edith Nutescu, PharmD that 90% (78/87) of 4F-PCC recipients and 75% (61/81) of plasma recipients achieved hemostasis in an intention-to-

treat analysis ((P=0.0142). Additionally, 55% (48/87) and 10% (8/81) of 4F-PCC and plasma recipients, respectively,

experienced a rapid reduction in INR, defined as 1.3 or less within 30 minutes of the end of the infusion ((P<0.0001). The median time between the start of infusion and the beginning of a surgical procedure was 3.6 hours in the 4F-PCC group, compared with 8.5 hours in the plasma group ((P=0.0098). That difference was due to a shorter infusion time for 4F-PCC (mean 20.9 vs. 140.7 minutes for plasma) and a

When facing the challenge of designated Enterobacteriaceae in cIAI and cUTI...

Take Action with AVYCAZ™ (ceftazidime-avibactam) • AVYCAZ combines a trusted cephalosporin, ceftazidime, with a non-β-lactam β-lactamase inhibitor (BLI), avibactam, which may provide activity against some isolates resistant to carbapenems1 • Avibactam is the first and only non-β-lactam BLI, which inactivates some ESBLs— including KPCs—some AmpCs, and certain oxacillinases1 • AVYCAZ demonstrated in vitro activity against some Enterobacteriaceae producing ESBLs, including KPCs1 • KPC-producing Enterobacteriaceae are a growing threat that has spread nationwide2 Discover more at AVYCAZ.com, and get the information you need to order AVYCAZ today.

INDICATIONS AND USAGE As only limited clinical safety and efﬁcacy ﬁ data for AVYCAZ (ceftazidime-avibactam) are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options. Complicated Intra-Abdominal Infections (cIAI) AVYCAZ, in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas aeruginosa in patients 18 years or older. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis AVYCAZ is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii, Proteus spp., and Pseudomonas aeruginosa in patients 18 years or older. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS AVYCAZ is contraindicated in patients with known serious hypersensitivity to AVYCAZ, avibactamcontaining products, ceftazidime, or other members of the cephalosporin class. WARNINGS AND PRECAUTIONS • In a Phase 3 complicated intra-abdominal infections (cIAI) trial, clinical cure rates were lower in a subgroup of patients with baseline creatinine clearance (CrCL) of 30 to 50 mL/min compared to those with CrCL greater than 50 mL/min. The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Clinical cure rates in patients with normal renal function/mild renal impairment (CrCL greater than 50 mL/min) was 85% (322/379) with AVYCAZ plus metronidazole vs 86% (321/373) with meropenem, and clinical cure rates in patients with moderate renal impairment (CrCL 30 to 50 mL/min) was 45% (14/31) with AVYCAZ plus metronidazole vs 74% (26/35) with meropenem. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCL 30 to 50 mL/min. Monitor CrCL at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly.

Clinical 15

Pharmacy Practice News • July 2015

Bleeding Disorders faster time to INR reduction, th he researcheers said. Both groups of patients eexperienced similar rates of adverse eveents, with the exceeption of fluid overloaad or similar cardiac events, which occcurred in 3% of 4F-PCC recipients and 113% of plasma recipients (P ( =0.0478).

IMPORTANT SAFETY INFORMATION (continued) • Serrious and occasionally fattal hypersensitivity (anaph hylactic) reactions and se erious skin reactions have been reported d in i patients i receiving i i beta-lactam b l antibacterial ib i l drugs. d Before B f therapy h with i h AVYCAZ is i instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs. fi -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial • Clostridium difficile drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs. If CDAD is suspected or confirmed, fi antibacterials not directed against C. difficile fi should be discontinued, if possible. • Seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance. • Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit fi to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS • The most common adverse reactions (incidence of ≥10% in either indication) were vomiting (14%), nausea (10%), constipation (10%), and anxiety (10%). cIAI, complicated intra-abdominal infection. cUTI, complicated urinary tract infection. KPCs, Klebsiella pneumoniae carbapenemases. ESBLs, extended-spectrum β-lactamases. References: 1. AVYCAZ™ (ceftazidime-avibactam) [prescribing information]. Cincinnati, OH: Forest Pharmaceuticals, Inc.; 2015. 2. Castanheira M, Farrell SE, Krause KM, Jones RN, Sader HS. Contemporary diversity of β-lactamases among Enterobacteriaceae in the nine US census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent β-lactamase groups. Antimicrob Agents Chemother. 2014;58:833-838.

Please see Brief Summary of full Prescribing Information on the following pages.

Actavis® and its design are trademarks of Actavis, Inc. or its affiliates. fi AVYCAZ™ and its design are trademarks of Actavis, Inc. or its affiliates. fi ©Actavis 2015. All rights reserved. AVY31166A 06/15

The investigators said the study had some limitations. The trial was not adequately powered to detect differences in safety outcomes and the investigators were not blinded. Additionally, there was no protocol to guide plasma infusion, they noted. —David Wild Dr. Goldstein reported receiving consulting fees and a research grant from CSL Behring. Dr. Nutescu reported no relevant ﬁnancial conﬂicts of interest.

16 Clinical

Pharmacy Practice News • July 2015

Pharmacogenomics

GENE SEQUENCING

what has often been left out of the sequencing conversation, Dr. Green said. That gap occurs, he noted, in part because of the residual narrative about overtly deterministic genetic testing that dominated the main stage at the beginning of the genomic era. “There was a period where [many individuals] were getting whole-body MRIs. We were finding incidental MRI findings in people, investigating and even putting people into surgery for

continued from page 1

Dr. Green said these findings should be handled similarly to secondary findings from imaging tests. For example, if a man receives a chest x-ray after an accident and a shadow is identified on his lung, the radiologist would include this information in his report to the patient’s physician, who would ask the patient whether he has any risk factors for lung disease. This contextualization of genomic findings is

AVYCAZTM (ceftazidime-avibactam) for injection, for intravenous use Brief Summary of full Prescribing Information Initial U.S. Approval: 2015 INDICATIONS AND USAGE: Complicated Intra-Abdominal Infections (cIAI) AVYCAZ (ceftazidime-avibactam), in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas aeruginosaa in patients 18 years or older. As only limited clinical safety and efﬁcacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options [see Clinical Studies in the full Prescribing Information]. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis - AVYCAZ (ceftazidime-avibactam) is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri,i Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii,i Proteus spp., and Pseudomonas aeruginosa in patients 18 years or older. As only limited clinical safety and efﬁcacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options [see Clinical Studies in the full Prescribing Information]. Usage - To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy [see Dosage and Administration in the full Prescribing Information]. CONTRAINDICATIONS: AVYCAZ is contraindicated in patients with known serious hypersensitivity to AVYCAZ, avibactam-containing products, ceftazidime, or other members of the cephalosporin class [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS: Decreased Clinical Response in Patients with Baseline Creatinine Clearance of 30 to 50 mL/min - In a Phase 3 cIAI trial, clinical cure rates were lower in a subgroup of patients with baseline CrCL of 30 to 50 mL/min compared to those with CrCL greater than 50 mL/min (Table 3). The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCL 30 to 50 mL/min. Monitor CrCL at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly [see Dosage and Administration in the full Prescribing Information, and Adverse Reactions]. Table 3. Clinical Cure Rate at Test of Cure, by Baseline Renal Function – mMITT Population1

Normal function / mild impairment (CrCL greater than 50 mL/min) Moderate impairment (CrCL 30 to 50 mL/min)

AVYCAZ + Metronidazole % (n/N)

Meropenem % (n/N)

85% (322/379)

86% (321/373)

45% (14/31)

74% (26/35)

Microbiological modiﬁed intent-to-treat (mMITT) population included patients who had at least one bacterial pathogen at baseline and received at least one dose of study drug.

Hypersensitivity Reactions - Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs. Clostridium difficile-associated Diarrhea - Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile. C. difficilee produces toxins A and B which

contribute to the development of CDAD. Hypertoxin producing strains of C. difficilee cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficilee may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. Central Nervous System Reactions - Seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance [see Dosage and Administration in the full Prescribing Information]. Development of Drug-Resistant Bacteria - Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage]. ADVERSE REACTIONS: The following are discussed in greater detail in the Warnings and Precautions section: Decreased Clinical Response in Patients with Baseline CrCL of 30 to 50 mL/min; Hypersensitivity Reactions; Clostridium difficile-Associated Diarrhea; Central Nervous System Reactions; Development of Drug-Resistant Bacteria [see Warnings and Precautions]. Clinical Trial 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. AVYCAZ was evaluated in two active-controlled Phase 2 clinical trials, one each in cIAI and cUTI, including pyelonephritis. The Phase 2 trials included a total of 169 adult patients treated with AVYCAZ and 169 patients treated with comparators. Complicated p Intra-Abdominal Infections - The Phase 2 cIAI trial included 101 adult patients treated with AVYCAZ (2 grams ceftazidime and 0.5 grams avibactam) administered intravenously over 30 minutes every 8 hours plus 500 mg metronidazole administered intravenously over 60 minutes every 8 hours and 102 patients treated with meropenem. The median age of patients treated with AVYCAZ was 41 years (range 18 to 79 years). Patients were predominantly male (69.3%) and Caucasian (55.4%). Patients with an estimated baseline CrCL 50 mL/min or less were excluded. Serious adverse reactions occurred in 9/101 (8.9%) of patients receiving AVYCAZ (with metronidazole) and 11/102 (10.8%) of patients receiving meropenem. The most common adverse reactions leading to discontinuation in patients receiving AVYCAZ were skin and subcutaneous tissue disorders (3%). Adverse reactions occurring in 10% or more of patients receiving AVYCAZ were vomiting and nausea. Increased Mortality - In a Phase 3 cIAI trial, death occurred in 2.5% (13/529) of patients who received AVYCAZ/metronidazole and in 1.5% (8/529) of patients who received meropenem. Among a subgroup of patients with baseline CrCL 30 to 50 mL/min, death occurred in 25.8% (8/31) of patients who received AVYCAZ/metronidazole and in 8.6% (3/35) of patients who received meropenem. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCL 30 to 50 mL/min [see Dosage and Administration in the full Prescribing Information and Warnings and Precautions]. In patients with normal renal function or mild renal impairment (baseline CrCL greater than 50 mL/min), death occurred in 1.0% (5/498) of patients who received AVYCAZ/metronidazole and in 1.0% (5/494) of patients who received meropenem. The causes of death varied and contributing factors included progression of un derlying infection, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention. Complicated p Urinaryy Tract Infections,, Includingg Pyelonephritis y p - The Phase 2 cUTI trial included 68 adult patients treated with AVYCAZ (0.5 grams ceftazidime + 0.125 grams avibactam) administered intravenously over 30 minutes every 8 hours and 67 patients treated with imipenem-cilastatin (0.5 grams intravenously every 6 hours). The dose of AVYCAZ in this trial was lower than the recommended dose [see Dosage and Administration in the full Prescribing Information]. Median age of patients treated with AVYCAZ was 47.5 years (range 18 to 85 years). Patients were predominantly female (75%) and Caucasian (58.8%). Patients with CrCL less than 70 mL/min were excluded. Serious adverse reactions occurred in 6/68 (8.8%) of patients receiving AVYCAZ and 2/67 (3.0%) of patients receiving imipenem-cilastatin. Two patients prematurely discontinued treatment with AVYCAZ: one due to an accidental overdose and one due to atrial fibrillation. Adverse reactions occurring in 10% or more of patients receiving AVYCAZ were constipation and anxiety. Table 4 lists adverse reactions occurring in 5% or more of patients receiving AVYCAZ in the Phase 2 cIAI trial or the Phase 2 cUTI trial.

Clinical 17

Pharmacy Practice News • July 2015

Pharmacogenomics things that didn’t make any sense.” Now, clinicians have learned to be more cautious when interpreting MRI findings, and “we have to be [similarly] judicious with genomic testing results,” he said. It is important to recognize the difference between people with an undiagnosed disease and healthy people seeking genomic testing. “People are walking into my office and saying, I have $5,000, I would like to be sequenced. But many people have something in their family or are worried about a personal health problem that is motivating them,” Dr.

Green said. “It might not be as distinctive as having a family history of three generations of cardiomyopathy, but it might be they are remembering a couple of uncles who have died from heart attacks. In these cases, we need to channel these questions away from using sequencing as a general screen, and toward more specifically established genetic tests.” Through the MedSeq Project at Brigham and Women’s Hospital and Harvard Medical School, researchers are conducting clinical trials to exam-

Table 4. Incidence of Selected Adverse Drug Reactions Occurring in 5% or more of Patients Receiving AVYCAZ in the Phase 2 cIAI Trial or the Phase 2 cUTI Trial Phase 2 cIAI Trial Phase 2 cUTI Trial AVYCAZ plus Meropenem b AVYCAZ c ImipenemCilastatin d Metronidazole a (N = 102) (N = 68) (N = 67) (N = 101) Gastrointestinal disorders Vomiting Nausea Constipation Abdominal pain Upper abdominal pain Investigations Increased blood alkaline phosphatase Increased alanine aminotransferase Nervous system disorders Dizziness Psychiatric disorders Anxiety

14% 10% 4% 8% 1%

5% 6% 1% 3% 0%

0% 2% 10% 7% 7%

0% 5% 3% 5% 2%

13%

10%

2.5 grams (2 grams/0.5 grams) intravenously over 30 minutes every 8 hours (with metronidazole 500 mg intravenously every 8 hours) b 1 gram intravenously over 30 minutes every 8 hours c 0.625 grams (0.5 grams/0.125 grams) intravenously over 30 minutes every 8 hours d 0.5 grams intravenously over 30 minutes every 6 hours

Other Adverse Reactions of AVYCAZ and Ceftazidime - The following selected adverse reactions were reported in AVYCAZ-treated subjects at a rate of less than 5% in the Phase 2 trials and are not described elsewhere in the labeling. Blood and lymphatic disorderss - Eosinophilia, Thrombocytopenia; Investigations - Increased gamma-glutamyltransferase, Prolonged prothrombin time; Metabolism and nutrition disorderss - Hypokalemia; Renal and urinary disorderss - Acute renal failure, Renal impairment; Skin and subcutaneous tissue disorderss - Rash. Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ clinical trials are listed below: Blood and lymphatic disorders - Agranulocytosis, Hemolytic anemia, Leukopenia, LLymphocytosis, Neutropenia, Thrombocytosis; General disorders and administration site conditions - Infusion site inﬂammation, Injection site hematoma, Injection site phlebitis, Injection site thrombosis; Hepatobiliary disorders - Jaundice; Infections and infestations Candidiasis; Investigations - Increased blood lactate dehydrogenase; Nervous system disorders - Dysgeusia, Paresthesia; Renal and urinary disorders - Tubulointerstitial nephritis; Reproductive and breast disorders - Vaginal inﬂammation; Skin and subcutaneous tissue disorders - Angioedema, Erythema multiforme, Pruritis, Stevens-Johnson syndrome, Toxic epidermal necrolysis, Urticaria. Laboratoryy Changes g - Seroconversion from a negative to a positive direct Coombs’ test result occurred in 6/82 (7.3%) of patients receiving AVYCAZ plus metronidazole and 2/84 (2.4%) of patients receiving meropenem in the cIAI trial. Seroconversion from a negative to a positive direct Coombs’ test result occurred in 1/52 (1.9%) of patients receiving AVYCAZ and 5/60 (8.3%) of patients receiving imipenem cilastatin in the cUTI trial. No adverse reactions representing hemolytic anemia were reported in any treatment group. DRUG INTERACTIONS: Probenecid - In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitroo and, therefore, has the potential to decrease the elimination of avibactam when co-administered. Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended [see Clinical Pharmacology in the full Prescribing Information]. Drug/ Laboratory Test Interactions - The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category B - Animal reproductive toxicity studies have been conducted with ceftazidime and with avibactam. However, there are no adequate and well-controlled studies of

ine the impact of genomic sequencing with incidental findings in the care of a hereditary illness and primary care of healthy adults (Trials 2014;15:85). In one trial, patients with heritable cardiomyopathy are being randomized to standard care plus a family history alone or with whole-genome sequencing and a genome report. In the second trial, healthy middle-aged individuals are being randomized to receive standard care from their primary care physician with or without a wholegenome sequencing report. Physicians

AVYCAZ, ceftazidime, or avibactam in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. Ceftazidime - Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime. Avibactam Avibactam was not teratogenic in rats or rabbits. In the rat, intravenous studies showed no embryofetal toxicity at doses of 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC). In a rat pre- and postnatal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weanling pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weanling pups became adults. Reproductive studies performed during early pregnancy in rabbits showed no effects on embryofetal development at doses of 100 mg/kg, twice the human exposure (AUC). At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed. Nursing Mothers - Ceftazidime is excreted in human milk in low concentrations. It is not known whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats in a dose dependent manner. Exercise caution if AVYCAZ is to be administered to a nursing woman. Pediatric Use - Safety and effectiveness in patients less than 18 years of age have not been established. Geriatric Use - Of the 169 patients treated with AVYCAZ in the Phase 2 cIAI and cUTI trials, 18 (10.7%) were 65 years of age and older. Because of limited data, differences in outcomes or specific risks with AVYCAZ cannot be ruled out for patients 65 years of age and older. Ceftazidime and avibactam are excreted primarily by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment. Because elderly patients are more likely to have renal impairment, care should be taken in dose selection in this age group and it may be useful to monitor renal function. Healthy elderly subjects had 17% greater exposure relative to healthy young subjects when administered the same single dose of avibactam, which may have been related to decreased renal function in the elderly subjects. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration and Clinical Pharmacology in the full Prescribing Information]. Renal Impairment - Dosage adjustment is required in patients with moderately or severely impaired renal function (CrCL 50 mL/min or less). For patients with changing renal function, CrCL should be monitored at least daily and dosage of AVYCAZ adjusted accordingly. Both ceftazidime and avibactam are hemodialyzable; thus, AVYCAZ should be administered after hemodialysis on hemodialysis days [see Dosage and Administration and Clinical Pharmacology in the full Prescribing Information]. OVERDOSAGE: In the event of overdose, discontinue AVYCAZ and institute general supportive treatment. Ceftazidime and avibactam can be removed by hemodialysis. In subjects with ESRD administered 1 gram ceftazidime, the mean total recovery in dialysate following a 4-hour hemodialysis session was 55% of the administered dose. In subjects with ESRD administered 100 mg avibactam, the mean total recovery in dialysate following a 4 hour hemodialysis session started 1 hour after dosing was approximately 55% of the dose. No clinical information is available on the use of hemodialysis to treat AVYCAZ overdosage [see Clinical Pharmacology in the full Prescribing Information]. Distributed by: y Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, LLC Cincinnati, Ohio 45209 Manufactured by: y GlaxoSmithKline Manufacturing S.p.A. Verona, 37135 Italy AVYCAZTM is a trademark of Actavis, Inc. or its affiliates.

AVY27616-A-02/15

Please also see full Prescribing Information at www.AVYCAZ.com

are challenged to understand and act on the information, but with support. An “intense” set of outcome measures will evaluate how the patient, family members and physicians act, and how the information is handled in the medical record, Dr. Green noted. Another of Dr. Green’s initiatives, co-led with Alan Beggs, PhD, of Boston Children’s Hospital, is the BabySeq Project. In this study, which is just getting started, 240 infants in the Boston Children’s Hospital neonatal ICU will be randomized to receive standard care plus a family history alone or with a genome report and indication-based genome results. A parallel trial will enroll 240 healthy newborns with a similar randomization. Like the MedSeq Project, investigators will study the medical, behavioral and economic effects of having this genomic information over time. “We are trying to make reports of genomic information less intimidating,” Dr. Green said. “Part of that means putting the responsibility for variant classification, which is complex, squarely in the hands of the laboratory, not in the hands of the clinician, and then coming up with a digestible one-page summary that an ordinary physician can read and understand.” To that end, the MedSeq Project has developed a concise five- to sixpage genome report featuring a single-page summary of results of potential medical relevance ((Public Health Genomics 2015;18[2]:123-129). The summary includes sections on monogenic disease risk, carrier status, pharmacogenomic associations and genomic predictions of serologic blood types.

A Bright Future Louis Fiore, MD, MPH, executive director, Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, said that only imagination would limit what can be done with whole-genome sequencing. “Physicians have limited query ability when they see something. If you saw a patient you thought had something, you could interrogate [them regarding their genomic information],” he said. “It would really be phenotype looking for genotype versus genotype informing clinical care about phenotype. That eliminates or largely reduces the incidental findings problem.” —Kate O’Rourke Dr. Green reported a research grant and compensated speaking from Illumina; uncompensated collaborations with Pathway and 23andMe; and compensated advisory positions with Bina, Invitae and Prudential. Dr. Fiore reported no relevant ﬁnancial conﬂicts of interest.

18 Clinical

Pharmacy Practice News • July 2015

Infectious Disease

Community-Acquired Pneumonia Boosts Long-Term Morbidity, Mortality

personal history of community-acquired pneumonia (CAP) greatly increases the risks for long-term morbidity and mortality compared with individuals who never had the disease, according to researchers in Canada, in the longest and largest outcomes study of such patients reported to date. “Although the short-term adverse health consequences of CAP are well known, the long-term effects of the disease are less clear,” said Dean T. Eurich, PhD, MSc, BSP, of the University of Alberta in Edmonton, Canada. “In our large, populationbased study of more than 6,000 adults with CAP and almost 30,000 matched controls, we found that CAP patients have high rates of long-term morbidity and mortality compared with those who have never had CAP, irrespective of their age.” Between 2000 and 2002, the researchers prospectively recruited 6,078 adults with CAP from six hospitals and seven emergency departments in Edmonton. Pneumonia was documented by radiographic evidence and two or more of the following symptoms: cough, pleuritic chest pain, shortness of breath, fever, and crackles or bronchial breath sounds. A validated clinical pathway was used to determine treatment. Each patient was matched by age, gender and site of treatment to five controls (n=29,402) who presented to the hospital or emergency department around the same time, but did not have pneumonia and had not had the

Clinicians Leery Of Naloxone for Opioid Overdose

oncerns over risks and offending patients hinder a clinician’s willingness to prescribe naloxone to counteract the effects of an opioid overdose, according to a Kaiser Permanente Colorado study (J Gen Intern Med 2015 Jun 9. [Epub ahead of print]). Naloxone typically is prescribed to patients taking opioid painkillers, so that family members or other bystanders can administer it in the event of an overdose. Thirty states have signed legislation that allow clinicians to prescribe naloxone or distribute the medication. The researchers conducted 10 focus groups with 56 clinicians from August 2013 to August 2014. They asked about attitudes regarding prescribing naloxone to patients also taking opioids prescribed for pain at internal medicine, family medicine and HIV clinics. Clinicians said: • They felt that naloxone could effectively prevent overdose deaths. • Prescribing the drug may increase patient understanding of the risks associated with opioid use. • They hesitated to prescribe naloxone because they did not want to offend patients by talking about

condition within the past year. All patients were followed until 2012. Forty-four percent of the patients were aged 65 years or older, and 53% were men. In addition, 3,425 patients (56%) were treated as outpatients, instead of admitted to the hospital. During follow-up, 2,858 CAP patients died compared with 9,399 of controls, an absolute risk difference of 30 excess deaths per 1,000 patient-years of follow-up and a greater than 50% relative increased rate of mortality among CAP patients. Young adults (those younger than 25 years) with CAP had the worst outcomes of all patients, even though the younger patients had the lowest absolute risk difference for mortality, and the older patients (those older than 80 years) had the highest absolute risk difference, the researchers found. Younger patients had more than a twofold increased rate of mortality relative to controls (Am J Respir Crit Care Med d 2015 June 11. [Published online]). The absolute rates of all-cause hospitalization, emergency department visits and CAP-related hospital visits were significantly higher in CAP patients than in controls. “Indeed, CAP is still considered ‘the old man’s friend’ because of the almost assured high mortality; however, our results lend strong support to the alternate proposition that CAP ought to also be considered the young adult’s adversary,” Dr. Eurich said.

their risk for overdose. • They wanted to be certain that the bystanders who would administer naloxone receive proper and confidential training, and would be able to recognize the signs of an overdose. • They were concerned about possible adverse effects of the drug in widespread use. Ingrid Binswanger, MD, MPH, a senior investigator in Kaiser Permanente Colorado’s Institute for Health Research, said that expanding access to naloxone could prevent future deaths. “However, research shows there are gaps in knowledge about how to use naloxone in routine clinical practice. It’s evident that more education is needed to support clinicians, as states begin legislating wider access of naloxone for bystanders of overdoses.”

Short-Course Antibiotics Deemed an Option For Abdominal Infection

atients with complicated intraabdominal infections taking a four-day course of antibiotics had similar outcomes to those given longer courses of antibiotics, according to a recent study. Complicated intraabdominal infections are the second most common cause of death due to infection in ICUs in the United States (Am Fam Physician 2010:15;82[6]:694-709). Management typically involves resuscitating patients with systemic inflammatory response syndrome (SIRS), controlling the source of contamination, removing

infected and necrotic debris, and providing antimicrobials to eradicate any remaining organisms. Antibiotics are given for seven to 14 days until symptoms of SIRS, such as fever, have resolved. However, interest in shorter courses of antibiotic has been increasing, because such a regimen would be less expensive, cause fewer adverse events and help prevent resistance. Researchers led by Robert G. Sawyer, MD, a surgeon at the University of Virginia, Charlottesville, enrolled more than 500 patients, aged 16 and older, in the multicenter Study to Optimize Peritoneal Infection Therapy (STOP-IT). All participants presented with a complicated intraabdominal infection with fever, leukocytosis or gastrointestinal dysfunction due to peritonitis, and all had undergone a procedure to remove the source of the infection. Half were randomized to receive standard treatment with antibiotics until two days after symptoms resolved or four full days of antibiotics after their sourcecontrol procedure (N Engl J Med 2015 May 21. [Epub ahead of print]). Patients taking the shorter course of antibiotics did as well as those who took the longer course; about 22% in each group died or experienced a surgical site infection or recurrent intraabdominal infection. Shortening the course of antibiotics for complicated intraabdominal infections could save the U.S. health care system nearly $100 million annually, the researchers noted.

Shingles Vaccine Lowers Post-Herpetic Neuralgia Risk

ndividuals can lower their risk for developing postherpetic neuralgia (PHN) by getting the shingles vaccine, a new study suggested. Researchers from Kaiser Permanente Southern California reviewed 2,400 medical records to examine if the vaccine protects against PHN in vaccinated patients who develop shingles. All patients included in the study were older than 60 years and developed shingles after Jan. 1, 2007. Vaccinated patients were matched 1:1 to unvaccinated patients based on gender and age. Researchers measured shingles-related pain one, two, four and six months after diagnosis. The researchers found that PHN occurred in 30 vaccinated women (4.2%) compared with 75 unvaccinated women (10.4%), for an adjusted relative risk of

0.41 (95% CI, 0.26-0.64). PHN was present in 26 vaccinated men (6%) compared with 25 unvaccinated men (5.8%), for an adjusted relative risk of 1.06 (95% CI, 0.260.64) (J Infect Dis 2015 June 1 [Epub ahead of print]). “Our study found that the shingles vaccine has an added protective benefit of reducing the risk of PHN for a vaccinated individual who still experiences shingles,” said co-investigator Hung Fu Tseng, PhD, MPH, in a press release. “This further confirms the importance of shingles vaccination for adults over age 60.” There are approximately 1 million new cases of shingles—with $1 billion worth of medical care-related costs—in the United States each year, according to the CDC. The risk for developing PHN, which can be severe and debilitating, increases with age.

Exclusively from Teva Generics…

Argatroban Injection in 0.9% Sodium Chloride, 250 mg/250 mL 250 mL Infusion Bags The only argatroban intravenous infusion bag on the market.

• Preservative-Free • The infusion bag is not made with natural rubber latex • Learn more about this and other quality generic medicines at TevaGenerics.com Argatroban Injection in 0.9% Sodium Chloride STRENGTH

DESCRIPTION

NDC

1 mg/mL, 250 mg

250 mL x 5 Bags

00703-0020-32

Store at 20° to 25°C (68° to 77°F). Protect from freezing. Retain in original carton to protect from light.

To place your order, call your wholesaler or distributor today. Please see brief summary of prescribing information on adjacent page.

12226

BRIEF SUMMARY OF PRESCRIBING INFORMATION Argatroban Injection in 0.9% Sodium Chloride, for intravenous infusion only 250 mg argatroban in 250 mL sodium chloride solution (1 mg/mL) SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Heparin-Induced Thrombocytopenia Argatroban Injection is indicated for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT). 1.2 Percutaneous Coronary Intervention Argatroban Injection is indicated as an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI). 4 CONTRAINDICATIONS Argatroban is contraindicated in: • Patients with major bleeding, • Patients with a history of hypersensitivity to argatroban. Airway, skin, and generalized hypersensitivity reactions have been reported [see Adverse Reactions (6.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Hemorrhage Hemorrhage can occur at any site in the body in patients receiving argatroban. An unexplained fall in hematocrit or hemoglobin or a fall in blood pressure should lead to consideration of a hemorrhagic event. Argatroban Injection should be used with extreme caution in disease states and other circumstances in which there is an increased danger of hemorrhage. These include severe hypertension; immediately following lumbar puncture; spinal anesthesia; major surgery, especially involving the brain, spinal cord, or eye; hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders and gastrointestinal lesions such as ulcerations. Concomitant use of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding. 5.2 Use in Hepatic Impairment Use caution when administering argatroban to patients with hepatic impairment by starting with a lower dose and carefully titrating until the desired level of anticoagulation is achieved. Upon cessation of argatroban infusion in the hepatically impaired patient, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance and increased elimination half-life of argatroban. Use of argatroban in PCI patients with clinically significant hepatic disease or AST/ALT levels * 3 times the upper limit of normal should be avoided. 5.3 Laboratory Tests Anticoagulation effects associated with argatroban infusion at doses up to 40 mcg/kg/min correlate with increases of the activated partial thromboplastin time (aPTT). Although other global clot-based tests including prothrombin time (PT), the International Normalized Ratio (INR), and thrombin time (TT) are affected by argatroban, the therapeutic ranges for these tests have not been identified for argatroban therapy. In clinical trials in PCI, the activated clotting time (ACT) was used for monitoring argatroban anticoagulant activity during the procedure. The concomitant use of argatroban and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse event 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. 6.1 Adverse Events in Patients with HIT (With or Without Thrombosis) The following safety information is based on all 568 patients treated with argatroban in Study 1 and Study 2. The safety profile of the patients from these studies is compared with that of 193 historical controls in which the adverse events were collected retrospectively. Adverse events are separated into hemorrhagic and non-hemorrhagic events. Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease * 2 g/dL, that led to a transfusion of * 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. Minor bleeding was overt bleeding that did not meet the criteria for major bleeding. Table 4 gives an overview of the most frequently observed hemorrhagic events, presented separately by major and minor bleeding, sorted by decreasing occurrence among argatroban-treated patients with HIT (with or without thrombosis). Table 4. Major and Minor Hemorrhagic Adverse Events in Patients With HIT*

Major Hemorrhagic Eventsa Argatroban-Treated Patients Historical (Study 1 and Study 2) Controlc (n = 568) (n = 193) % % 5.3 6.7

Overall bleeding Gastro2.3 1.6 intestinal Genitourinary 0.9 0.5 and hematuria Decrease in 0.7 0 hemoglobin and hematocrit Multisystem 0.5 1 hemorrhage and DIC Limb and 0.5 0 BKA stump 0.5 Intracranial 0b hemorrhage Minor Hemorrhagic Eventsa Argatroban-Treated Patients Historical (Study 1 and Study 2) Controlc (n = 568) (n = 193) % % Gastro14.4 18.1 intestinal Genitourinary 11.6 0.8 and hematuria Decrease in 10.4 0 hemoglobin and hematocrit Groin 5.4 3.1 Hemoptysis 2.9 0.8 Brachial 2.4 0.8 *with or without thrombosis a Patients may have experienced more than 1 adverse event. b One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation. c The historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel. DIC = disseminated intravascular coagulation. BKA = below-the-knee amputation. Table 5 gives an overview of the most frequently observed non-hemorrhagic events sorted by decreasing frequency of occurrence (* 2%) among argatroban-treated HIT/HITTS patients. Table 5. Non-hemorrhagic Adverse Events in Patientsa With HITb Argatroban-Treated Patients Historical (Study 1 and Study 2) Controlc (n = 568) (n = 193) % % Dyspnea 8.1 8.8 Hypotension 7.2 2.6 Fever 6.9 2.1 Diarrhea 6.2 1.6 Sepsis 6 12.4 Cardiac arrest 5.8 3.1 Nausea 4.8 0.5 Ventricular 4.8 3.1 tachycardia Pain 4.6 3.1 Urinary tract 4.6 5.2 infection Vomiting 4.2 0 Infection 3.7 3.6 Pneumonia 3.3 9.3 Atrial 3 11.4 ﬁbrillation Coughing 2.8 1.6 Abnormal renal 2.8 4.7 function Abdominal pain 2.6 1.6 Cerebrovascular 2.3 4.1 disorder a Patients may have experienced more than 1 adverse event. b with or without thrombosis

The historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel. 6.2 Adverse Events in Patients with or at Risk for HIT Patients Undergoing PCI The following safety information is based on 91 patients initially treated with argatroban and 21 patients subsequently re-exposed to argatroban for a total of 112 PCIs with argatroban anticoagulation. Adverse events are separated into hemorrhagic (Table 6) and non-hemorrhagic (Table 7) events. Major bleeding was deﬁned as bleeding that was overt and associated with a hemoglobin decrease * 5 g/dL, that led to a transfusion of * 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. The rate of major bleeding events in patients treated with argatroban in the PCI trials was 1.8%. Table 6. Major and Minor Hemorrhagic Adverse Events in Patients With HIT Undergoing PCI Major Hemorrhagic Eventsa Argatroban-Treated Patients (n = 112)b % Retroperitoneal 0.9 Gastrointestinal 0.9 Intracranial 0 Minor Hemorrhagic Eventsa Argatroban-Treated Patients (n = 112)b % Groin 3.6 (bleeding or hematoma) Gastrointestinal 2.6 (includes hematemesis) Genitourinary 1.8 (includes hematuria) Minor Hemorrhagic Eventsa Argatroban-Treated Patients (n = 112)b % Decrease in hemoglobin 1.8 and/or hematocrit CABG 1.8 (coronary arteries) Access site 0.9 Hemoptysis 0.9 Other 0.9 a Patients may have experienced more than 1 adverse event. b 91 patients who underwent 112 interventions. CABG = coronary artery bypass graft. Table 7 gives an overview of the most frequently observed non-hemorrhagic events (> 2%), sorted by decreasing frequency of occurrence among argatroban-treated PCI patients. Table 7. Non-hemorrhagic Adverse Eventsa in Patients With HIT Patients Undergoing PCI Argatroban Proceduresa (n = 112)b % Chest pain 15.2 Hypotension 10.7 Back pain 8 Nausea 7.1 Vomiting 6.3 Headache 5.4 Bradycardia 4.5 Abdominal pain 3.6 Fever 3.6 Myocardial infarction 3.6 a Patients may have experienced more than 1 adverse event. b 91 patients who underwent 112 interventions. There were 22 serious adverse events in 17 PCI patients (19.6% in 112 interventions). Table 8 lists the serious adverse events occurring in argatrobantreated patients with or at risk for HIT undergoing PCI. Table 8. Serious Adverse Events in Patients With HIT Undergoing PCIa Argatroban Proceduresb Coded Term (n = 112) Myocardial infarction 4 (3.5%) Angina pectoris 2 (1.8%) Coronary thrombosis 2 (1.8%)

Myocardial ischemia 2 (1.8%) Occlusion coronary 2 (1.8%) Chest pain 1 (0.9%) Fever 1 (0.9%) Retroperitoneal 1 (0.9%) hemorrhage Aortic stenosis 1 (0.9%) Arterial thrombosis 1 (0.9%) Gastrointestinal (0.9%) hemorrhage Gastrointestinal 1 (0.9%) disorder (GERD) Cerebrovascular 1 (0.9%) disorder Lung edema 1 (0.9%) Vascular disorder 1 (0.9%) a Individual events may also have been reported elsewhere (see Tables 6 and 7). b 91 patients underwent 112 procedures. Some patients may have experienced more than 1 event. 6.3 Intracranial Bleeding in Other Populations Increased risks for intracranial bleeding have been observed in investigational studies of argatroban for other uses. In a study of patients with acute myocardial infarction receiving both argatroban and thrombolytic therapy (streptokinase or tissue plasminogen activator), the overall frequency of intracranial bleeding was 1% (8 out of 810 patients). Intracranial bleeding was not observed in 317 subjects or patients who did not receive concomitant thrombolysis [see Drug Interactions (7.4)]. The safety and effectiveness of argatroban for cardiac indications other than PCI in patients with HIT have not been established. Intracranial bleeding was also observed in a prospective, placebo-controlled study of argatroban in patients who had onset of acute stroke within 12 hours of study entry. Symptomatic intracranial hemorrhage was reported in 5 of 117 patients (4.3%) who received argatroban at 1 to 3 mcg/kg/min and in none of the 54 patients who received placebo. Asymptomatic intracranial hemorrhage occurred in 5 (4.3%) and 2 (3.7%) of the patients, respectively. 6.4 Allergic Reactions One hundred ﬁfty-six allergic reactions or suspected allergic reactions were observed in 1,127 individuals who were treated with argatroban in clinical pharmacology studies or for various clinical indications. About 95% (148/156) of these reactions occurred in patients who concomitantly received thrombolytic therapy (e.g., streptokinase) or contrast media. Allergic reactions or suspected allergic reactions in populations other than patients with HIT (with or without thrombosis) include (in descending order of frequency): • Airway reactions (coughing, dyspnea): 10% or more • Skin reactions (rash, bullous eruption): 1 to < 10% • General reactions (vasodilation): 1 to 10% Limited data are available on the potential formation of drug-related antibodies. Plasma from 12 healthy volunteers treated with argatroban over 6 days showed no evidence of neutralizing antibodies. No loss of anticoagulant activity was noted with repeated administration of argatroban to more than 40 patients. 7 DRUG INTERACTIONS 7.1 Heparin If argatroban is to be initiated after cessation of heparin therapy, allow sufﬁcient time for heparin’s effect on the aPTT to decrease prior to initiation of argatroban therapy. 7.2 Oral Anticoagulant Agents Pharmacokinetic drug-drug interactions between argatroban and warfarin (7.5 mg single oral dose) have not been demonstrated. However, the concomitant use of argatroban and warfarin (5 to 7.5 mg initial oral dose, followed by 2.5 to 6 mg/day orally for 6 to 10 days) results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR). 7.3 Aspirin/Acetaminophen No drug-drug interactions have been demonstrated between argatroban and concomitantly administered aspirin or acetaminophen. 7.4 Thrombolytic Agents The safety and effectiveness of argatroban with thrombolytic agents have not been established [see Adverse Reactions (6.3)]. 7.5 Glycoprotein IIb/IIIa Antagonists The safety and effectiveness of argatroban with glycoprotein IIb/IIIa antagonists have not been established. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B

continued

Clinical 21

Pharmacy Practice News • July 2015

Hepatology

LIVER INJURY

Over the past 10 years, sales of gingko biloba, ginseng and Echinacea have fallcontinued from page 1 en, while sales of fish oil, omega-3 fatty physicians. Furthermore, unlike pre- acids, probiotics and melatonin have scription or over-the-counter drugs, increased, according to D. Craig Hopp, dietary supplements do not require pre- PhD, the program director for NIH’s National Center for Complementary and market review or approval by the FDA. Integrative Health. This trend reflects A $35 Billion Black Box what science is showing in research and Dietary supplements are a big busi- “tells us that the public is paying attenness in the United States, where tion to some degree of what is about half of the population being shown through cliniregularly consumes them— cal trials,” he said. Supplements To monitor cases of often daily, said Paul represent Coates, PhD, the direcdrug-induced liver injury (DILI), the NIH tor of the National Institute of Health’s Office in 2003 established the of DILI of Dietary Supplements. Drug-Induced Liver InjuEven one-third of children ry Network, or DILIN, which take them, he said. Sales in the has six contributing hospitals. United States were roughly $35 bil- Research conducted by the network has lion in 2013, including multivitamins, shown that supplements are the second juices, botanicals and herbs. most common class of agents causing livThe NIH doesn’t know exactly how er injury, after antimicrobials, representmany products are available, but the ing some 16% of DILI in a study of 845 agency is compiling a database of patients ((Hepatologyy 2014;60:1399-1408). dietary supplement labels that contains Problems seen among these patients information on about 40,000 products were largely from supplements that conand is growing by about 1,000 a month, tained a mix of ingredients, “sometimes Dr. Coates said. Fact sheets are avail- baffling mixtures,” Dr. Hoofnagle said. Products marketed for bodybuilding able online, in English and Spanish, at ods.od.nih.gov. can cause liver injury, although more

16%

Resources for More Information About Herbal and Dietary Supplements The NIH Ofﬁce of Dietary Supplements Label Database contains information for about 40,000 products www.dsld.nlm.nih.gov/dsld The Ofﬁce of Dietary Supplements also has fact sheets that give a current overview of individual vitamins, minerals, and other supplements, in English and Spanish ods.od.nih.gov The Drug-Induced Liver Injury Network, established by NIDDK, analyzes cases of severe liver injury caused by prescription medicines, over-the-counter drugs or herbal and dietary supplements. dilin.dcri.duke.edu The U.S. National Library of Medicine maintains a database of medications and supplements known to cause liver injury www.livertox.nih.gov The FDA runs MedWatch, a safety information and adverse event reporting program, through which individuals and practitioners can report events linked to medications or supplements www.fda.gov/Safety/MedWatch

There are no adequate and well-controlled studies of argatroban use in pregnant women. Developmental studies performed in rats with argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the maximum recommended human dose, based on body surface area) and in rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the maximum recommended human dose, based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether argatroban is excreted in human milk. Argatroban is detected in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from argatroban, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of argatroban, including the appropriate anticoagulation goals and duration of therapy, have not been established among pediatric patients. 8.5 Geriatric Use Of the total number of subjects (1340) in clinical studies of argatroban, 35% were 65 and over.

In the clinical studies of adult patients with HIT (with or without thrombosis), the effectiveness of argatroban was not affected by age. No trends were observed across age groups for both aPTT and the ACT. The safety analysis did suggest that older patients tended to have an increased incidence of events compared to younger patients; however, older patients had increased underlying conditions, which may predispose them to events. The studies were not sized appropriately to detect differences in safety between age groups. 8.6 Hepatic Impairment Dose reduction and careful titration are required when administering argatroban to patients with hepatic impairment. Reversal of anticoagulation effect may be prolonged in this population [see Warning and Precautions (5.2)]. Manufactured In Hungary By: Teva Pharmaceutical Works Ltd. Hungary H-2100 Gödöllö Táncsics M. út 82 Hungary Manufactured For: TEVA PHARMACEUTICALS USA, INC North Wales, PA 19454 Brief summary based on Prescribing Information Iss. 11/2014

severe injuries have been associated with products that tout weight loss and improved sexual performance, according to Victor Navarro, MD, the chair of hepatology at the Einstein Healthcare Network in Philadelphia, and a contributor to the network. But DILIN is not population-based, and it’s tough to determine how big a problem DILI is nationally, Dr. Navarro said. There are three big barriers, he said: rare events, lack of recognition and possible underreporting of events. “Clinicians simply don’t recognize sometimes when their patient has an injury due to a supplement,” Dr. Navarro said. DILIN has created a cohort for population-based surveillance in Delaware, which demographically can serve as a model for the United States, he noted. Liver injuries have also been associated with green tea extract, black cohosh, anabolic steroids and ephedra, the last of which was banned by the FDA in 2004, speakers at the workshop said. In 2013, 92 people developed acute nonviral hepatitis, many in Hawaii. Of those patients, 70

reported taking the weight loss supplement OxyElite Pro; at least 45 of them were hospitalized, at least three needed liver transplants and one died, said Ethel Taylor, DVM, MPH, an epidemiologist with the Centers for Disease Control and Prevention, who investigated the case. Although the FDA recalled OxyElite Pro in 2012, the manufacturer substituted an ingredient and reissued it without notifying the agency. This case highlights the need to ask patients about supplement use in acute hepatitis cases, Dr. Taylor said. Several journal publications about the incident are pending.

Registry Efforts Gaining Regulation of supplements around the world varies widely, but similar registry efforts have been underway in the European Union, Latin America, Iceland, India and China, international researchers said. Supplements have been implicated in liver injury in these countries, too, representing 16% of 96 cases in Iceland, 10% of 198 cases in the Spanishsee LIVER INJURY, page 22

22 Clinical

Pharmacy Practice News • July 2015

Hepatology

LIVER INJURY continued from page 21

Latin American DILI Network of 10 countries, and 6% of 906 cases in Spain. Assessing DILI is more complicated in India and China, where traditional healers and herbs have been part of the culture for centuries. In India, more than 2 million health care providers (63%) practice an alternative medicine called AYUSH (Ayurveda, Yoga, Unani, Siddha and Homeopathy); 95% of medicines used by these providers are plants or

herbs, said Harshad Devarbhavi, MD, head of gastroenterology and hepatology at St. John’s Medical College Hospital, in Bangalore, India. Between 70% and 80% of residents, especially in rural areas, use AYUSH medicines, said Dr. Devarbhavi, who spoke at the NIH conference. A DILI network established in India in March 2013 found that reports of hepa-

totoxicity from supplements are not rare, accounting for 7% of cases. In China, researchers are finding that traditional Chinese medicinal herbs account for about 20% of cases of DILI, “but the current clinical evidence is poor,” said Chenghai Liu, MD, PhD, the director of the Institute of Liver Diseases at Shunguang Hospital, in Shanghai. A network and

BD PhaSeal™ Closed System Drug Transfer Device Work safe. Enjoy life.

website launched in 2014, www.hepatox. org, aims to enroll and characterize DILI cases attributable to prescription and traditional Chinese medicines, Dr. Liu said. Supplements are regulated as foods, not drugs, and several factors limit the FDA’s ability to detect concerns about supplements and remove products from the market, said Lisa Van Arsdale, a senior analyst with the U.S. Government Accountability Office. The agency has limited information on the number and types of products available; consumers may underreport adverse events; and the agency has difficulty establishing causality between products and their alleged health outcomes. Requiring supplement manufacturers to provide information on the products they sell has been part of many proposed legislative efforts but has not become law, Ms. FDA Van Arsdale said. The inspected FDA inspected just just 18% of manufacturing facilities in 2012, and sampled or examined on of average 3% to 5% manufacturing of imported supfacilities in plement shipments 2012 between fiscal year 2002 and March 2008, according to GAO studies. For now, no specific test can identify a DILI, and assigning causality is challenging, said Leonard Seeff, MD, a hepatology consultant for the Einstein Healthcare Network. Early signs include abnormal serum enzymes and the occurrence of nonspecific symptoms such as jaundice, fatigue or itching. All other causes of liver injury first must be excluded through an extensive medical history and physical examination; defining the category of liver injury as hepatocellular, cholestatic or mixed; and searching for past evidence of liver injury induced by the drug, Dr. Seef said. The U.S. Library of Medicine maintains a database of medications and supplements known to cause liver injury (www.livertox.nih.gov). Clinicians who suspect that a patient has been harmed by a supplement should obtain and keep the bottle the product came in, along with any unused portion, advised Pieter Cohen, MD, an internist with Harvard Medical School’s Cambridge Health Alliance, in Boston. Report adverse events to the FDA through MedWatch, the agency’s safety information and adverse event reporting program, he added, and if appropriate, also contact the local department of public health.

18%

Protecting Monica th he pharmacist, and Monica the gourmet. Ph harmacists often tell us how satisfying it is to be such an important part of a patient’s treeatment. But, you’re also important to maany other people in your life—so please takke care of your health, too. Studies connect hazardous drug exposure to serious heealth risks for pharmacists. We’re helping to change that, by protecting thousands of ph harmacists every day from the hazardous dru ugs they handle. We can’t do what you do o, but we can help you do it safely.

Work safe. Enjoy life. bd.com/phaseal

—Karen Blum

BD Medical 1 Bectton Drive Franklin Lakes, NJ 07417 www.bd.com

The sources reported no relevant ﬁnancial conﬂicts of interest.

Clinical 23

Pharmacy Practice News • July 2015

Hepatology

Commentary: Diagnosing Dietary Supplement–Related Hepatotoxicity Cathy Rosenbaum, PharmD, MBA, RPh Founder & CEO, Rx Integrative Solutions

epatotoxicity related to dietary supplement use is difficult to assess and confirm. Temporal association of clinical symptoms with the product is not the only criterion for a valid evaluation. Clinicians must go through the daunting task of excluding autoimmune, infectious, and multiple liver diseases, factoring in the role of concomitant over-the-counter (OTC) and prescription medications, before thinking about the possibility of supplement-related side effects. Hundreds of dietary supplements may be linked to liver damage based on case reports in the published literature. Symptoms such as fatigue, appetite loss, abdominal pain, jaundice, dark urine and pale stool are nonspecific. The bottom line is that there is a need for a uniformly accepted causality assessment agreed on by clinicians, product manufacturers, and health agencies worldwide for consistency and ease of use.

high cholesterol, valerian root extract for sleep, and green tea extract or usnic acid for weight loss. This patient requires our time for investigation and counseling to help her avoid unintended adverse outcomes.

Pharmacist Recommendations • Encourage patients to report all supplement use, including product and manufacturer names.

• Ask patients to bring supplement bottles in for ingredient evaluation, possible testing and symptom reporting to FDA MedWatch. • Dissuade patients from taking herbal weight loss products that have shown minimal effects on weight loss or body fat composition, and may be adulterated with unsafe prescription medications. • Encourage patients who are taking

weight loss supplements longterm to keep their physician office appointments for routine check of liver enzymes. • Visit http://goo.gl/x3MeMi or http:// goo.gl/By2eDT for a list of supplements implicated in liver damage. For relevant literature, access online version at pharmacypracticenews.com/ DILIHerbs.

Unit Dose Done Right

Unit Do se Bar Cod , ing, Pharma c Nursing y & Supply Experts !

Qualitative Assessment Qualitative scales used for causality assessment of hepatotoxicity linked to dietary supplement use include the Council for International Organizations of Medical Sciences (CIOMS) Scale and the Roussel Uclaf Causality Assessment Method. In addition, an improved CIOMS scale is preferred because it queries for validated quantitative information, including surrogate markers that may not be easily accessible to officebased practitioners. Examples of surrogate markers include plasma and urinary levels of dietary supplement ingredients (and/or their metabolites), and genetic polymorphism of cytochrome P450 isoenzymes.

Ultraviolet Inhibitant Moisture Resistant Tamper-Evident Cold Seal 6 and 12-month Beyond-Use Dating 1-D and 2-D Bar Coding Flexible Label and Report Formatting Multiple Sizes to Fit Your Meds and SStorage N Needs d

Persons at Risk Women may be predisposed to liver damage more than men, especially if they are taking weight loss supplements such as green tea extract or usnic acid. Pharmacists should thoroughly evaluate use of supplement and medication combinations. Consider the female patient taking acetaminophen or nonsteroidal anti-inflammatory agents for osteoarthritis pain, black cohosh for menopausal hot flash management, red yeast rice or a prescription statin for

Simple. Reliable.

800.523.8966

MediDose.com

24 Clinical

Pharmacy Practice News • July 2015

Immunology

Individualized Approach Drives Success in CIDP I

n patients with severe chronic inflammatory demyelinating polyneuropathy (CIDP), there is evidence that IV immune globulin (IVIG) therapy is superior to corticosteroids as a first-line strategy. However, this is not a general statement applicable to all patients with CIDP, particularly

should be the treatment. According to Dr. Siegel and others, therapy should be individualized and adjusted at appropriate intervals. “CIDP is not curable; it is just controllable. Most patients will require therapy at least periodically for the rest of their lives,” Dr. Siegel explained.

‘In some [CIDP] patients, as little as 400 mg/kg [IVIG] administered every three or four weeks may be sufficient for adequate control.’ —Jerry Siegel, PharmD on a cost-benefit basis, according to published reviews. Essentially, the literature and IVIG experts advocate an individualized approach. “IVIG was always considered the second-line option, but it is increasingly being employed first-line in selected patients. Relative to steroids, the response is faster and it is typically better tolerated,” reported Jerry Siegel, PharmD, a clinical associate professor at the Ohio State College of Pharmacy, in Columbus. However, just as the presentation of CIDP is heterogeneous, so

The chronicity of CIDP creates manyy of the challenges. Steroids are effective but bring a long list of significant adverse events, particularly over extended use. Although better tolerated, IVIG imposes a high cost that can be particularly onerous when it is provided as a maintenance regimen over an indefinite period. Moreover, IVIG has its own potential for adverse events, including an increased risk for thromboembolism. Less frequently used therapies, such as mycophenolate, cyclosporine and azathioprine, are

generally reserved for patients who fail first-line treatments. Plasma exchange is also considered among front-line therapies, but this treatment, which requires multiple treatment sessions to provide benefit, is associated with a higher rate of relapse than the other two options ((Adv Neurol Disord d 2011;4:193-200). As a result, the recent debate over the optimal first-line choice has usually focused on the merits

Risk for Airway Infection in PID Patients Receiving Immune Globulins Linked to IgG Isotope 3

he newest potential wrinkle in optimizing IV immune globulins (IVIG) for the treatme ent of primary immunodeficiency disease (PID) is immunoglobulin G (IgG) isotype comp position. This focus on IgG isotypes has arisen because of evidence that subclinical respirato ory infections, which are seen frequently in PID patients and are suspected of producing lung function deterioration, may be due to insufficient replacement of IgG isotype 3 (IgG3). “Research has shown that one of underlying reasons for the deterioration in lung function is the differential distribution and concentration of Ig isotopes in the airway lumen,” explained Ralph S. Shapiro, MD, consultant neurologist, Midwest Immunology Clinic, Plymouth, Minn. The co-author of a review of this phenomenon (Clin Exp Immunol 2014;178[suppl 1]:65-66), Dr. Shapiro reported that there is now substantial research inte erest in determining whether new clinical strategies are needed. Particularly, he suggested d that therapeutic adjustments may be needed to prevent the IVIG end-of-dose wearing o off that may permit these subclinical infections to persist. The four IgG isotypes, IgG1, IgG2, IgG3 and IgG4, have long been understood to have dif-ferent roles in preventing infection in the respiratory tract, with IgG1 and IgG3 most implicated in preventing infection in the lower respiratory tract (Ann Allergy y 1993;70:3-8). With increasing concern that subclinical respiratory infections result in progressive lung deterioration, attention is being paid to whether these specific isotypes are adequate in replacement therapies. “It appears that IgG3 has a very short half-life relative to the other isotypes. This has led to speculation that there is insufficient IgG3 at the end of [the] dosing interval to prevent low-level infections,” explained Jerry Siegel, PharmD, a clinical associate professor at the Ohio State College of Pharmacy, in Columbus. He suggested that this is leading to a great deal of interest in the relative composition of IgG isotypes and their concentration over the course of treatment. “This is the science behind this issue. It makes sense in theory, but there are no clinical studies yet to demonstrate that the risk of subclinical respiratory infections can be reduced by manipulating these isotypes,” Dr. Siegel added. Several strategies are being considered. One approach is to provide a more favorable composition of IgG isotypes, particularly increasing the IgG3 concentration suspected of being important to defending against these infections. Another is to improve the therapeutic concentration of IgG3 over the dosing interval. “There is greater attention being paid to the isotype make-up of the available formulations,” Dr. Siegel noted, but he cautioned that more evidence is needed to confirm that differences in composition translate into dissimilar clinical effects. —Ted Bosworth Dr. Shapiro reported no relevant ﬁnancial conﬂicts of interest. Dr. Siegel reported a consulting contract with Amgen, a teaching contract with Kedrion and a research contract with CSL Behring.

of IVIG compared with corticosteroids. If cost was eliminated as a factor, IVIG would be likely to win on the basis of tolerability if not efficacy. Although some patients develop allergic reactions or unacceptable side effects, such as headache or nausea, IVIG carries a lower burden of risks than steroids, which can produce a broad range of systemic adverse events, including weight gain, impaired bone metabolism, fat deposits and increased susceptibility to infection. The risk for many of these adverse events increases with treatment duration. “IVIG, in view of the latest trial data, represents a more justified first choice if function is severely impaired, because it offers a higher likelihood of side effect–free therapeutic response in the short term,” said Yusuf A. Rajabally, MD, a consultant neurologist at Regional Neuromuscular Clinic, Queen Elizabeth Neurosciences Center, at the University of Birmingham, in the United Kingdom. However, in a recent review attempting to sort out when to consider IVIG over steroids in CIDP, Dr. Rajabally hesitated to advocate IVIG as a uniform first-line standard ((Muscle Nerve 2015;51:657-661). Like Dr. Siegel, Dr. Rajabally pointed out that IVIG is not without risks, particularly the risk for thromboembolism that may make it an unattractive choice for patients who have an increased risk for clotting. In addition, Dr. Rajabally suggested that steroids might be a better initial choice in mild disease when withdrawal of therapy after a limited course is anticipated. He cited evidence that remissions achieved on steroids are more durable ((J Neurol Neurosurg Psychiatry 2014;85:901-906). Despite several published studies, it is unclear whether IVIG is more effective than corticosteroids for initial control

Clinical 25

Pharmacy Practice News • July 2015

Immunology of CIDP, according to Dr. Rajabally. He observed that most of the comparisons have concluded that the therapies are equivalent. The one exception, a multicenter, randomized, double-blind trial, found that IVIG was less likely to be discontinued at six months due to intolerance, lack of efficacy or side effects ((Lancet Neuroll 2012;11:493-502). However, relapse rates were higher after discontinuation of IVIG than after discontinuation of steroids. Citing the more recently published extension of that double-blind study, which followed patients for a median of 42 additional months, Dr. Rajabally said the proportion of patients with a return of symptoms was similar, but the median time to deterioration after discontinuing therapy was 4.5 months in the IVIG group versus 14 months in the group initially randomized to steroids ((J Neurol Neurosurg Psychiatry 2014; Sept 22. [Epub ahead of print]). “In cases with relatively mild functional disability and without contraindications, corticosteroids may need to be considered as first-line, given the possible greater chance of future relapse-free treatment withdrawal or a longer period of remission,” Dr. Rajabally advised in his review article. For cases in which IVIG is a more attractive choice, cost remains an issue. Using relatively low doses at greater than normal dosing intervals may work for some individuals. In providing some practical advice for CIDP patients in whom good control has been achieved with the standard starting dose of 2 g/kg divided over two to five days, Dr. Siegel noted that there is no welldefined maintenance dose, which may differ among patients. “It is reasonable to reduce the dose in patients who are doing well. In some patients, as little as 400 mg/kg administered every three or four weeks may be sufficient for adequate control,” Dr. Siegel suggested. “If patients continue to do well, one might consider back-

Cytokine production by T cells

Immune cell activation • Macrophage-T-cell interaction via costimulatory molecules • T-cell-mediated stimulation of B cells via cytokines • Antibody production by B cells

CIDP, chronic inflammatory demyelinating polyneuropathy; MAC, membrane attack complex; MHC, major histocompatibility complex; TCR, T-cell receptor Source: Nat Rev Neurol. doi:10.1038/nrneurol.2011.121

ing off the IVIG altogether to see if a remission can be sustained without drug therapy or with intermittent use of steroids.” For the same reasons, Dr. Rajabally also suggested that withdrawal of therapy, whether achieved by slow incremental weaning or a sudden halt of therapy, is justifiable. He cautioned, however, that the reduction in medication cost may be counteracted by a need for more office visits to verify sustained disease control. Drug holidays offer an

numbers What Is Plasma?

Coagulation factors

15%

20%

Immune globulin (IVIG)

Others

60%

Albumin

In order to obtain the necessary amounts of these proteins (plasma derivatives), a considerable amount of human plasma is needed as raw material, because not all the proteins are present in the same proportions in the plasma. Source: Grifols

Complement activation and MAC formation

Figure. Main immunopathogenic network involved in CIDP.

by the

Fc receptor expression and function on macrophages

T-cell adhesion and migration

opportunity to reduce drug costs while decreasing the risk for drug-related adverse events, but the chronicity of CIDP means a high likelihood of eventual relapse off therapy. CIDP has complex underlying mechanisms of action (Figure) and a variable course even with treatment. Both Drs. Siegel and Rajabally recommended objective and periodic disease assessment to consider whether dose adjustments are required. Cautioning against overtreatment with an expensive medication, Dr. Rajabally specifically recommended the sequential use of functional scales that capture relative change in disability. These, he asserted, can be useful for evaluating whether patients are taking the minimally effective dose. Subcutaneous formulations of immune globulins (SQIG) are not a strategy for reducing the costs of IVIG, but some CIDP patients may prefer this route of administration, which is sometimes perceived as more convenient, according to Dr. Siegel. Most appropriate as a maintenance therapy because the IG doses are lower in most of the available SQIG products, this route of administration is often also better tolerated because it is associated with fewer peaks and troughs in plasma

drug concentration, reducing the risk for dose-related adverse events. A new SQIG entry, called HyQvia (Baxter), provides IG doses equivalent to those in IVIG formulations while retaining more favorable pharmacokinetics, but this is the exception. The greatest opportunity for optimizing therapy with IVIG may await biomarkers that reveal disease activity and the effectiveness of treatments in suppressing that activity. Such biomarkers would be expected to permit more rational strategies by identifying the minimally effective dose of any maintenance therapy, not just IVIG or steroids. However, both Drs. Siegel and Rajabally concurred that IVIG may be the most appropriate first-line choice in many CIDP patients, particularly those presenting with significant impairment and in whom continued treatment is likely to be required to maintain symptom control. —Ted Agres Dr. Siegel reported a consulting contract with Amgen, a teaching contract with Kedrion and a research contract with CSL Behring. Dr. Rajabally reported consultant fees, honoraria or other compensation from Baxter, BPL, CSL Behring, Grifols, LfB France and Octapharma.

26 Technology

Pharmacy Practice News • July 2015

Drug Safety

A Molecular Approach To Managing Drug Waste E

mergency rooms treat poisoned and overdosed patients with activated carbon. Now, a resealable pouch called the Deterra Drug Deactivation System, using MAT12 molecular adsorption technology from Verde Technologies, applies the same chemistry principles to help health facilities discard drug waste safely. Deterra renders inert the active ingredients in most of a hospital’s pharmaceutical formulary. It neutralizes nar-

‘If this system is used for controlled substances, it is the burden of the facility disposing the [drugs] to demonstrate that the wastes are all irrecoverable.’ —Firouzan “Fred” Massoomi, PharmD, FASHP cotics, antibiotics, transdermal patches and more—although not hazardous drugs defined by the Resource Conservation and Recovery Act (RCRA) such

as chemotherapy treatments, warfarin or epinephrine, according to Carter Anderson, Verde president and chief technology officer.

Read Pharmacy Practice News Anywhere, Anytime!

To start the deactivation process, a user simply places drugs into the pouch, adds water and seals the top. Liquid morphine in a dissolved state deactivates 99.4% in eight hours; pills and liquids on average deactivate about 80% in eight hours. Because the process takes time, Mr. Anderson suggests the pouch be kept in secure locations with signin sheets for users to log all disposed inventory. Users can safely discard the bag and its contents with the regular trash once drugs are inert, explained Christine Horton, vice president of sales and marketing at Verde.

The patented technology grew out of two research grants from the National Institute on Drug Abuse, a branch of the National Institutes of Health. “The specific activated carbons we use in MAT12 are effective and tenacious in absorbing active pharmaceutical ingredients. Not all carbons are the same. Ours bind to drug molecules very consistently across drug classes and treatments,” Mr. Anderson said. “This is a proven chemistry—and a relatively new application.” To send inert drug waste to the landfill can be better for the environment than incinerating unused drugs, Ms. Horton pointed out. “The pouches have little to no effect on the watershed because drugs are rendered waterinsoluble,” she added. “It [provides] significantly better prevention against watershed contamination than sink and toilet disposal, which is still a com-

Technology 27

Pharmacy Practice News • July 2015

Drug Safety mon hospital occurrence today.” Pouches come in multiple sizes: 15, 45 and 90 pill size, a multipack of three 90s for hospice use, and an 11×11-inch XL size that holds 450 pills, 60 ounces of liquid or 60 patches. All pouches can accommodate liquid waste as well. Users can seal and reseal the pouch repeatedly. Before buying, pharmacists should check with distributors that the pouch meets local, state and federal regulations. Deterra evolved from the Medsaway pouch, which Verde has distributed since 2012 to the public through police departments and advocacy groups; interest is up since the Drug Enforcement Administration apparently ended its drug take-back programs last fall. Also, Mr. Anderson said the largest private surgery center in Minneapolis, an orthopedic clinic, plans to send discharged patients home with pouches to safely dispose of painkillers. “About 70% of painkillers prescribed for patient use at home result in leftover amounts that go unused,” he said. Separately, a few dozen hospitals use Verde’s ContraPatch to safely discard transdermal patches.

‘An Intriguing Option’ To Firouzan “Fred” Massoomi, PharmD, FASHP, a pharmacy operations coordinator at Nebraska Methodist Hospital in Omaha, Deterra could be an “intriguing option” to help home health agencies, hospice nurses, hospice facilities, clinics and physician offices address lowvolume, nonhazardous waste—as long as it meets all regulations, required waste documentation is collected, and drugs aren’t recoverable through manipulation. “If this system is used for controlled substances, it is the burden of the facility disposing the controlledsubstances waste to demonstrate that the wastes are all irrecoverable,” he said. Moreover, facilities that conduct

studies to prove irrecoverability “must include all controlled substances wasted and not representative agents,” Dr. Massoomi emphasized. He also urged that users “associate pouches with a secure container or process” to limit their removal and the risk for diversion. —Al Heller

MAT12 Molecular Adsorption Technology Patented, proprietary activated carbon bonds to pharmaceutical compounds, rendering drugs ineffective and safe for disposal.

Mr. Anderson and Ms. Horton are employees of Verde Technologies. Dr. Massoomi reported no relevant ﬁnancial conﬂicts of interest.

WE TAKE PAIN PERSONALLY REASON #1

THE NEED FOR NON-NARCOTIC PAIN MANAGEMENT THERAPY HAS NEVER BEEN GREATER. Hospitals are looking to reduce adverse events and opioid consumption. 1-3 Patients receiving an opioid prescription within 7 days of surgery were 44% more likely to become long-term opioid users within 1 year when compared with those who received no such prescription.4 ON-Q* is proven to reduce the amount of narcotics patients receive after surgery. 5 For more than 16 years, we have been focused on improving patient outcomes. By continuously working together with clinicians to improve catheter placements and block techniques, the ON-Q* Pain Relief System has been able to reduce the amount of narcotics needed to effectively manage post surgical pain—for each patient and procedure.

FOR MORE INFORMATION CALL (800) 448-3569 OR VISIT HALYARDHEALTH.COM/ON-Q

And send your Twitter handle to davidb@mcmahonmed.com so we can follow you.

There are inherent risks in all medical devices. Please refer to the product labeling for Indications, Cautions, Warnings, and Contraindications. Failure to follow the product labeling could directly impact patient safety. Physician is responsible for prescribing and administering medications per instructions provided by the drug manufacturer. manufacturer Refer to www www.halyardhealth.com halyardhealth com for product safety Technical Bulletins Buulletins.

PAIN MANAGEMENT YOU CAN DEPEND ON.

1. The Joint Commission. Sentinel Event Alert. A complimentary publication of The Joint Commission. Issue 49, August 2012. 2. Attarian, David E. What is a preventable adverse event? AAOS Now. 2008, May. 3. unknown. (12, December). Lifespan adopts emergency department guidelines created to curb opioid misuse and abuse. Retrieved from http://www.acphospitalist.org/archives/2014/02/coverstoryy.htm. 4. Alam et al. Long-term analgesic use after low-risk surgery: a retrospective study. Arch Intern Med. 2012 Mar 12;172(5):425-30. doi: 10.1001/aarchinternmed.2011.1827. 5. Data on ﬁle. ON-Q* Pain Relief System. *Registered Trademark or Trademark of Halyard Health, Inc. or its affiliates. © 2015 HYH. All rights reserved. RX Only. MK-00754

28 Policy

Pharmacy Practice News • July 2015

Profiles in Pharmacy

Roots in Care for Migrant Workers P

atients walking into Salud Family Health Centers in Colorado are just as likely to be greeted with “Hola, puedo ayudarle?” as they are with “Hello, how can I help you?” Bilingual service is just one way that the clinicians at these nine community centers deliver quality health care to individuals who can least afford it. “At least 50% of our patients speak Spanish or prefer to have their health care delivered in Spanish, so we are both bilingual,” said Jeff Freund, PharmD, BCACP, who with Emily Kosirog, PharmD, is one of two clinical pharmacists here. In a unique relationship, both Drs. Freund and Kosirog are assistant professors at the University of Colorado (CU) Skaggs School of Pharmacy and Pharmaceutical Sciences at Anschutz h Medical d l Campus, but spend most of their time at Salud. “Salud and the school of pharmacy are separate entities,” Dr. Freund said. “Our positions are now funded by Medicaid, and we are employees at CU, but we spend just about all our time here at Salud, which makes for a great partnership.” One of the reasons CU is involved is to teach students the importance of caring for patients in the community, he explained. Drs. Freund and Kosirog implemented programs to provide direct and indirect clinical pharmacy services at Salud, which was founded in an onion shed to serve migrant workers in the mid-1970s. It has not forgotten its roots. Although Salud still provides health services through a mobile unit that travels to farms around the state, its primary patient today is indigent, but not necessarily a migrant worker. The pharmacists originally were funded through a Colorado Health Foundation grant. This year, Salud received funding from the Regional Care Collaborative Organizations (RCCOs) that contract with Medicaid to manage patient care and outcomes. The partnership with the RCCOs allows Salud to support Drs. Freund and Kosirog and hire two more clinical pharmacists. “Medicaid is our major insurer, which is why we went to the RCCOs for support,” he said. The pharmacists showed the Centers for Medicare & Medicaid Services (CMS) that their intervention programs improved patient care. Diabetes and heart disease are two primary areas in which the clinical pharmacists make a difference. In one year of pharmacy service: • 69% of patients seen by a pharmacist

had a hemoglobin A1c (HbA1cc) less than 9% versus 44% before the service started; • 72% had a low-density lipoprotein less than 100 mmoL versus 40%; and • 60% had a blood pressure less than 140/90 mm Hg versus 35%. “The biggest thing we do is direct patient care visits,” Dr. Freund said. Patients are referred to the pharmacists by their primary care providers (PCPs), which include physicians, nurse practitioners or physician’s assistants. The

ver. For instance, if Dr. Kosirog increases a patient’s insulin, Dr. McKitrick can review the pharmacy record, see that the patient has not filled a prescription for months and then check back with her to make sure that is what she wants to do. “Despite the number of different ways we ask questions about adherence, sometimes the [retail] pharmacist will provide that additional information patients are unwilling to share,” Dr. Kosirog said. “Then, I can talk to the patient, and they might say, ‘Oh, my cousin gave me all her

Mexico, which adds a unique challenge to patient care, Dr. Kosirog explained. They see doctors in both countries, where their care is managed differently. “So when they come back [to the United States], either their diabetes is super well controlled because they walked everywhere or it is not controlled because they stopped all their meds and ate their grandmother’s cooking,” she said, smiling wryly. “There are a lot of different scenarios,” she added. “A lot of planning has to take place,” Dr. Freund said, to ensure that the issues are managed while patients are away. This includes making sure that patients have enough medication to last their trip. “They will tell us, ‘I’m going to Mexico for three months, I need enough medication.’ This is their life, and they ride the bus back and forth.” Dr. McKitrick tries to work with the patients to ensure that they have enough medication, which is easier to do because the copays are low.

AmeriCorps Lends Support

The dispensing pharmacy at Salud enables patients to take advantage of the best pricing. Inset: The front of Salud—far from its beginnings in an onion shed.

clinical pharmacy visit “goes further than medication reconciliation,” he said. Through Collaborative Drug Therapy Management Protocols, the pharmacists can start, stop and titrate medications based on patient interviews and medical history, which they can access through the electronic medical record (EMR). Salud pharmacists have agreements to manage diabetes, hypertension, dyslipidemia and anticoagulation. “We are making sure that [patients] are taking the medications they say they are, but we are also starting and stopping medications and making sure they are taking them appropriately,” he said. The pharmacy team also provides indirect patient care. If a patient asks a PCP about a medication and the PCP is unsure of the answer or thinks there might be a better option for the patient, a message will be placed in the EMR and the pharmacists will answer as quickly as possible. They might just pop into the room to talk to the patient. “I call these curbside consults,” Dr. Freund said. It is all part of the team approach, explained Ryan McKitrick, PharmD, who manages the dispensing pharmacy at the Salud center in Commerce City, and is a student preceptor for CU Den-

boxes of insulin or I picked up 15 boxes when I was in Mexico.’” Because of the patient mix, the retail pharmacy must manage three different inventories: a normal retail, a 340B and a patient assistance program (PAP) inventory. “I come from a retail background. In retail, you usually have one inventory, and you order your products through your wholesaler—we use AmerisourceBergen—and the drug costs X number of dollars, and you mark up the costs a little. “Here, people get medications at a steeply discounted rate,” Dr. McKitrick said, “and that is very rewarding because they would not be able to afford them otherwise. I managed retail pharmacies, and it felt like it was just numbers, numbers and numbers. Here, I feel we make a difference.” The 340B pricing is an important mechanism that allows Salud to offer products at a substantially discounted rate to qualified patients. (Read more about 340B on page 29.) The PAP program is another way to get expensive drugs into the hands of poorer patients, he said. Although most patients are not migrant workers, many do travel back and forth between the United States and

Another unique program at Salud focuses on transitions of care after hospitalizations, which is spearheaded by AmeriCorps. Volunteers from this federally funded community service group visit the area hospitals, rounding with the care manager, and then offer home visits to help with the transition home. If the patient asks any question about medication while in the hospital, a CU pharmacy student accompanies the volunteer on the home visit. “Probably 95% of students come back from those visits wide-eyed. I tell them, ‘After six weeks here, you will feel like the luckiest person alive.’ Those home visits provide a new perspective on things,” Dr. Freund said. Because Salud believes in caring for the whole patient, the centers also provide dental care, behavioral care and civil legal services, often centered on immigration and housing. “Housing is a huge issue,” Dr. Kosirog said. “It is hard to take care of patients who live in a terrible environment.” In one case, the lawyers and law students convinced a landlord to clean up a moldy apartment, greatly improving a child’s asthma. “Pharmacists are medication experts, and it makes a lot of sense in my mind to have patients who are struggling with management [of their conditions] to see a pharmacist,” Dr. Freund said. For other issues—medical, dental, behavioral or legal—there are other experts at Salud waiting to help. —Marie Rosenthal PHOTOS BY MARIE ROSENTHAL

Policy 29

Pharmacy Practice News • July 2015

Finance

More Oversight of 340B Program Looms

he 340B Drug Pricing Program is undergoing a transformation. Some in Congress are trying to scale back or significantly reduce the program, according to the American Hospital Association, which opposes these actions. Others are trying to hold participants accountable. Along these lines, in mid-June, the Health Resources and Services Administration (HRSA) placed a notice in the Federal Register regarding the calculation of the 340B ceiling price and the imposition of civil monetary penalities. According to the proposal, manufacturers that intentionally overcharge 340B covered entities will be subject to fines of not more than $5,000 for each “instance.”

requirements for the increasing numbers of contract pharmacy arrangements, hospital eligibility criteria and the eligibility of off-site facilities. The withdrawal happened after a federal district court in May last year decided that HRSA’s rulemaking authority for the 340B program is limited to specified areas. Meanwhile, a U.S. Government Accountability Office report, issued March 24, noted that HRSA in fiscal year 2012

implemented two of GAO’s four recommendations from 2011 “to provide reasonable assurance that program participants could comply with the program.” Some critics of the 340B program are calling for its abolishment—a position that makes little sense to Ernest R. Anderson Jr., MS, RPh, a consultant in Brockton, Mass., who attended the ACCC meeting. “One of the things I find remarkable about 340B in Congress is

that politicians wonder how an institution can charge for drugs at their regular fees and still get discounts,” Mr. Anderson said. “It shows they don’t understand 340B at all. If we didn’t have 340B, we would have had a lot of hospitals go out of business.” —Karen Blum None of the sources reported any relevant ﬁnancial conﬂicts of interest.

by the

numbers An example of a 340B discount

How a simple click can help save your life

100

Drug Price ($)

0 Average 340B manufacturer program price ceiling price ($100) ($76.90)

Unit rebate amount/340B discount

Later this year, HRSA is also expected to include a process for manufacturers to issue refunds to covered entities in case of an overcharge, and a process to calculate and validate 340B ceiling prices, according to Leah Ralph, the manager of provider economics and public policy for the Association of Community Cancer Centers (ACCC). “We still need clear, comprehensive rules about how the program should work,” she said. Additionally, “we need clear definitions of what [an eligible] patient and a covered entity is, to be sure that our members can remain compliant in the program.” Last November, HRSA withdrew the “mega rule” it had submitted to the Office of Management and Budget, which was expected to cover the definition of an eligible patient, as well as the compliance

With the ChemoLock™ CSTD, it’s never been easier to minimize exposure to hazardous drugs Keeping safe while preparing hazardous drugs doesn’t need to be complicated. ChemoLock’s intuitive, needlefree “click to lock” design fits seamlessly into your workflow to help you minimize exposure to hazardous medications and maintain drug sterility, while ensuring compliance with USP <800> safe handling recommendations. Don’t you love it when everything just clicks?

Learn more today by visiting go.icumed.com/chemolock-ppn15

* U.S. Pharmacopeial Convention (USP) General Chapter <800> proposed language as of October 10th, 2014.

800.824.7890 | www.icumed.com

NEW

NOW INTRODUCING

CONVENIENCE WITH FEWER VIALS

40 g VIAL

Avoid potential IG waste—With the widest range of vial sizes, dispense IG according to prescription 1 g 2.5 g 5 g 10 g 20 g 40 g Important Safety Information

Visit gamunex-c.com to learn more.

GAMUNEX®-C (immune globulin injection [human], 10% caprylate/chromatography purified) is indicated for the treatment of primary humoral immunodeficiency disease (PIDD), idiopathic thrombocytopenic purpura (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Thrombosis may occur with immune globulin products, including GAMUNEX-C. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer GAMUNEX-C at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IVIG) products in predisposed patients. Patients predisposed to renal dysfunction include those with any degree of preexisting renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIG products containing sucrose. GAMUNEX-C does not contain sucrose. For patients at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable. GAMUNEX-C is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. It is contraindicated in IgA-deficient patients with antibodies against IgA and history of hypersensitivity. Severe hypersensitivity reactions may occur with IVIG products, including GAMUNEX-C. In case of hypersensitivity, discontinue GAMUNEX-C infusion immediately and institute appropriate treatment. Monitor renal function, including blood urea nitrogen (BUN), serum creatinine, and urine output in patients at risk of developing acute renal failure. Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IVIG treatment, including GAMUNEX-C. There have been reports of noncardiogenic pulmonary edema (transfusion-related acute lung injury [TRALI]), hemolytic anemia, and aseptic meningitis in patients administered with IVIG, including GAMUNEX-C. The high-dose regimen (1g/kg x 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern. Because GAMUNEX-C is made from human blood, it may carry a risk of transmitting infectious agents, eg, viruses, and, theoretically, the CreutzfeldtJakob disease (CJD) agent. Do not administer GAMUNEX-C subcutaneously in patients with ITP because of the risk of hematoma formation. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of GAMUNEX-C and at appropriate intervals thereafter. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies, because of the potentially increased risk of thrombosis. If signs and/or symptoms of hemolysis are present after an infusion of GAMUNEX-C, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient’s serum. After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. In clinical studies, the most common adverse reactions with GAMUNEX-C were headache, fever, chills, hypertension, rash, nausea, and asthenia (in CIDP); headache, cough, injection-site reaction, nausea, pharyngitis, and urticaria with intravenous use (in PIDD) and infusion-site reactions, headache, fatigue, arthralgia and pyrexia with subcutaneous use (in PIDD); and headache, vomiting, fever, nausea, back pain, and rash (in ITP). The most serious adverse reactions in clinical studies were pulmonary embolism (PE) in 1 subject with a history of PE (in CIDP), an exacerbation of autoimmune pure red cell aplasia in 1 subject (in PIDD), and myocarditis in 1 subject that occurred 50 days post-study drug infusion and was not considered drug related (in ITP). © 2014 Grifols Inc.

October 2014

GX239-1014

Please see brief summary of GAMUNEX-C full Prescribing Information on adjacent page.

GAMUNEXÂŽ-C

C ?6+8685:+/4+3/' =/:. 8+9;2:'4: ).'4-+9 /4 9+8;3 </9)59/:? '4* +2+):852?:+ /3('2'4)+9 3'? 5));8 /4 6':/+4:9 8+)+/</4- # :.+8'6? Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified C !.853(59/9 .'9 5));88+* /4 6':/+4:9 8+)+/</4- # :.+8'6? 54/:58 6':/+4:9 =/:. 145=4 8/91 ,'):589 ,58 :.853(59/9 )549/*+8 HIGHLIGHTS OF PRESCRIBING INFORMATION ('9+2/4+ '99+993+4: 5, (255* </9)59/:? ,58 :.59+ ': 8/91 5, .?6+8 </9)59/:? These highlights do not include all the information needed to use GAMUNEXÂŽ-C safely and effectively. See full prescribing C 9+6:/) +4/4-/:/9 ?4*853+ .'9 (++4 8+658:+* =/:. information for GAMUNEX-C. " $ '4* 5:.+8 # :8+':3+4:9 +96+)/'22? =/:. ./-. *59+9 58 8'6/* /4,;9/54 GAMUNEXÂŽ-C, [Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified] C +352?:/) '4+3/' )'4 *+<+256 9;(9+7;+4: :5 # :.+8'6? *;+ :5 +4.'4)+* 9+7;+9:8':/54 54/:58 6':/+4:9 ,58 .+352?9/9 '4* Initial U.S. Approval: 2003 .+352?:/) '4+3/' WARNING: THROMBOSIS, RENAL DYSFUNCTION C 54/:58 6':/+4:9 ,58 6;2354'8? '*<+89+ 8+'):/549 :8'49,;9/54 and ACUTE RENAL FAILURE 8+2':+* ');:+ 2;4- /40;8? %! & See full prescribing information for complete boxed warning. C #52;3+ 5<+825'* E $3=:8-:>4> 8,y occur with immune globulin products, including GAMUNEX-C. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors.

E := ;,?409?> at risk of thrombosis, administer GAMUNEX-C at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. E "09,7 /Csfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. E "09,7 /Csfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. GAMUNEX-C does not contain sucrose. E := ;,?409?> at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable.

C " $ /9 3'*+ ,853 .;3'4 62'93' '4* 3'? )54:'/4 /4,+):/5;9 '-+4:9 + - </8;9+9 '4* :.+58+:/)'22? :.+ 8+;:@,+2*: '15( */9+'9+ '-+4: C " $ /9 45: '6685<+* ,58 9;();:'4+5;9 ;9+ /4 ! 6':/+4:9 ;+ :5 ' 65:+4:/'2 8/91 5, .+3':53' ,583':/54 *5 45: '*3/4/9:+8 " $ 9;();:'4+5;92? /4 6':/+4:9 =/:. ! C '99/<+ :8'49,+8 5, '4:/(5*/+9 3'? )54,5;4* 9+8525-/) :+9:/4- ----------------------------ADVERSE REACTIONS ---------------------------+8/5;9 '*<+89+ 8+'):/549 =./). 5));88+* /4 :.+ )2/4/)'2 :8/'29 =+8+ '4 +>')+8(':/54 5, ';:5/33;4+ 6;8+ 8+* )+22 '62'9/' /4 54+ 9;(0+): '4* 6;2354'8? +3(52/93 /4 54+ 9;(0+): =/:. ' ./9:58? 5, !.+ 359: )53354 '*<+89+ 8+'):/549 5(9+8<+* /4 âą&#x2013; 6':/+4:9 =+8+ PI 4tra<enous +'*').+ )5;-. /40+):/54 9/:+ 8+'):/54 4';9+' 6.'8?4-/:/9 '4* ;8:/)'8/' ;();:'4+5;9 4,;9/54 9/:+ 8+'):/549 .+'*').+ ,':/-;+ '8:.8'2-/' '4* 6?8+>/' ITP +'*').+ <53/:/4- ,+<+8 4';9+' (')1 6'/4 '4* 8'9. CIDP +'*').+ ,+<+8 )./229 .?6+8:+49/54 8'9. 4';9+' '4* '9:.+4/'

To report SUSPECTED ADVERSE REACTIONS, contact Grifols Therapeutics Inc. at 1-800-520-2807 or FDA at 1-800-FDA-1088 or GAMUNEX-C is an immune globulin injection (human), 10% liquid www.fda.gov/medwatch. indicated for treatment of: ----------------------------DRUG INTERACTIONS ---------------------------C 8/3'8? ;358'2 33;45*+A)/+4)? C !.+ 6'99/<+ :8'49,+8 5, '4:/(5*/+9 3'? :8'49/+4:2? /4:+8,+8+ =/:. C */56':./) !.853(5)?:56+4/) ;86;8' ! :.+ 8+96549+ :5 2/<+ </8'2 <'))/4+9 9;). '9 3+'92+9 3;369 '4* C .854/) 4B'33':58? +3?+2/4':/4- 52?4+;856':.? 8;(+22' --------------------------INDICATIONS AND USAGE -------------------------

----------------------------CONTRAINDICATIONS ----------------------------

---------------------USE IN SPECIFIC POPULATIONS ---------------------

C 4'6.?2'):/) 58 9+<+8+ 9?9:+3/) 8+'):/549 :5 .;3'4 C immunoglobulin C C - *+A)/+4: 6':/+4:9 =/:. '4:/(5*/+9 '-'/49: - '4* ' ./9:58? 5, .?6+89+49/:/</:?

8+-4'4)? 45 .;3'4 58 '4/3'2 *':' "9+ 542? /, )2+'82? 4++*+* +8/':8/) 4 6':/+4:9 5<+8 ?+'89 5, '-+ *5 45: +>)++* :.+ recommended dose, and infuse GAMUNEX-C at the minimum /4,;9/54 8':+ 68'):/)'(2+

----------------------WARNINGS AND PRECAUTIONS---------------------C - *+A)/+4: 6':/+4:9 =/:. '4:/(5*/+9 '-'/49: - '8+ ': -8+':+8 8/91 5, *+<+256/4- 9+<+8+ .?6+89+49/:/</:? '4* '4'6.?2'):/) 8+'):/549 '<+ +6/4+6.8/4+ '<'/2'(2+ /33+*/':+2? :5 :8+': '4? ');:+ 9+<+8+ .?6+89+49/:/</:? 8+'):/549 C 54/:58 8+4'2 ,;4):/54 /4)2;*/4- (255* ;8+' 4/:85-+4 9+8;3 8/,529 !.+8'6+;:/)9 4) )8+':/4/4+ '4* ;8/4+ 5;:6;: /4 6':/+4:9 ': 8/91 5, *+<+256/4- ');:+ +9+'8). !8/'4-2+ '81 " 8+4'2 ,'/2;8+ " /)+49+ 5

3036439/3036440-BS Revised: 7/2014

32 Policy

Pharmacy Practice News • July 2015

Supply Chain

Preparation is crucial for track-and-trace legislation to work

Make a Plan for DSCSA Compliance David Aguero, PharmD Pharmacy Supervisor Inova Health System Alexandria, Virginia

he Drug Supply Chain Security Act (DSCSA) was signed into law on November 27, 2013, as Title II of the Drug Quality and Security Act (DQSA) of 2013. While Title I contains important provisions related to oversight of compounding of drugs for use in humans, Title II outlines critical steps to build an electronic, interoperable system to identify and trace prescription drugs throughout the supply chain. DSCSA went into effect on January 1, 2015 for wholesalers and distributors. Dispensers (pharmacies) are required to be in compliance as of July 1 (Table, page 35). Under the act, all trading partners must be licensed and authorized. Some requirements of the law, such as maintaining digital records, will be phased in over the next decade. (For more information on DSCSA compliance for pharmacists, see Pharmacy Practice News, http://goo.gl/1opbqo.)

nate data processing and storage. • Dispenser: An entity licensed under the law (state law for dispensers) to dispense drugs to a patient (see box for examples of dispensers).

Describing Traceability The ability to verify the history, location and transaction information of a product in the supply chain is under-

TS (Figure). This still applies to loan and/or borrow situations where a transaction is taking place.

Key Exemptions to DSCSA Some drugs are exempt; they are not considered DSCSA “products” and thus are not subject to DSCSA regulations. The following is a list of products that are exempt from the DSCSA:

Transaction history

Manufacturer

• Transaction information

Wholesaler

• Transaction statement

mation against a database wherein the theft would become apparent, and the thief would go to jail. Applying this analogy to DSCSA, the officer would stop the driver, ask for his or her registration information, but if the driver could produce this information (any track and trace information), the police officer would simply let them go! Recording information without verifica-

Transaction history • Second transaction information • Transaction information • Transaction statement

Hospital (Dispenser)

Figure. As a drug product moves through the supply chain, transaction information and other key documents need to be in place to ensure DSCSA compliance and product integrity.

Who are the Players? The legislation standardizes the definition of several entities, including: • Manufacturer: A person or entity that is licensed under DSCSA to manufacture products or a co-licensed partner that obtains the product from that entity. • Repackager: An entity that owns or operates an establishment that repackages and relabels a product or package pursuant to the law. • Wholesale distributor: A person or entity other than the manufacturer or repackager engaged in distribution of a prescription product to someone other than the patient. • Third-party logistics provider: A contracted vendor that will help warehouse product track-and-trace information. These entities coordi-

Examples Of Dispensers • Chain or independent pharmacies • Health systems • Retail clinics • Dispensing oncology clinics • Dentists or physicians, if dispensing

stood as traceability. DSCSA defines three terms used in traceability: • Transaction information (TI) is information likely already received but never generated: name, strength and dosage form, lot, and National Drug Code (NDC) number, container size, number of containers, date of the transaction, and names of the new and former owners of the product. • Transaction history (TH) is a statement, in paper or electronic form, that includes the transaction information for each prior transaction going back to the manufacture of the product. • Transaction statements (TS) take the form of a binding paper or electronic statement documenting that an entity did not knowingly ship a suspect or illegitimate product. These materials also show that the entity received the product from a DSCSAlicensed facility. The DQSA legislation focuses on change of ownership (the entity that actually owns the product) rather than change of custody (the physical location of the product). These changes of ownership, generally from wholesale distributors to dispensers or from manufacturers to dispensers, are called transactions in the legislation. Any medication sold from one dispenser to another is considered a transaction and needs to be accompanied by TI, TH and

• Compounded drugs (regulated under Title I of DQSA) • Imaging drugs • Medical gases • IV fluids • Irrigation products and sterile water • Over-the-counter drugs • Radioactive drug products (regulated by the Nuclear Regulatory Commission)

When Good Drugs Go Bad When was the last time you experienced a hiccup in your supply chain? The law coins two terms: A suspect product is one wherein there is reason to believe that the product may be potentially counterfeit, adulterated, diverted, subject to a fraudulent transaction, or otherwise unfit for sale/ distribution. Once this product is confirmed to be unfit for distribution, the law refers to the product as an illegitimate product. Any number of issues could trigger an investigation in the supply chain, and dispensers will need to be prepared to respond to any request to investigate. Consider the following scenario: A thief is driving a stolen car. Unfortunately for that thief, an officer has just pulled him or her over because the stolen car’s taillight is out. Normally, the officer would ask for a license and registration information, check the infor-

tion of its integrity has limited utility. The current DSCSA implementation reality is that any tracing is retroactive. An investigation must be launched to discover whether or not a transaction is of a questionable nature. There is no master database against which one can verify product information.

To Loan or Not To Loan Consider the following hypothetical situation: On a Friday afternoon, an oncology patient is transferred to your facility. The patient urgently needs a medication that you do not stock and cannot obtain through your wholesaler. First, if you’re part of a health system, can you obtain it from anywhere else in your network? All entities under common control (e.g., hospitals in a system or groups of chain pharmacies) are viewed as a single dispenser under DSCSA. As such, affiliated warehouses and distribution centers under common ownership are also considered under common control of the parent organization. This means that hospitals in the same system can lend to each other without recording or transmitting TI, TH and TS. Second, the law allows for the transfer of a product between dispensers to fill a prescription for an identified patient in need (specific patient need), which is not see DSCSA, page 35

Si plify Now available Kabiven® and Perikabiven® Fresenius Kabi’s three-chamber bags for parenteral nutrition contain: • Amino Acids and Electrolytes • Dextrose • Lipids (Intralipid® 20% IV Fat Emulsion) www.KabivenUSA.com. To order, call 1-888-386-1300. Kabiven and Perikabiven three-chamber bags must be activated prior to infusion. For activation instructions see DIRECTIONS FOR ACTIVATING THE BAG in the prescribing information available at www.KabivenUSA.com. Neither Kabiven nor Perikabiven is recommended for use in pediatric patients < 2 years, including preterm infants because the ﬁxed content of the formulations do not meet the nutritional requirements in this age group. WARNING: DEATH IN PRETERM INFANTS

See full prescribing information for complete boxed warning • Deaths in preterm infants have been reported in literature. • Autopsy ﬁndings included intravascular fat accumulation in the lungs. • Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products, or to any of the active substances or excipients. Monitor patient closely for signs and symptoms of infection, hypertriglyceridemia, hyperglycemia and refeeding complications. Monitor laboratory parameters for alterations in electrolytes, liver and renal impairment, ﬂuid status and coagulation parameters. Adjust rate and dose of Kabiven and Perikabiven according to clinical status. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, Vigilance & Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see Brief Summary of Prescribing Information, including Boxed Warning, for Kabiven and Perikabiven on the following page.

BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Kabiven and Perikabiven safely and effectively. See full prescribing information, including Boxed Warning, for Kabiven and Perikabiven available at www.KabivenUSA.com. KABIVEN® (Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion), for intravenous use Initial U.S. Approval: 2014 PERIKABIVEN® (Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion), for intravenous use Initial U.S. Approval: 2014 WARNING: DEATH IN PRETERM INFANTS See full prescribing information for complete boxed warning • Deaths in preterm infants have been reported in literature. • Autopsy findings included intravascular fat accumulation in the lungs. • Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. INDICATIONS AND USAGE Kabiven and Perikabiven are each indicated as a source of calories, protein, electrolytes and essential fatty acids for adult patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Kabiven and Perikabiven may be used to prevent essential fatty acid deficiency or treat negative nitrogen balance in adult patients. Limitation of Use: Not recommended for use in pediatric patients < 2 years, including preterm infants, because the fixed content of the formulation does not meet nutritional requirements in this age group.

DOSAGE AND ADMINISTRATION

WARNINGS AND PRECAUTIONS

• Kabiven is for intravenous infusion only into a central vein • Perikabiven is for intravenous infusion into a central or peripheral vein • Recommended dosage depends on clinical status, body weight and nutritional requirements • Kabiven adult dosage: 19 to 38 mL/kg/day (0.63 to 1.26 g/kg/day of amino acids, 1.85 to 3.71 g/kg/day of dextrose, 0.74 to 1.48 g/kg/day of lipid) • The maximum infusion rate for Kabiven is 2.6 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.1 g/kg/hour of lipid) • Perikabiven adult dosage: 27 to 40 mL/kg/day (0.64 to 0.94 g/kg/day of amino acids, 1.83 to 2.71 g/kg/day of dextrose, 0.95 to 1.4 g/kg/day of lipid) • The maximum infusion rate for Perikabiven is 3.7 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.13 g/kg/hour lipid) • The recommended infusion period is 12 to 24 hours

• Hypersensitivity reactions: Monitor for signs or symptoms and discontinue infusion if reactions occur • Infection, fat overload, hyperglycemia and refeeding complications: Monitor for signs and symptoms; monitor laboratory parameters

DOSAGE FORMS AND STRENGTHS • Kabiven and Perikabiven are sterile, hypertonic emulsions in a three-chamber container. The individual chambers contain one of the following: amino acids and electrolytes, dextrose, or lipid injectable emulsion, respectively • Kabiven is available in four sizes 2566 mL, 2053 mL, 1540 mL and 1026 mL • Perikabiven is available in three sizes 2400 mL, 1920 mL and 1440 mL CONTRAINDICATIONS • Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products, or to any of the active substances or excipients • Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1000 mg/dL • Inborn errors of amino acid metabolism • Cardiopulmonary instability • Hemophagocytic syndrome

ADVERSE REACTIONS The most common adverse reactions to Kabiven (>3%) are nausea, pyrexia, hypertension, vomiting, decreased hemoglobin, decreased total protein, hypokalemia, decreased potassium and increased gamma glutamyltransferase. The most common adverse reactions to Perikabiven (> 3%) are hyperglycemia, hypokalemia, pyrexia and increased blood triglycerides. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, Vigilance & Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Coumarin and coumarin derivatives, including warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters USE IN SPECIFIC POPULATIONS Renal Impairment: Patients on hemodialysis or continuous renal replacement therapy may require additional supplementation to meet nutritional requirements. If required, adjust the volume of Kabiven or Perikabiven administered based on serum electrolyte levels and ﬂuid balance.

Policy 35

Pharmacy Practice News • July 2015

Advocacy the looming

It’s Time To Get Serious About Provider Status crisis 90,000 Denver—Bills granting provider status to pharmacists are gaining ground in Washington, but there is still a lot of work to do before they become law, according to Joe Hill, the director of federal legislative affairs at the American Society of Health-System Pharmacists (ASHP). “Provider status is the biggest issue facing [the profession],” Mr. Hill told Pharmacy Practice News at the ASHP Summer Meeting. If approved, the two bills (H.R. 592/S. 314) would enable patient access to, and reimbursement for, Medicare Part B services by state-licensed pharmacists in medically underserved communities. The pharmacist services would be consistent with states’ scope of practice laws. “We’ve made significant progress in terms of getting support from both parties,” Mr. Hill said. Many members of the House and the Senate represent indi-

DSCSA continued from page 32

considered a transaction and does not require tracking information. Dispensers should have an honest conversation about how to handle loan and borrow situations. Because transfer of a product between pharmacies under common control does not have to be tracked, some health systems are choosing to only loan between different facilities belonging to the health system. Some health systems have chosen not to record lot-level information as part of their strategy, whereas others will choose full compliance and will hire staff to record lot and expiration information for all incoming products. Note, however, that manually recording the lot and expiration information for every product may be prone to error.

viduals living in areas with limited access to health care providers, and they are looking favorably at these bills. “We have been able to work with these members of Congress and demonstrate how we are going to help their constituents.” Despite the support, the bills still face challenges. The biggest obstacle is financial. Legislators are hesitant to approve a change that will increase Medicare costs, Mr. Hill said, so he will be working with the Congressional Budget Office to develop a score—an official cost estimate— for the bills. Although there will be an increase initially, there should be downstream savings in terms of fewer surgeries, emergency department visits, and hospital admissions and readmissions. “We believe [pharmacy-provided care] is a cost-effective approach to addressing a looming health care crisis,” he said.

Another key to the bills’ passage is getting as many legislators as possible to sign on as cosponsors, Mr. Hill noted, stressing that pharmacists can help in such advocacy efforts. Beyond writing letters and sending emails to their legislators, he said, pharmacists should call the district office and ask to meet with a staff member about this issue. (According to the Congressional Management Foundation, 94% of Capitol Hill staffers believe that visits to district offices influence representatives.) Many legislators hold local town hall meetings in August, and local ASHP chapters are organizing groups to attend these meetings. Go with them, he urged. When meeting with representatives, Mr. Hill suggested that pharmacists discuss their training, what they do and how they can improve patient care. “No

Table. Important DSCSA Compliance Dates For Dispensers Dates

Comments

January 1, 2015

Trading partners must be licensed and authorized.

July 1, 2015

Receive TI, TH and TS for all purchased medication stock and provide this information for any product sold. Respond to audits or requests from regulatory agencies within 2 business days. Archive TI, TH and TS in a retrievable format for 6 years after transaction or investigation.

November 27, 2020

Dispensers may only purchase or sell medication stock that has a unique product-level identifier (2D barcode) on each unit level package. Serialization requirements include a unique standardized numerical serial number for each package.

November 27, 2023

Transaction data must be exchanged in a secure interoperable electronic manner, including serialization information at the smallest saleable unit level. Unit-level traceability for all members in the supply chain expected.

DSCSA, Drug Supply Chain Security Act; TH, transaction history; TI, transaction information; TS, S, ttransaction a sact o statements state e ts

The 340B Dilemma The federal 340B Drug Pricing Program facilitates the provision of outpatient medications to eligible health care organizations at reduced prices, easing costs to providers who service governmental program enrollees. The DSCSA does not address the 340B program at all, and there is a lack of clarity about contract pharmacy 340B product responsibilities. Drug stock that is purchased by the health system is shipped by the wholesale distributor to a local contract pharmacy for dispensing. The product goes to the local contract pharmacy, but the TI, TH and TS documentation would currently go to the administering health system, which is generally under different ownership and not covered by common control.

Many entities involved in compliance documentation have requested that the FDA exempt contract pharmacies from participating in compliance tracking due to the nature of contract pharmacy workflow, but the FDA has not yet issued any rule in response to this request.

Pharmacy’s To-Do List Compliance and uninterrupted patient care are the end goals. First and foremost, make sure to understand the law; there are likely individuals with legal resources within your organization who can help. A number of items need to be considered as departments prepare for compliance. At minimum, they should establish written policies and procedures. Dispensers should have

systems in place to trace drug stock and investigate its origin. If suspect or illegitimate product is discovered, how will the pharmacy notify regulatory agencies and other trading partners? How will the quarantine process be handled? How will the pharmacy actually respond if a request for information from a regulatory agency is received? What is the process for handling product returns? Departments may want to work with their wholesalers to determine a process for when product arrives at the pharmacy with no track-and-trace information or when expected product does not arrive, the latter only requiring the product be sent to the dispenser based on change of ownership. In addition, take the following actions:

Fewer physicians

58 million New retirees As the number of physicians continues to decrease, the number of Medicare recipients will increase. Source: HRSA

one can do that better than you,” he said. “We really need to make a push this summer that we are serious about this legislation. Now is the time to [get it passed].” —Marie Rosenthal To watch a video interview with Mr. Hill on provider status and other key policy issues affecting the pharmacy profession, visit pharmacypracticenews.com/Hill0715.

• Review the law with your legal team. Make sure you’re familiar with the pertinent regulations. • Establish procedures to identify and quarantine suspect product, to notify stakeholders and to respond to inquiries from public officials. • Begin communication with your wholesale distributor and consider how the information retention requirements will affect your contract. • Communicate with your drop-ship or non-wholesale suppliers and plan for how you will receive and store TI, TH and TS from these entities. • Plan for record retention and access, including budgeting for implementing a plan to store and retrieve compliance information. • Consider contracting with a thirdparty logistics provider to obtain storage and retrieval solutions.

Discretionary Enforcement On June 30th, the FDA announced a delay in enforcement to dispensers, meaning that the agency will not take action against dispensers who, prior to Nov. 1, 2015, accept product without the required compliance documentation. However, other federal or state agencies are able to enforce the DSCSA law. Additionally, this enforcement delay does not apply to dispensers who resell or loan product, wherein appropriate compliance documentation must still be provided and recorded. Thus, the time is still now to prepare for the regulation’s eventual implementation. Readers are encouraged to follow the above guidance and pursue compliance. For relevant literature and suggested reading, see online version at pharmacypracticenews.com/0715DSCSA

36 Policy

Pharmacy Practice News • July 2015

Reimbursement Matters

Under Pressure From Three Big Issues!

ou may feel overwhelmed and helpless amid the onslaught of changes that health care payment reform has brought about and will continue to do so. These changes are coming from all payors, not just from Medicare in response to the realization that the pace of increasing costs is not sustainable. Since a substantial portion of these cost increases is related to drugs, pharmacy plays an important role in strategically shaping a response.

Learning to be cross-functional and recognizing how addressing one issue may solve others are vital skills. Let’s look at three major interrelated issues that all facilities are grappling with. Rather than being overwhelmed by the perceived complexity of solving all three of these challenges, think of how solutions to one can depend upon and can assist with solutions to the other two.

The issues consist of: • The transition from International Classification of Diseases, 9th revision (ICD-9) to ICD-10 • The increasing burden of recovery audit contractor (RAC) audits • The need to streamline prior authorizations and meet local coverage determination (LCD) and national coverage determination (NCD) requirements In tackling these three issues, re-

Advances in Probiotic Therapy For Diarrhea-Associated Illness To participate in this FREE CME activity, log on to

www.CMEZone.com

Release Date: February 10, 2014

Expiration Date: August 11, 2015

Chair

Statement of Need

Intended Audience

William D. Chey, MD

Probiotics can be powerful tools in managing a number of medical conditions. However, efficacy may be suboptimal if these agents are not used appropriately. As public interest in the benefits of probiotics increases, so does the need for clinical education. Many physicians and patients are unfamiliar with the nuances of probiotic pharmacology, or—with many probiotics available for over-the-counter purchase— may not be aware that their patients are selecting ineffective therapies. Thus, it is important for health care professionals to familiarize themselves with the latest research data on probiotic use.

Gastroenterologists, primary care physicians, nurse practitioners, nurses, physician assistants, pharmacists, and other health care professionals involved in the care of patients who may beneﬁt from the use of probiotic therapy.

Professor of Internal Medicine Director, Gastrointestinal Physiology Laboratory Co-Director, Michigan Bowel Control Program H. Marvin Pollard Institute Scholar Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Faculty Brooks Cash, MD Professor of Medicine Division of Gastroenterology University of South Alabama Mobile, Alabama

Shanti Eswaran, MD Clinical Assistant Professor Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Goal The goal of this educational activity is to provide clinicians with current evidence and strategies for eﬀective probiotic therapy in a variety of disease states.

Learning Objectives Upon completion of this activity, the participant will be better prepared to do the following: 1 Review key diﬀerentiating characteristics of various probiotic therapies, including mechanism of action. 2 Describe the importance of strain speciﬁcity in the clinical applicability of probiotic therapies.

Estimated Time for Completion 1 hour

Course Format Monograph

Accreditation Statement 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.

Credit Designation AKH Inc. designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should claim only the credit commensurate with the extent of their participation in the activity.

3 Discuss the role of probiotic therapy in clinical digestive ailments. 4 Review strategies for appropriate patient selection and education in the use of probiotic therapies.

Jointly sponsored by AKH Inc. and Applied Clinical Education

Supported via an educational grant from Procter & Gamble

Distributed via CMEZone and Gastroenterology and Endoscopy News

“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health. Please email the author at BonnieKirchen baum2@gmail.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP

member that they all are linked by a common goal: the need to tell the patient’s story accurately and completely through documentation. The transition from ICD-9 to ICD-10 is scheduled to occur Oct. 1, 2015. ICD-9 is such old technology—it was created in 1979! Why is anyone even thinking of objecting to upgrading? Of course there are some new skill sets to learn, just as there are with any new upgrade that you embrace (think of your phone, tablet, etc.). The coders who are a part of the revenue cycle team comb over what is in the patient’s medical record and assign codes to the disease states and conditions that they find along with procedures and treatments. A requirement for success is a substantial improvement in documentation in the electronic health record (EHR) and the modification of order sets in computerized prescriber order entry (CPOE). This is equally important in both the inpatient and outpatient settings. The increasing burden of RAC audits affects health care facilities both administratively and financially. Currently, most of these RAC audits focus on medical necessity issues. As an example, a payor sees a reimbursement request for a biologic but does not receive any information regarding its medical necessity. Perhaps the oversight is due to poor documentation, but whatever the cause, if there is nothing in the medical record to code, nothing can be sent to the payor. This too is equally important in both the inpatient and outpatient settings. The need to streamline prior authorizations and meet LCD and NCD requirements is essential to receiving proper payment. Pharmacy holds a large part of this responsibility and can use existing systems to improve this process.

Key Tasks To Ensure Payment • Using the data available on your Medicare Administrative Contractor (MAC) website, list the drugs and biologics that have LCD and NCD requirements. • Determine your largest payors, then list those drugs and biologics that have prior authorization requirements. • Integrate the need for these prior authorizations into your pharmacy computer system. Although a variety of methods exist for adding this information, the goal for any approach is to trigger a pop-up message that asks for documentation of prior authorization when the drug order is entered. • If payor information is not routinely

Policy 37

Pharmacy Practice News • July 2015

Reimbursement Matters

Table. New HCPCS Codesa Effective for Dates of Service On or After:

HCPCS Code

March 6, 2015

Long Description

Short Description

Type of Service (TOS)

Q5101

Injection, Filgrastim (GCSF), Biosimilar, 1 microgramb

Inj filgrastim g-csf biosim

1, P

July 1, 2015

Q9976

Injection, Ferric Pyrophosphate Citrate Solution, 0.1 mg of iron

Inj Ferric Pyrophosphate Cit

1, L

July 1, 2015

Q9978

Netupitant 300 mg and Palonosetron 0.5 mg, oral

Netupitant Palonosetron oral

July 1, 2015

Q9977

Compounded Drug, Not Otherwise Classified

Compounded Drug NOC

1, P

Status Indicator (SI)

This release also updates Section 20.1.2 Average Sales Price (ASP) Payment Methodology in Chapter 17 of the “Medicare Claims Processing Manual” to show that, beginning in July 2015, claims for compounded drugs should be submitted using a compounded drug, NOC HCPCS code. b

The e first st d drug ug e entry t y iss in a anticipation t c pat o o of tthe e co commercial e c a release e ease o of tthe eb biosimilar os a GCS GCSF p product. oduct

available to you upon order entry, work with information technology (IT) to correct the omission. • Determine who in your facility is responsible for handling prior authorizations and meeting LCD and NCD requirements (e.g., patient navigator). • Working with the patient navigator, create a place in the EHR for documentation of prior authorizations and LCD/NCD requirements. • When frustrations start to overwhelm you, remember that it’s the pharmacy’s budget that bears the brunt of failure to make this work! What do these three issues share in common? They all depend on using the substantially improved in-depth clinical descriptions in the ICD-10 codes to document why the patient is being treated, and for which conditions. They also involve meeting the requirements posed by prior authorizations and LCDs and NCDs to ensure accurate payment—and in the process avoid painful RACs! It’s all about documentation.

Additions for Your e-Library! I would strongly suggest making MLN Matters Number: SE1516 Chronic Care Management (CCM) Services Frequently Asked Questions (FAQs) a part of your e-library on proper payment procedures. CCM is one of the critical components of primary care that contributes to better outcomes for individuals, as well as reduced spending. Recognizing this, Medicare pays separately under the Physician Fee Schedule (PFS) under American Medical Association Current Procedural Terminology (CPT) code 99490, for non–face-to-face care coordination services furnished to Medicare beneficiaries with multiple chronic conditions. This became effective Jan. 1, 2015. The CCM Services Fact Sheet is a resource that succinctly identifies the newly payable CCM service, identifies eligible providers and patients, and details the PFS billing requirements. The revised Fact Sheet is available at https:// goo.gl/G5Jo3M on the Centers for Medicare & Medicaid Services (CMS) website. Your e-library should also include MLN Matters Number: MM9167 Quarterly Healthcare Common Procedure Coding

System (HCPCS) Drug/Biological Code Changes—July 2015 Update. The document lists updated HCPCS codes (Table) that your billing department needs to heed to ensure proper reimbursement.

July 2015 Average Sales Price Files Now Available CMS has posted the July 2015 Average Sales Price (ASP) and Not Otherwise Classified (NOC) pricing files and crosswalks. All are available for download on the 2015 ASP Drug Pricing Files Web page at http://goo.gl/rsJRGI. ■

Oncology Pharmacy Practice Management Program September 18–19, 2015 | Hilton Rosemont/Chicago O’Hare | Chicago Program Highlights • USP <800> Compliance • Standardized Training Programs • Billing and Reimbursement • Medication Assistance Programs • Networking with the Experts

Preconference Workshop Utilizing Medication Assistance Programs, Handling Off-Label Requests, Managing HighDollar Medications, and Other Financial Pearls

Examine how to provide a high level of clinical practice when patients demand more even as front offices and third-party payers require it to be done with less. Learn how to implement ﬁnancially efficient pharmacy services to a patient group that is in dire need. Get perspectives from leaders who have achieved this balance and provide practical solutions for challenges you may face at your facility.

View the full agenda at www.hoparx.org. Register before August 17 to save $70 on full member rate.

38 Operations & Management

Pharmacy Practice News • July 2015

Leadership in Action

Resolve To ‘Own It All’ “In the long run we shape our lives and shape ourselves. The process never dies. And the choices we make are ultimately our own responsibility.” —Eleanor Roosevelt

oday’s leaders are overwhelmed by complex responsibilities, overloaded by a flood of information and overstressed by the pace of crisis management and the pressures of dealing with difficult people. This “leader shock” is a huge challenge that managers must overcome. Fortunately, there is a way through this multitasking mess. In his book, “Leader Shock and How To Triumph over It: Eight Revolutionary Rules for Becoming a Powerful and Exhilarated Leader” (McGraw-Hill, 2004), Greg Hicks offers several strategies for coping with this ever-growing list of tasks and responsibilities.

Intention and Responsibility Last month, we concentrated on Hicks’ idea of “being intentional” in everything we do, and communicating our inten-

tion to our coworkers. This month, we’ll expand on that, and also look at taking responsibility to “own it all.” Pharmacy leadership is no cakewalk, to be sure. As I have watched our profession for the past 39 years, I have seen a surge in the complexity of practice. I remember years ago how computerizing all that we do was celebrated because we thought it would “simplify” our lives. Ha! Our computer age has only added more complexity by increasing our connectivity to a point that it seems we are working 24/7/365. Our smartphone replaced the beeper years ago. Anyone can call at any time to ask questions that are deemed important to him or her. Here’s a case in point: I remember getting a call from the chief medical officer (CMO) of my health system on a Saturday afternoon while I was at my grand-

son’s basketball game. She wanted me to immediately act to resolve an adverse drug reaction (ADR) that was occurring to a brand of lisinopril at one of our hospital’s emergency departments that seemed to be “a trend” (three cases). The system’s cardiologist was involved as well. I responded that the ADR situation would have to wait until Monday, because the FDA was not open on Saturday. The CMO then asked me why there was cheering in the background. I stated that my priorities had taken me to my grandson’s basketball game. What enabled me to reject my CMO’s push to “fix it now”? Why didn’t I move into the crisis mode she seemed to be slipping into? Part of the answer is intention: I had decided that my grandson’s basketball game was the most important thing to me that day, and barring a real crisis, my goal was to “own” that decision and follow through on it, even when outside circumstances could have thrown me off track. This is a page out of Hicks’ playbook: He urges us to become 100% responsible for our intentions, rather

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, of Brockton, Mass. Mr. Anderson welcomes your input on leadership issues, at ernestanderson1130 @gmail.com

Ernest R. Anderson Jr., MS, RPh

than seeing ourselves as victims when others try to dictate the terms of our day, our responsibilities, etc. This concept of intention extends to the people we manage and the culture we create in our departments. Try remembering this mantra—I am responsible! I am accountable! I own it all!—even if that mindset seems counterintuitive. It’s a worthwhile exercise, because if we instead assume that people and outside factors control how we feel and act at work, then we are no longer in charge. Of course, this doesn’t mean you don’t hold others accountable for their negative behavior. But leaning too heavily on blame in such situations can be toxic to effective leadership. As Hicks states in his book, “it’s virtually impossible to feel invigorated, competent or powerful, and indulge in blaming at the same time. Blame is a swamp.”

CLASSIFIEDS

Career Opportunities Education Financial & Legal Services

Career Opportunities

Got Job Openings? Promote your positions to the largest audience Contact Craig Wilson, Sales Associate, Classiﬁeds 212-957-5300 xĂăĆƫƫđƫƫcwilson@mcmahonmed.com

Medical Equipment

For classiﬁed advertising, contact Craig Wilson 212-957-5300 x235 cwilson@mcmahonmed.com

Education

Got Fellowships? Promote your GME/CME, updates & conferences Contact Craig Wilson, Sales Associate, Classiﬁeds 212-957-5300 xĂăĆƫƫđƫƫcwilson@mcmahonmed.com

Operations & Management 39

Pharmacy Practice News • July 2015

Leadership in Action Table. Example Statements As soon as we start the blame game, we are giving up our control. A simple way to determine if you are caught in the trap is to listen to your speech patterns for the differences between reactive, blaming language and proactive, accountable language (Table).

When Bad Things Happen I recognize that unfortunate events sometimes happen. In such cases, I endeavor to make my response one of acceptance, with an attitude of moving on and making the best of the circumstances. I also do a mental review and ask what role I may have played in the occurrence. Did I somehow contribute to the problem? I also try not to become defensive and attack or withdraw; either type of reaction is harmful. I also remind myself that I am not right all the time. And I ask myself what I can do proactively to remedy the situation and prevent a repeat. This puts me back in control again. Sometimes there is a need to ask clarifying questions to determine the next steps, rather than making assumptions. Misunderstandings often lead to conflict due to lack of clarity. As a leader, your responsibility is to make sure your team members understand their roles clearly. Leading your team through their verbal and nonverbal responses is critical.

Control Your Own Response All of these communication strategies can help you “own” your own responses to a given situation. When you own your responses, they are driven by chosen, cognitive thought processes, versus automatic, autonomic reactions. The latter often gets you in trouble. If you have an outburst—which any of us is capable of doing—take responsibility, apologize quickly and move on. The best leaders spend the least time responding defensively. In fact, the less time you spend in a defensive mode, the more effective you are in a leadership mode. This is by no means an easy task. Often our defensive reactions are ingrained in our mental programming, so it takes effort to undo these neuronal pathways. The suggestion to break this habit is to go back to our first rule of “intention.” State the intentions first that you are seeking the honest, authentic response.

Giving Constructive Feedback As a leader, you have the responsibility to give feedback to your employees. Sometimes that feedback will be correctional. When you own it all, you’ll have the wisdom and presence of mind to deliver that feedback in a constructive way so that employees can improve their performance. One of the keys to this process is effective listening. If you state up front that your intention is to help them improve their performance and you listen intently to their response, showing

Reactive, Blaming Language

Proactive, Accountable Language

There’s nothing I can do.

Let’s look at our alternatives.

He/she makes me so mad.

I control my own feelings.

They won’t allow that.

I can create an effective presentation.

I can’t.

I choose

I must or I have to

I prefer

That’s just the way I am.

I can choose a different approach.

empathy, then you increase their receptivity to hear what you will have to say when it is your turn to talk. We actually

hold the power to defuse our employee’s defensiveness if we listen well. “Owning it all,” however, does not

mean that you do it all; in fact, it’s quite the opposite. As a leader, you have the responsibility to hold others accountable and create a culture in which each person pulls his or her own weight, a culture in which you do not allow backstabbing, gossip and pettiness. Through your interactions with your staff, you set the tone for a professional department that becomes a reflection of your own professionalism, character and values. Create a department in which support, collaboration, teamwork and respect are promoted and celebrated. ■

Don’t Miss Our Debut Issue,, Mailing in September Editorial Highlights: Automated Drug Cabinets: Several studies show ADCs can boost patient safety—but only if the implementation is spot-on. ISMP’s Matt Grissinger offers tips for maximizing safety benefits. The Internet of Things (IoT): It sounds weird, but IoT is a serious tool that hospitals are using to improve smart pump functionality, reduce drug diversion and boost supply chain safety. The Safety Connection: A new federal report touts the safety benefits of Clinical Decision Support (CDS), Computerized Prescriber Order Entry (CPOE) and Electronic Health Records (EHRs). PTR profiles hospitals that successfully rolled out these technologies and documented improvements in patient safety. Telepharmacy. A Connecticut hospital uses a cutting-edge telepharmacy system to provide direct pharmacist supervision of chemotherapy in its nine new community cancer clinics. CPOE: A JAMA study says CPOE remains the No. 1 challenge for hospitals trying to meet meaningful use requirements. PTR profiles hospitals that have overcome the main roadblocks to e-prescribing. Big Data. A Massachusetts health system mines a huge data set to identify heart-failure patients who are at risk for hospital readmission.

KITS contain everything you need to compound individual prescriptions quickly and easily.

Mouthwash BLM

Mouthwash BXN

Duke’s Mouthwash

Mary’s Mouthwash

Lansoprazole

Omeprazole

Vancomycin

Progesterone

Hydrocortisone

Testosterone

Testosterone MC

To learn more about how FIRST® KITS are transforming compounding, call

1-800-461-7449 Time-Saving Convenience - pre-measured, pre-weighed ingredients Streamlined Process - a single NDC number eases reimbursement

or visit: www.CutisPharma.com