January 2011 digital edition of Pharmacy Practice News by McMahon Group

D in Bre Av A di a ca st as ti Se tio ca e n nc n: pa in er ge p 37 eri l

The Pharmacist’s News Source

pharmacypracticenews.com Printer-friendly versions available online

IT, drug safety featured

A Larger String Of Pearls Bestowed At ASHP Midyear Anaheim, Calif.—The pearls sessions held during the ASHP Midyear Clinical Meeting have become so popular that they’ve been expanded to cover topics including safety and quality, informatics and emergency medicine, in addition to the traditional clinical pearls. This is the first in a series of articles covering highlights of these pearls sessions.

Bigger Automation Rollouts May Trigger Bigger Problems

he far-reaching multicomponent automation systems that many hospitals and health systems are implementing present opportunities for far-reaching mistakes, according to medication safety consultant Mary E. Burkhardt, MS, RPh, FASHP. “The bigger we are, the harder we fall,” cautioned Ms. Burkhardt during the informatics

•

Volume 38 • Number 1 • January 2011

McMahon Publishing

in this issue Clinical

Medication Safety Hospital slashes hydromorphone error rate, wins ISMP Cheers Award.

‘Natural’ supplements can lead to potentially deadly atrial fibrillation.

NEW FEATURE!

Case Report Topical arnica and warfarin pose serious herb–drug interaction.

Opinion

Leadership in Action Having to read your boss’s mind not a good thing, according to Ernest Anderson Jr., MS, RPh.

Worst Drug Shortage Ever Puts Cancer Centers in Crisis Hem/onc pharmacists, physicians cite treatment delays that could compromise patient safety

n unprecedented nationwide shortage of chemotherapy drugs has left many cancer centers scrambling to prioritize their patient loads, snarled some clinical trials and delayed treatment for at least some patients. As of the first of December, 199 new drug shortages had been identified for 2010, according to Erin Fox, PharmD, who coordinates the Drug Information Service at the University of Utah Healthcare Hospitals and Clinics, in Salt Lake City. By comparison, “we only had 166 new short-

ages for all of 2009, and 149 for 2008,” she said. Chemotherapy drugs make up an alarmingly high percentage of the medications in short supply—a potentially dangerous subplot to the general shortages reported earlier this year by the Institute for Safe Medication Practices (ISMP). “That’s one of the things that makes this year so concerning and such a challenge,” Dr. Fox said. “To date, we’ve had 20 shortages of chemotherapy drugs. It’s never been nearly that

•

see SHORTAGES, page 8

see PEARLS ROUNDUP, page 13

Policy

To Err Is Still Human: Medication Errors Are A Persistent Challenge

ore than a decade has elapsed since the Institute of Medicine (IOM) published its landmark report on medical errors, “To Err Is Human,” which found that as many as 98,000 people die as a result of preventable medical errors every year. After 10 years of intense focus on quality improvement in health care, you’d think things might have gotten better. But according to two new studies, they haven’t. A recent report from the Department of Health and Human Services’ (HHS) Office of Inspector General (OIG) found that 13.5% of Medicare beneficiaries—134,000 patients—experienced some type of adverse event during a sample month (October 2008). Some 15,000 patients

•

see ERRORS, page 4

FDA Watch First new lupus treatment since 1950s nears approval.

Technology

Practice Pearls Effective leadership can help ensure successful CPOE adoption.

Supportive role can be fertile ground for pharmacists

Educational Review

Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations see page

Preserving Pregnancy Options In Cancer Patients an Unmet Need

he cancer patient, a young man, was engaged to be married. But fighting cancer wasn’t the only issue on his mind. He also wanted to know if the treatment would undercut his ability to have children one day, recalled Sandra Cuellar, PharmD, BCOP, clinical oncology pharmacist at the University of Illinois

Medical Center in Chicago. “So the physician comes to me and says, ‘What do you know about Gleevec and fertility?’ ” It’s not the first time in the past few years that Dr. Cuellar has combed the medical literature, searching for clinical insights into potential fertility risks, as treatment options continue to multiply

•

The Book Page Anticoagulation Therapy: A Point-ofCare Guide William E. Dager; Michael P. Gulseth; Edith A. Nutescu See page

see FERTILITY, page 34

New Product Cactus SMART SINK™ prevents the unauthorized use of unused or waste drugs. See page

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

Lot number is imprinted for easier tracking

TALLman lettering, used when appropriate, helps reduce dispensing errors

Bar Coded with a scannable Standard RSS bar code

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

Manufacturing location of product

Expiration Date

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

8430 A

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

Pharmacy Practice News • January 2011

Up Front 3

Capsules

by the

numbers

surf

watch

JANUARY 2011

The five most-viewed articles last month on pharmacypracticenews.com:

1. FDA Heeds Advisory Panel, OKs Pradaxa for Stroke in AF Patients 2. Patients Remain the Focus for Change at PPMI Summit 3. Ongoing Drug Shortages Place Patients, Hospitals at Risk: ISMP 4. Dollars and Sense of Anticoagulation: Pharmacists Crucial 5. New Hormone Therapy Will Shake Up Treatment for mCRPC Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘Pharmacists should take a stand that we are going to be our patients’ source of information on supplements, instead of the clerk at the health food store or the chiropractor or the Internet.’

See article, page 16

3.7|

From the American Society of HealthSystem Pharmacists Midyear Clinical Meeting, in Anaheim, Calif.

he average number of additional medications T obtained by pharmacists taking drug histories of patients in the emergency department, compared with histories taken by other health care professionals (abstract 3-128).

percentage reduction in the incidence of 42| The inappropriate metformin use at a health system one year after pharmacists began to review each order for potential contraindications. In rare cases, metformin can cause lactic acidosis—a serious metabolic complication that is fatal in 50% of cases (abstract 3-114).

percentage of pediatric ICU patients given 48| The their first dose of antibiotics after a quality improvement project was initiated. The effort— targeted clinician education, enhanced e-prescribing and drug distribution—doubled the 24% pre-implementation rate (abstract 3-195).

—Jennifer Strohecker, PharmD

amount saved when a pharmacy quality $291,000| The improvement team identified ways to reduce IV

2-D Bar Codes in PPN

drug waste. Among the fixes: preparing shortstability products closer to the time of administration, adjusting the IV batch preparation times and frequency, and purchasing more premixed IV products (abstract 3-044).

1. Get the FREE Microsoft Tag Reader application through your smartphone browser by going to http://gettag.mobi and follow the steps to download. (There may be a charge from your wireless provider for the data services.) 2. Open the Tag Reader and find the PPN bar-code image in this publication. 3. Let the Tag Reader focus on the bar-code image to instantly access related materials and/or Web sites.

—David Bronstein

EDITORIAL BOARD

ART/PRODUCTION STAFF

Administration

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

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

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

Volume 38 • Number 1 • January 2011 • pharmacypracticenews.com

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

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

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

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

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

McMAHON PUBLISHING

James Prudden, Group Editorial Director

C. Michael White, PharmD, Storrs, CT

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

Van Velle, President, Partner

Robin B. Weisberg, Manager, Editorial Services

Matthew McMahon, General Manager, Partner

CNS/Psychiatry

Robert Ignoffo, PharmD, San Francisco, CA Philip E. Johnson, MS, RPh, FASHP, Tampa, FL

Elizabeth Zhong, Associate Copy Chief

Cindy O’Bryant, PharmD, Aurora, CO

Brian Dunleavy, Editorial Director, Promotional Medical Education

Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY Biotechnology Indu Lew, PharmD, Livingston, NJ Cardiology

Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA Larry Ereshefsky, PharmD, San Antonio, TX Complementary and Alternative Medicine Cathy Rosenbaum, PharmD, Cincinnati, OH Critical Care Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Jim M. Koeller, MS, San Antonio, TX Ali McBride, PharmD, MS, BCPS, St. Louis, MO Pediatrics Gretchen Brummel, PharmD, BCPS, Hudson, OH Reimbursement Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

SALES David Kaplan, Group Publication Director dkaplan@mcmahonmed.com Phil Redgate, Publication Director predgate@mcmahonmed.com

Raymond E. McMahon, Publisher and CEO, Managing Partner

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

Robert P. Rapp, PharmD, Lexington, KY

David Bronstein, Editorial Director, Hospital Group davidb@mcmahonmed.com

David Nathanson, Account Manager dnathanson@mcmahonmed.com

Copyright © 2011 McMahon Publishing, New York, NY 10036. All rights reserved. Pharmacy Practice News (ISSN 0886-988x) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Send address changes to Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036.

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

with Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036. You can also fax your request to (212) 977-3645, or send it via e-mail, 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

subscription 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 38-year-old, first-generation, family-owned publishing company dedicated to providing

medical professionals with essential, up-to-date news. As the second largest publisher of medical newspapers, McMahon produces Anesthesiology News, Clinical Oncology News, Gastroenterology & Endoscopy News, General Surgery News, Infectious Disease Special Edition, Pain Medicine News, Pharmacy Practice News and Rheumatology Practice News.

Infectious Diseases Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH Peggy McKinnon, PharmD, Detroit, MI David P. Nicolau, PharmD, Hartford, CT

Technology Thomas Van Hassel, RPh, Yuma, AZ

EDITORIAL STAFF

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

Nancy Parker, Executive Manager, Classified Advertising nparker@mcmahonmed.com

4 Clinical

Pharmacy Practice News • January 2011

Medication Safety

continued from page 1

who died during that month were victims of medical errors that contributed at least in part to their deaths. Meanwhile, a study of 10 North Carolina hospitals published in The New England Journal of Medicine in November (2010;363:2124-2134) found that 18% of patients were harmed by medical care, and in many of those cases (63.1%) the injuries were preventable. In a small but significant number of cases (2.4%), the errors had a part in the patient’s death.

Many of these lapses (31% in the OIG report and 28% in the North Carolina hospitals) were medication errors—a fact that doesn’t surprise Lyle Matthews, PharmD, director of pharmacy at Eisenhower Medical Center in Los Angeles. “Sure, there are the rare cases where a physician leaves an instrument inside a patient. And patients can always slip and fall. But I always say that to really injure a patient, you have to get the pharmacy involved. That carries with it a lot of responsibility.” Indeed, more than 7,000 patients die each year due to medication errors, according to a 2006 IOM report. Why

50 40

Rate, %

ERRORS

30 20 10 0

Medication Errors

Patient Care Errors

Surgery/Other Procedural Errors

Infections

Figure. Categories of adverse events in Medicare beneficiaries. Source: HHS/OIG, November 2010

ISMP Hosts Webinar On Hydromorphone Safety …

etween January 2008 and October 2009, more than 1,600 medication errors and nearly 1,000 adverse events involving hydromorphone (Dilaudid) were reported in Pennsylvania alone, leading the Pennsylvania Patient Safety Authority to issue a special alert about the drug, a semisynthetic opioid that is used in place of morphine. Dosing errors and other problems involving hydromorphone are common—and because the drug is five to seven times more potent than morphine, can be deadly. On Nov. 17, 2010, the ISMP hosted a webinar to educate pharmacists about safe hydromorphone practices. Some people aren’t familiar with the proper dosage, and even the product labeling isn’t correct. Surveys involving mostly experienced nurses show a lack of understanding of the proper dosing of hydromorphone and the differences between that drug and morphine, presenters noted during the webinar. Many responded incorrectly when asked the difference in potency between hydromorphone and morphine. To make matters worse, a starting dose of morphine 2.5 to 5 mg IV for opioid-naïve patients should translate to a 0.375 to 0.75 mg dose of hydromorphone, said webinar hosts Matthew Grissinger, RPh, FISMP, FACSP and Susan Paparella, RN, MSN. Yet some references say to start hydromorphone at 1 to 2 mg IV.

The similar-sounding names of morphine and hydromorphone result in ‘the No. 1 name mix-up in hospitals.’ —Matthew Grissinger, RPh They also pointed to a study that found that one-third of patients given 2 mg of hydromorphone after presenting to the emergency department with acute severe pain developed oxygen desaturation. Doses of greater than 2 mg of hydromorphone require great caution, but although there are 2- and 4-mg syringes, there’s no 0.5-mg syringe, the speakers noted. “Another problem we’ve had repeatedly with the drug and have warned hospitals about is mix-ups name-wise between morphine and hydromorphone,” Mr. Grissinger said. “It’s the No. 1 name mix-up in hospitals.”

Teachable Moments The webinar discussed several examples of preventable medical errors involving hydromorphone from the Pennsylvania database. For example, after being admitted with abdominal pain and given 25 mg of Demerol IV push at noon and 1 p.m., a patient then received 2 mg of hydromorphone IV push once every hour between 2 and 4 p.m., and again at 6 p.m. At 7 p.m., he was found unresponsive, with shallow respiration, and was revived with Narcan. The orders were changed to 1 mg hydromorphone every two hours. The webinar presenters discussed a number of risk-control strategies, including technology support such as smart infusion devices, barriers around distribution and drug selection, standardized policy and processes, staff education and designated handoff procedures after opioid use. Michael Cohen, RPh, MS, ScD, president of ISMP, suggested that states take a harder line with a drug like hydromorphone. “Enough already with voluntary safe practices. The Joint Commission ought to be going in and asking to see a hospital’s hydromorphone dosing policies and asking what kind of monitoring they’re doing when patients have a hydromorphone PCA [patient-controlled analgesia],” he said. “When we see a handful of drugs causing a big problem, we need to work on that.”

‘We have a long way to go, but I don’t think we should lose sight of the progress that’s already happened.’ —Michael Cohen, RPh, MS, ScD hasn’t more headway been made against this problem, and what can be done? One reason that errors are still so prevalent may be that it has taken time to develop, implement and adopt the technologies needed to reduce medication errors, according to Kevin Scheckelhoff, RPh, MBA, senior managing consultant with McKesson Pharmacy Optimization. “We’re not going to see the benefit right away. It’s not like turning on a light switch.” For example, a 2008 practice survey by the American Society of Health-System Pharmacists found that only 23% of hospital pharmacies had adopted bar code medication administration (BCMA) technology, and just 44% had implemented smart IV infusion pumps, two technologies that have been found to play a key role in reducing medication errors. “A lot of this is still building,” said Mr. Scheckelhoff. “As more and more hospitals acquire this technology, you’re going to see the results.” Eisenhower Medical Center was one of the first hospitals in California to adopt BCMA technology, and has been using it since 2003. “Bedside barcode administration and verification of medication has eliminated a lot of errors that we otherwise might not have caught,” Dr. Matthews said. “Over the past five years, we’ve decreased our significant medication errors by at least 90%. Next, we’re going to upgrade to a system whereby when we receive an order, it already has the patient-identifying bar code on the order itself. It’s verified at the physician level and automatically goes into the pharmacy system under the correct patient’s record. That’s another chance for human error [to be] taken out of the system.”

In 2009, Eisenhower began phasing in an automated physician order entry system; by the end of 2010, all physicians were required to use it.

Automated Reporting Helps Reduce Heparin Errors by 70% Automated systems have led to major changes at Northeast Georgia Health System (NGHS), Gainesville, said director of pharmacy services Steve Carlson, RPh, MHA. “We use an automated reporting system called RL Solutions,” he said. “Our [medication error] reporting rate did go up, but that’s what happens when you have an automated system versus a written one. Reporting is a good thing, not a bad thing.” NGHS adopted McKesson’s MedCarousel automated dispensing system, as well as a robot. “Our goal is to reduce human touch as much as possible using bar-coding technology,” said Mr. Carlson. “With high-risk drugs, it’s much easier to put them in the carousel and separate them clearly. We now have many fewer picking errors. We have wireless smart pumps, bar coding at the bedside and the vast majority of the pharmacy is automated. We also are in the process of building a computerized physician order entry system.” NGHS also has begun using the Six Sigma methodology, a quality improvement approach aimed at a zero error rate that began as the in-house system at Motorola. “We’ve done heparin Six Sigma, and it worked out very well,” Mr. Carlson said. “We reduced our heparin errors by about 70%, and we’ll probably be presenting on that at ASHP next year.” Eisenhower is directing specific efforts at “problem drugs.” “We maintain a list

Pharmacy Practice News • January 2011

Clinical 5

Medication Safety Table. Adverse Events Related to Medications in Medicare Beneficiaries Error

Number of Events

Excessive bleeding

Delirium or change in mental status

Hypoglycemic event

Acute renal insufficiency (kidney failure)

Severe hypotension

Respiratory complications

Severe allergic reactions

Source: HHS/OIG, November 2010

… And Gives Cheers Award to Christiana For Cutting Hydromorphone-related ADEs

of high-risk, high-alert medications. For example, chemotherapy drugs have to have the calculation of the dose, as well as the dose as it’s made, double-checked by two pharmacists, as does any medication for a pediatric patient,” Dr. Matthews said. “Our smart pumps are programmed not to allow the dosage of heparin to exceed a certain amount, so you can’t accidentally ‘bump the button’ and boost the dosage from 10 mL to 100 mL. And we learn from others’ mistakes: After the incident at Cedars-Sinai with [actor] Dennis Quaid’s children, we took the 10,000-unit heparin vials out of our hospital completely. We’re not so arrogant as to think we’re better than Cedars-Sinai and it couldn’t happen here.” Although it is important to take care with high-alert drugs, it is the process overall that needs to be improved, said Cathy Rosenbaum, PharmD, MBA, RPh, clinical effectiveness and safety officer at Bethesda North Hospital in Cincinnati. “Medication errors are all about process breakdown. Very few pharmacists— very few health care professionals in general—are trained to analyze process breakdown and do root-cause analyses and failure mode-effect analyses.” She suggested that all pharmacists should take a class, or a continuing medical education program, on process improvement, and that this element should also become an integral part of pharmacy education. “What are the quality tools? How do you do a flowchart of a process? How do you put together a

multidisciplinary team to look at rootcause analysis? Focus on the process, not a punitive person-based approach.” And while you’re using scanners, robots, smart pumps and automated dispensing cabinets to help prevent errors, don’t forget to use the data they collect to help you understand the errors that still occur. “We need to become more vigilant in datamining reports out of these various technologies,” Dr. Rosenbaum said. “That’s pretty complicated and isn’t happening in most institutions yet. At least one pharmacist per institution should be trained in how to data-mine reports out of these various technologies and pull together analyses, and then share that information with nursing and physicians as well as pharmacists.”

ISMP’s Take: Glass Half Full Despite the grim picture painted by the HHS OIG report and the NEJM article, a lot has been done to improve medication safety over the past decade, according to Michael Cohen, RPh, MS, ScD, president of the Institute for Safe Medication Practices (ISMP). “There are many drugs and drug categories where [products] have been taken off the market, labels have been changed, and practices have been changed. People have worked hard and improvements have been made. We have a long way to go, but I don’t think we should lose sight of the progress that’s already happened.” —Gina Shaw

naheim, Calif.—A five-year project to improve injectable hydromorphone safety at Christiana Care Health Services in Wilmington, Del., reduced adverse events related to the drug to zero and increased compliance with recommended dosing ranges from 64% to 84%. The effort received a Cheers Award from the Institute for Safe Medication Practices, presented at the 2010 midyear meeting of the American Society of Hospital Pharmacists in December. “Hydromorphone is our primary acute pain opioid injectable,” said Terri Corbo, PharmD, BCPS, FASHP, medication safety officer and director of clinical pharmacy services at Christiana Care. “It’s a high-volume, high-alert drug. Prior to initiating the program, we had seen an increase in hydromorphone use and realized that we needed to take steps for appropriate prescribing in order to limit adverse events.” At the time, Christiana Care did not have computerized physician order entry (CPOE), so the tools available to the pharmacy team were limited. “We established dose ranges based on age [less than 65 years and 65 or older], standardized our paper order sets and put out pocket guides to appropriate hydromorphone dosing,” Dr. Corbo said. Additionally, “we delivered education programs, with pharmacists and doctors going out to speak to sections and departments.” When CPOE was established at Christiana Care, one of the pharmacy’s first priorities was hydromorphone. The hospital’s CPOE system can be programmed so that either the physician can fill in the desired dosage for a drug, or a preset dosage can automatically be filled in. “For hydromorphone, we hard-wired the dosages into the system and built it so that only our recommended dosage, based on age, would come up,” she said. Sometimes opioid-tolerant chronic pain patients do need hydromorphone doses outside the usual range, so doctors can override the system. If a doctor prescribes a dose outside the usual range, the system issues an alert reminding the clinician why the default dose is set, by describing the risk for falls and other adverse events such as respiratory distress. When the campaign began, 64% of hydromorphone prescriptions fell within the recommended dosing range. The education campaign raised that proportion to 74%; after CPOE was implemented, it reached 84%. “It’s important to note that this [compliance] figure can never be 100%,” Dr. Corbo noted. “We have more than 1,000 beds and are a central draw for a lot of service lines, including chronic pain patients who can’t be backed down to the initial dosing range.” At baseline, many physicians were writing orders for 1 mg of hydromorphone because the drug comes in a 1-mg syringe. “The doctors figured if it came in that formulation, that was the dosage they should use,” Dr. Corbo said. “Even after we educated them that packaging does not dictate appropriate dosing, 34% of initial hydromorphone orders were still prescribed at 1 mg. With CPOE, that dropped to 18%.” The rate of hydromorphone-related adverse events at Christiana Care fluctuated prior to and throughout the campaign, but during the first two quarters after implementation of CPOE, adverse events related to hydromorphone totaled zero. Education on the potency of hydromorphone and proper safety precautions continues. “Every time we have an event or learn a lesson from a doctor who’s prescribed this drug, we’ll do an analysis,” Dr. Corbo said. “And we have a new residency class every year, and a new group of people who need to be informed about the appropriate prescribing of hydromorphone. You’re never done.”

—G.S.

B A L A N C E It’s different for every pharmacy.

L I Q U I D & F R O Z E N P R E M I X M E D I C AT I O N S

Medication Delivery

111335A 09/10

•

M I N I - B A G P L U S C O N TA I N E R S Y S T E M S

•

V I A L - M AT E A D A P T E R S

•

M I N I - B A G C O N TA I N E RS

W W W. BA X T E R . C O M

1.888.229.0001

Consulting versus filling prescriptions. Optimizing new products versus existing processes. Spending more here versus spending less there. You weigh decisions like these every day. Drug delivery from Baxter Healthcare Corporation can help you strike a balance between the give and take. And we do it by combining the right products and services to help you achieve a more effective relationship between costs and benefits, custom and standard solutions, operational and clinical activities. That’s the true value we bring. That’s how drug delivery from Baxter delivers more.

•

PHARMACYADVISOR.COM

•

CONSULTING SERVICES

•

E-COMMERCE

8 Clinical

Pharmacy Practice News • January 2011

Medication Safety

SHORTAGES continued from page 1

high before; in past years, we would have perhaps 10 or 12 chemotherapy drug shortages. This year, it’s just exploded.” The past year has seen almost a perfect storm of supply chain issues for all drugs—one that has hit oncology particularly hard. “Many chemotherapy drugs are generic, and we don’t have many generic suppliers,” Dr. Fox explained. “If one company has a manufacturing problem, that almost guarantees that there’s going to be some kind of a shortage. And this year two of our very largest manufacturers of generics, Teva Injectables and Hospira, both had manufacturing problems at the same time.” The shortages are not all that surprising. “The manufacturing capacity at these firms is limited,” noted Capt. Valerie Jensen, RPh, associate director of the Center for Drug Evaluation and Research’s Drug Shortage Program at the FDA. “These older sterile injectables get discontinued by firms, often in favor of newer, more profitable products. “Sterile injectables have a long manufacturing lead time and a complex process,” Ms. Jensen added. “When one of the few firms making these products experiences a problem, a shortage almost always occurs since it is extremely difficult for the remaining firms to keep up with demand.” Dr. Fox compared the situation to the federal government’s financial bailout of the insurance giant AIG. “You’ve heard about banks that are too big to fail? Well, we almost have generic companies that are too big to fail, but we don’t have anyone stepping in” to help fix the company’s manufacturing issues, she said. Compounding the problem is the fact that while manufacturers are encouraged to alert the FDA if they are anticipating a supply chain issue with one of their drugs, they’re not required to do so. “If a manufacturer is having trouble with raw materials, the FDA can smooth the pathway there. They can approve new generics in line if a company’s going to have problems,” Dr. Fox said. “They can suggest to competitors to ramp up production of a product. But it takes time to do those things, and if manufacturers don’t alert the FDA, they can’t take action.” The following oncology-related drugs have been in particularly acute short supply this year, according to recent reports: • Bleomycin • Cisplatin • Doxorubicin • Etoposide • Leucovorin • Nitrogen mustard

• Vinblastine • Vincristine T he i m pac t on patients, treatment centers and clinical trials has been enormous, say oncologists across the country. “I’m in a very big practice; we have 45 doctors in 20 offices in three states. So far, we have not failed to give a patient cura-

tively low toxicity,” h e said. “L i ke wise, doxorubicin is critical in the tre a t m e n t of lymphomas, osteosarcoma and Ewing sarcoma. Etoposide also has shown clear activity in Ewing sarcoma, with one study [N Engl J Med 2003;348:694-

‘I know my stocking up [on drugs in short supply] may impact other practices, but my goal is to not interrupt therapy and never have the availability of a drug determine the regimen that a patient receives.’ —Melissa Dinolfo, PharmD, BCOP tive therapy because of these shortages, but it’s easy to see how that could happen, and that raises the whole level of anxiety,” said Michael Neuss, MD, past chair of the American Society of Clinical Oncology’s (ASCO) Clinical Practice Committee. “Last year, with the leucovorin shortage, you could find it if you really needed it. Now, one day we have leucovorin and one day we don’t. And we really are out of doxorubicin, just plain out of it.” In some cases, there is an acceptable substitute for a drug on the shortage list. For example, for breast cancer, epirubicin can be substituted for doxorubicin. “But it’s not 100% clear exactly what conversion factor to use when switching from doxorubicin to epirubicin,” Dr. Neuss pointed out. “There are different versions of what dose you can use, and as a generic, there’s no one to call to ask.” And although it may be acceptable clinically, substituting epirubicin for doxorubicin in a clinical trial may well violate that trial’s protocol and put its results in jeopardy, he added. (A number of clinical trials have been slowed or stopped because of the shortages.) In other cases, a substitute for the missing drug does not exist. “For lymphoma, doxorubicin is curative and there is no substitute,” Dr. Neuss said. “Vincristine in childhood tumors—there’s no substitute. Leucovorin as a rescue agent in childhood tumors—there may or may not be a substitute.” ASCO president-elect John Link, MD, further highlighted the critical nature of many of these drugs in an ASCO Action Alert interview held on Nov. 23. “Vincristine simply has no substitute in diseases such as acute lymphocytic leukemia, Hodgkin and non-Hodgkin lymphoma and Wilms’ tumor. Not only does it improve outcomes, it has rela-

701] demonstrating a 15% improvement in the cure rate when added with ifosfamide to the three-drug standard which, incidentally, included doxorubicin. Since etoposide was the specific drug that was studied in that setting, we cannot extrapolate these results to another, alternative drug.”

Dealing With Doxorubicin Shortages At Georgia Cancer Specialists, an Atlanta-based community hematology and oncology practice, some 220 patients usually receive regimens containing doxorubicin. “We’ve had to switch about one-third of them to epirubicin,” said Cheryl Jones, MD, a breast specialist with the practice. “The shortage hit suddenly and unexpectedly for us, around the end of November. We no longer stockpile or maintain a large inventory, since typically you can get what you need very rapidly.” Since Georgia Cancer Specialists has a robust electronic medical records system, they were able to quickly identify all patients currently receiving doxorubicin-containing regimens. “As a core team of physicians, we prioritized patients who are receiving adjuvant and curative therapy first, compared with those patients getting metastatic or palliative regimens,” Dr. Jones said. “Then we identified other alternative, published regimens that might give us similar results

for patients who would not receive doxorubicin.” Similarly, when the etoposide shortage hit, they limited that drug to patients with limited-stage small cell lung cancer and testicular germ-cell carcinoma, because those were curative regimens. “With leucovorin, every adjuvant or curative patient got a full dose, and every palliative patient got a reduced dose,” Dr. Jones said. “We used the guidelines for standard dose reductions, supported by the literature, but it was a significant reduction.”

Transplants Delayed “We’ve had to delay patients starting chemotherapy until we were able to get an emergency supply of a drug in,” said Ali McBride, PharmD, MS, BCPS, a clinical pharmacy specialist at the Alvin J. Siteman Cancer Center at BarnesJewish Hospital, in St. Louis. In some cases, autologous transplants also have been delayed, he said. “With the etoposide shortage, one thing physicians have been doing for lung cancer patients is switching from an IV to a PO formulation. But there is a risk of dosage errors, because patients usually have to double up on PO medication.” A Sept. 23 report from the ISMP documented a number of dosage errors that have indeed occurred with chemotherapy drugs as a result of the need for substitutions. So far, none of the “at least six” deaths attributable to the drug shortage has involved an oncology drug, according to ISMP president Michael Cohen, RPh, MS, ScD. But there have been a number of errors and adverse events, he noted, including: • A dosing error made when a vinblastine shortage led to replacement with vincristine for a patient with a hematologic disease • An error in converting IV etoposide to oral dosing, which needs to be double the IV dose • An incorrect dose prescribed when levoleucovorin was substituted for leucovorin. [The ISMP report, based on a nationwide survey of health care practitioners, documented severe shortages of a wide range of medications, including propofol, neuromuscular blocking agents, morphine, epinephrine, heparin,

Pharmacy Practice News • January 2011

Clinical 9

Medication Safety fosphenytoin and certain antibiotics. In some cases, survey respondents noted, patients died as a result of not getting the best available drug in a timely manner. [For more details, visit www.pharmacypracticenews.com or scan the 2-D bar code on p. 12]

‘A Horrible Position To Be In’ Like the Georgia practice, Dr. McBride said Barnes-Jewish also has had to prioritize patients who are on curative regimens. “It’s a horrible position to be in,” he said. “That’s a difficult discussion to have

‘We are very concerned that things will get worse before they get better.’ —Bona E. Benjamin, BS Pharm with patients,” agreed Dr. Jones. “They’re comfortable and they know that you’ve planned the best regimen for them. Then you come back and say there’s a shortage: manufacturing problems, regulatory delays, downsizing in the pharmaceutical industry. But economics don’t mean much to patients who are in a very personal fight for their individual life.”

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Hizentra, Immune Globulin Subcutaneous (Human), 20% Liquid Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. 1 INDICATIONS AND USAGE Hizentra is an Immune Globulin Subcutaneous (Human) (IGSC), 20% Liquid indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. 4 CONTRAINDICATIONS Hizentra is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin or to components of Hizentra, such as polysorbate 80. Hizentra is contraindicated in patients with hyperprolinemia because it contains the stabilizer L-proline (see Description [11] ). Hizentra is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity (see Description [11] ). 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Severe hypersensitivity reactions may occur to human immune globulin or components of Hizentra, such as polysorbate 80. In case of hypersensitivity, discontinue the Hizentra infusion immediately and institute appropriate treatment. Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including anaphylaxis and shock) after administration of blood components containing IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions with administration of Hizentra. Hizentra contains 50 mcg/mL IgA (see Description [11] ). 5.2 Reactions Reported to Occur With IGIV Treatment The following reactions have been reported to occur with IGIV treatment and may occur with IGSC treatment. Renal Dysfunction/Failure Renal dysfunction/failure, osmotic nephropathy, and death may occur with use of human immune globulin products. Ensure that patients are not volume depleted and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Hizentra and at appropriate intervals thereafter. Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure.1 If renal function deteriorates, consider discontinuing Hizentra. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are overweight or use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), administer Hizentra at the minimum rate practicable. Thrombotic Events Thrombotic events may occur with use of human immune globulin products2-4. Patients at increased risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity. Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Hizentra at the minimum rate practicable. Aseptic Meningitis Syndrome (AMS) AMS may occur with use of human immune globulin products.5 The syndrome usually begins within several hours to 2 days following IGIV treatment. AMS is characterized by signs and symptoms including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. Cerebrospinal fluid (CSF) studies frequently show pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, with elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. Conduct a thorough neurological examination, including CSF studies, to rule out other causes of meningitis in patients exhibiting signs and symptoms of AMS. Discontinuation

Melissa Dinolfo, PharmD, BCOP, director of pharmacy and clinical operations at Premiere Oncology in Santa Monica, Calif., confessed that she has stockpiled drugs as she’s seen shortages coming. “The first six years I was here, there were probably two to four shortages overall that were impactful, and I learned from that experience to watch trends.

of IGIV treatment has resulted in remission of AMS within several days without sequelae. Hemolysis Hizentra can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin (Coombs’) test result and hemolysis.6-8 Delayed hemolytic anemia can develop subsequent to immune globulin therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported.9 Monitor recipients of Hizentra for clinical signs and symptoms of hemolysis. If these are present after a Hizentra infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving Hizentra, perform adequate cross-matching to avoid exacerbating on-going hemolysis. Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients administered human immune globulin products.10 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Typically, it occurs within 1 to 6 hours following transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. Monitor Hizentra recipients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. 5.3 Transmissible Infectious Agents Because Hizentra is made from human plasma, it may carry a risk of transmitting infectious agents (e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease [CJD] agent). The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for Hizentra. Report all infections thought to be possibly transmitted by Hizentra to CSL Behring Pharmacovigilance at 1-866-915-6958. 5.4 Laboratory Tests Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing. 6 ADVERSE REACTIONS The most common adverse reactions (ARs), observed in 5% of study subjects receiving Hizentra, were local reactions (i.e., swelling, redness, heat, pain, and itching at the injection site), headache, vomiting, pain, and fatigue. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, AR rates observed in clinical studies of a product cannot be directly compared to rates in the clinical studies of another product and may not reflect the rates observed in clinical practice. The safety of Hizentra was evaluated in a clinical study for 15 months in subjects with PI who had been treated previously with IGIV every 3 or 4 weeks. The safety analyses included 49 subjects in the intention-to-treat (ITT) population. The ITT population consisted of all subjects who received at least one dose of Hizentra (see Clinical Studies [14] ). Subjects were treated with Hizentra at weekly doses ranging from 66 to 331 mg/kg body weight during the wash-in/wash-out period and from 72 to 379 mg/kg during the efficacy period. The 49 subjects received a total of 2264 weekly infusions of Hizentra. No deaths or serious ARs occurred during the study. Two subjects withdrew from the study due to ARs. One subject experienced a severe injection-site reaction one day after the third weekly infusion, and the other subject experienced moderate myositis. Both reactions were judged to be “at least possibly related” to the administration of Hizentra. Table 2 summarizes the most frequent adverse events (AEs) (experienced by at least 4 subjects), irrespective of causality. Included are all AEs and those considered temporally associated with the Hizentra infusion, i.e., occurring during or within 72 hours after the end of an infusion. Local reactions were the most frequent AEs observed, with injection-site reactions (i.e., swelling, redness, heat, pain, and itching at the site of injection) comprising 98% of local reactions. Table 2: Incidence of Subjects With Adverse Events (AEs)* (Experienced by 4 or More Subjects) and Rate per Infusion, Irrespective of Causality (ITT Population) All AEs*

AE ( 4 Subjects)

Local reactions‡

Number (%) of Subjects (n=49)

Number (Rate†) of AEs (n=2264 Infusions)

49 (100)

1340 (0.592)

AEs* Occurring During or Within 72 Hours of Infusion Number Number (Rate†) (%) of AEs of Subjects (n=2264 (n=49) Infusions) 49 (100)

1322 (0.584)

I don’t like running out of things,” she said. “If I see that a drug is manufactured by three different people, and one of the houses is back-ordered—I hate to do this, but I start buying. I feel badly, because my peers in other places may not have the opportunity to watch as closely as I do, and I know my stocking up may impact other practices, but my goal is to not interrupt therapy and never have the availability of a drug determine the regimen that a patient receives.” Because she saw the doxorubicin shortage coming, Dr. Dinolfo has a

•

see DRUG SHORTAGES, page 10

10 Clinical

Pharmacy Practice News • January 2011

Medication Safety

DRUG SHORTAGES continued from page 9

600-mg supply. She also set aside 13 vials of cisplatin. “I was, however, impacted by a shortage of etoposide the practice was using to treat a young man with testicular cancer. There’s nothing we can substitute, so we had to go to the brand-name drug, which costs $135 more per vial,” she related. “I said I don’t care, we’re buying it, and laid aside as much of the expensive stuff as I could get my hands on so I wouldn’t have to interrupt this kid’s care.”

Parents ‘Distraught’ Over Treatment Delays

‘As a core team of physicians, we prioritized patients who are receiving adjuvant and curative therapy first, compared with those patients getting metastatic or palliative regimens.’

Dr. Dinolfo said she spoke to pharmacists elsewhere in the country who are having similar problems. “I talked to a colleague in a pediatric practice in San Francisco, who is switching patients to different regimens five to eight times a week, and has therapy being delayed two to five times a week,” she said. “Parents are distraught about their child’s regimen; they’re angry, frustrated and anxious about outcomes as regimens change and therapy is delayed.” It’s not just antineoplastic agents that

—Cheryl Jones, MD are running short. Limited access to hundreds of other supportive drugs has impacted oncology practices. “I couldn’t get injectable Lasix, which is part of our chemotherapy regimen, for months. So I had to give oral, which is not as rapid-

Table 2: (Continued) All AEs*

AE ( 4 Subjects) Other AEs: Headache Cough Diarrhea Fatigue Back pain Nausea Abdominal pain, upper Rash Pain in extremity Migraine Pain Epistaxis Pharyngolaryngeal pain Arthralgia

Number (%) of Subjects (n=49)

Number (Rate†) of AEs (n=2264 Infusions)

13 (26.5) 8 (16.3) 7 (14.3) 6 (12.2) 5 (10.2) 5 (10.2) 5 (10.2) 5 (10.2) 4 (8.2) 4 (8.2) 4 (8.2) 4 (8.2) 4 (8.2) 4 (8.2)

40 (0.018) 9 (0.004) 8 (0.004) 6 (0.003) 11 (0.005) 5 (0.002) 5 (0.002) 7 (0.003) 7 (0.003) 5 (0.002) 5 (0.002) 6 (0.003) 6 (0.003) 5 (0.002)

AEs* Occurring During or Within 72 Hours of Infusion Number Number (Rate†) (%) of AEs of Subjects (n=2264 (n=49) Infusions) 12 (24.5) 5 (10.2) 5 (10.2) 4 (8.2) 4 (8.2) 4 (8.2) 3 (6.1) 2 (4.1) 4 (8.2) 3 (6.1) 3 (6.1) 2 (4.1) 2 (4.1) 2 (4.1)

32 (0.014) 6 (0.003) 6 (0.003) 4 (0.002) 5 (0.002) 4 (0.002) 3 (0.001) 3 (0.001) 6 (0.003) 4 (0.002) 4 (0.002) 3 (0.001) 2 (<0.001) 3 (0.001)

* Excluding infections. † Rate of AEs per infusion. ‡ Includes injection-site reactions as well as bruising, scabbing, pain, irritation, cysts, eczema, and nodules at the injection site.

The ratio of infusions with temporally associated AEs, including local reactions, to all infusions was 1338 to 2264 (59.1%; upper 95% conﬁdence limit of 62.4%). Excluding local reactions, the corresponding ratio was 173 to 2264 (7.6%; upper 95% conﬁdence limit of 8.9%). Table 3 summarizes the most frequent ARs (i.e., those AEs considered by the investigators to be “at least possibly related” to Hizentra administration) experienced by at least 2 subjects. Table 3: Incidence of Subjects With Adverse Reactions (Experienced by 2 or More Subjects) to Hizentra and Rate per Infusion (ITT Population) Adverse Reaction ( 2 Subjects) Local reactions† Other ARs: Headache Vomiting Pain Fatigue Contusion Back pain Migraine Diarrhea Abdominal pain, upper Nausea Rash Arthralgia

Number (%) of Subjects (n=49) 49 (100)

Number (Rate*) of Adverse Reactions (n=2264 Infusions) 1338 (0.591)

12 (24.5) 3 (6.1) 3 (6.1) 3 (6.1) 2 (4.1) 2 (4.1) 2 (4.1) 2 (4.1) 2 (4.1) 2 (4.1) 2 (4.1) 2 (4.1)

36 (0.016) 3 (0.001) 4 (0.002) 3 (0.001) 3 (0.001) 3 (0.001) 3 (0.001) 2 (<0.001) 2 (<0.001) 2 (<0.001) 2 (<0.001) 2 (<0.001)

* Rate of ARs per infusion. † Includes injection-site reactions as well as bruising, scabbing, pain, irritation, cysts, eczema, and nodules at the injection site.

Table 4 summarizes injection-site reactions based on investigator assessments 15 to 45 minutes after the end of the 683 infusions administered during regularly scheduled visits (every 4 weeks). Table 4: Investigator Assessments* of Injection-Site Reactions by Infusion Injection-Site Reaction Edema/induration Erythema Local heat Local pain Itching

Number† (Rate‡) of Reactions (n=683 Infusions§) 467 (0.68) 346 (0.50) 108 (0.16) 88 (0.13) 64 (0.09)

* 15 to 45 minutes after the end of infusions administered at regularly scheduled visits (every 4 weeks). † For multiple injection sites, every site was judged, but only the site with the strongest reaction was recorded. ‡ Rate of injection-site reactions per infusion. § Number of infusions administered during regularly scheduled visits.

Most local reactions were either mild (93.4%) or moderate (6.3%) in intensity. 6.2 Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

acting,” Dr. Dinolfo said. “We were short for many months on injectable Ativan.” A few months ago, she switched several of her patients with head and neck cancer, who were so nauseated that they couldn’t take anything orally, to Sancuso

The following adverse reactions have been identified and reported during the postmarketing use of IGIV products11: Infusion reactions: Hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis) Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test Gastrointestinal: Hepatic dysfunction, abdominal pain General/Body as a Whole: Pyrexia, rigors To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 7 DRUG INTERACTIONS 7.1 Live Virus Vaccines The passive transfer of antibodies with immunoglobulin administration may interfere with the response to live virus vaccines such as measles, mumps, rubella, and varicella (see Patient Counseling Information [17] ). 7.2 Serological Testing Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Hizentra. It is not known whether Hizentra can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Hizentra should be given to pregnant women only if clearly needed. 8.3 Nursing Mothers Hizentra has not been evaluated in nursing mothers. 8.4 Pediatric Use Hizentra was evaluated in 10 pediatric subjects (3 children and 7 adolescents) with PI. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. Hizentra was not evaluated in neonates or infants. 8.5 Geriatric Use Of the 49 subjects evaluated in the clinical study of Hizentra, 6 subjects were 65 years of age or older. No overall differences in safety or efficacy were observed between these subjects and younger subjects. 15 REFERENCES 1. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol 1997;8:1788-1793. 2. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-226. 3. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-218. 4. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000;65:30-34. 5. Gabor EP, Meningitis and skin reaction after intravenous immune globulin therapy. Ann Intern Med 1997;127:1130. 6. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26:410-412. 7. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993;15:3789. 8. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997;20:1142-1145. 9. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999;13:129-135. 10. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41:264-268. 11. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003;17:241-251. Manufactured by: Distributed by: CSL Behring AG CSL Behring LLC Bern, Switzerland Kankakee, IL 60901 USA US License No. 1766 Based on March 2010 version

Pharmacy Practice News • January 2011

Clinical 11

Medication Safety (Prostrakan), a seven-day release transdermal patch version of Roche’s antinausea medication Kytril (granisetron). “I had one young man gain seven pounds in a month,” she said. “It makes all the difference. I have four people now on the patch who are doing so much better—but now I can’t get the patches. So they have to go back to being miserable for a few weeks, at least.” No one expects the shortage to improve anytime soon. “This is a serious and widespread problem; it didn’t evolve overnight and won’t be fixed overnight,” said Bona E. Benjamin, BS Pharm, direc-

tor of medication use quality improvement with ASHP, which hosted a drug shortage summit in early November

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Vivaglobin® Immune Globulin Subcutaneous (Human) 16% Liquid Before prescribing, please consult prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. 1 INDICATIONS AND USAGE Vivaglobin is an Immune Globulin Subcutaneous (Human) (IGSC), 16% Liquid indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the primary immunodeficiency in common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. 4 CONTRAINDICATIONS Vivaglobin is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of Immune Globulin (Human). Vivaglobin is contraindicated in IgA-deficient patients with antibodies against IgA or a history of hypersensitivity (see Description [11]). 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Severe hypersensitivity reactions may occur (see Patient Counseling Information [17.2]). In case of hypersensitivity, discontinue the Vivaglobin infusion immediately and institute appropriate treatment. Epinephrine should be immediately available to treat any acute severe hypersensitivity reactions. Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including anaphylaxis and shock) after administration of blood components containing IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Vivaglobin contains 1.7 mg/mL IgA (see Description [11]). The minimum concentration of IgA that will provoke a hypersensitivity reaction is not known; therefore all IgG preparations carry the risk of inducing an anaphylactic reaction to IgA. 5.2 Aseptic Meningitis Syndrome (AMS) AMS has been reported to occur infrequently with IGIV treatment5 and with Vivaglobin treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. AMS is characterized by signs and symptoms including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. Cerebrospinal fluid (CSF) studies frequently show pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. 5.3 Reactions Reported with IGIV Treatment The following reactions have been reported to occur with IGIV treatment and may occur with IGSC treatment. Renal Dysfunction/Failure Renal dysfunction/failure, osmotic nephropathy, and death may occur with use of human immune globulin products. Ensure that patients are not volume depleted and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Vivaglobin and at appropriate intervals thereafter. Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure.1 If renal function deteriorates, consider discontinuing Vivaglobin. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are overweight or use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), administer Vivaglobin at the minimum rate practicable. Thrombotic Events Thrombotic events may occur with use of human immune globulin products.2-4 Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity. Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/ markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Vivaglobin at the minimum rate practicable.

jointly with ASCO, ISMP and the American Society of Anesthesiologists. “We are very concerned that things will get

Hemolysis Vivaglobin may contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin (Coombs’) test result and hemolysis.6-8 Delayed hemolytic anemia can develop subsequent to immune globulin therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemoylysis, has been reported.9 Monitor recipients of Vivaglobin for clinical signs and symptoms of hemolysis. If these are present after Vivaglobin infusion, perform appropriate conﬁrmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving Vivaglobin, perform adequate cross-matching to avoid exacerbating on-going hemolysis. Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients administered human immune globulin products.10 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Typically, it occurs within 1 to 6 hours following transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. Monitor recipients of Vivaglobin for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. 5.4 Transmissible Infectious Agents Because Vivaglobin is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of Vivaglobin. Report all infections thought possibly to have been transmitted by Vivaglobin to the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The physician should discuss the risks and beneﬁts of this product with the patient before prescribing or administering it to the patient (see Patient Counseling Information [17.2]). 5.5 Laboratory Tests After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test. 6 ADVERSE REACTIONS The most common adverse reactions (those AEs considered by the investigator to be at least possibly related to Vivaglobin administration) observed in 5% of study subjects receiving Vivaglobin were local injection-site reactions (swelling, redness, and itching), headache, nausea, rash, asthenia, and gastrointestinal disorder. 6.1 Clinical Studies Experience Because clinical studies 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. US-Canada Study The safety of Vivaglobin was evaluated in a clinical study in the US and Canada for 12 months in 65 subjects with PI who had been previously treated with IGIV every 3 or 4 weeks (see Clinical Studies [14.1]). After 3 months, subjects were switched from IGIV to weekly subcutaneous administration of Vivaglobin for 12 months. Subjects were treated weekly with Vivaglobin at a mean dose of 158 mg/kg body weight (range: 34 to 352 mg/ kg). The 65 subjects received a total of 3,656 infusions of Vivaglobin. Table 2 shows the number of subjects who withdrew from the US-Canada study due to adverse events (AEs) and the AEs leading to discontinuation. Table 2: Subjects with Adverse Events (AEs) Leading to Discontinuation, USCanada Study AEs Subjects with at least 1 AE leading to discontinuation Injection-site reaction Intestinal obstruction Hyperventilation Tachycardia

Subjects with Subjects with AEs Total Number AEs At Least Irrespective of (%) of Subjects Possibly Related Causality 4

5 (8%)

3 – 1* 1*

– 1 – –

3 (5%) 1 (2%) 1 (2%) 1 (2%)

* One subject experienced hyperventilation and tachycardia.

Table 3 summarizes the most frequent AEs (experienced by more than 5% of subjects), irrespective of causality. It includes all AEs and those considered temporally associated with the Vivaglobin infusion, i.e., occurring during the infusion or within 72 hours after the end of the infusion.

worse before they get better.” Ms. Benjamin urges anyone who becomes aware of a looming drug shortage to immediately report it to ASHP using its drug shortages site (http:// www.ashp.org/shortages). “Not just pharmacists—anyone in the health care community, including patients—can report a shortage to our Web site if they know or suspect that [a shortage] is pending,” she said. “Our site simultaneously notifies the FDA, and we’ve heard that sometimes these reports are their first notification of a shortage. The

•

see DRUG SHORTAGES, page 12

12 Clinical

Pharmacy Practice News • January 2011

Medication Safety

SHORTAGES

‘It’s not like there’s not enough peanut butter on the shelves— people can die as a result of [chemotherapy drug shortages].’

continued from page 11

sooner the agency knows, the more latitude they have to activate their management plans and work with other firms t o e n c o u r a g e Scan for more drug ramping up pro- shortage news. See duction. On our p. 3 for instructions. part, we work with our partners to get information and shortage management

—Erin Fox, PharmD resources posted on our Web site as soon as possible.” “I know Hospira is working very hard on improving quality,” said Dr. Fox. “They had manufacturing problems and stepped up their quality improvement activities. They are an incredibly large

Table 3: Incidence of Subjects With Adverse Events (AEs)* (Experienced by >5% of Subjects) and Rate† per Infusion, Irrespective of Causality, in the US-Canada Study AEs Occurring During or Within 72 Hours of Infusion Number Number Number Number (Rate†) of (Rate†) of (%) of (%) of AEs per AEs Per Subjects Subjects Infusion Infusion (n=65) (n=65) (n=3656) (n=3656) 1767 60 (92%) 1789 (0.49) 60 (92%) (0.4848) All AEs

AEs* (>5% of Subjects)

AEs at the injection site‡ Other AEs Headache Gastrointestinal disorder Fever Nausea Rash Sore throat Allergic reaction Pain Diarrhea Cough increased Gastrointestinal pain Migraine Skin disorder Asthma Arthralgia Asthenia Malaise

31 (48%) 24 (37%) 16 (25%) 12 (18%) 11 (17%) 10 (15%) 7 (11%) 6 (9%) 6 (9%) 6 (9%) 5 (8%) 5 (8%) 5 (8%) 5 (8%) 4 (6%) 4 (6%) 4 (6%)

159 (0.04) 35 (0.01) 28 (0.008) 18 (0.005) 22 (0.006) 17 (0.005) 8 (0.002) 8 (0.002) 6 (0.002) 6 (0.002) 6 (0.002) 5 (0.001) 7 (0.002) 8 (0.002) 4 (0.001) 4 (0.001) 5 (0.001)

30 (46%) 18 (28%) 12 (8%) 11 (17%) 10 (15%) 8 (12%) 5 (8%) 4 (6%) 5 (8%) 5 (8%) 4 (6%) 2 (3%) 3 (5%) 3 (5%) 3 (5%) 2 (3%) 2 (3%)

104 (0.033) 24 (0.007) 20 (0.005) 15 (0.004) 16 (0.004) 11 (0.003) 5 (0.001) 4 (0.001) 5 (0.001) 5 (0.001) 5 (0.001) 2 (0.001) 5 (0.001) 4 (0.001) 3 (0.001) 2 (0.001) 2 (0.001)

* Excluding infections. † Rate, number of AEs per infusion. ‡ Includes injection-site inﬂammation.

The total number of AEs, irrespective of causality, including injection-site reactions, that began during or within 72 hours after the end of an infusion was 2262 (a rate of 0.62 AEs per infusion); excluding injection-site reactions, the rate of AEs per infusion was 0.14. Table 4 summarizes the severity of local AEs by infusion, irrespective of causality. Table 4: Severity of Local Adverse Events (AEs) by Infusion, Irrespective of Causality, in the US-Canada Study AEs (Number of infusions: 3656) AEs at the injection site Mild† Moderate‡ Severe§ Unknown severity Discontinuations due to AEs at the injection site

Number (Rate*) of AEs Occurring During or Within 72 Hours of Infusion 1767 (0.48) 1100 (0.30) 593 (0.16) 64 (0.02) 10 (<0.01)

Number (Rate*) of AEs 1789 (0.49) 1112 (0.30) 601 (0.16) 65 (0.02) 11 (<0.01)

3 subjects

* Rate, number of AEs per infusion. † Defined as those reactions that did not interfere with routine activities. ‡ Defined as those reactions that interfered with routine activities. § Defined as those reactions that made it impossible to perform routine activities.

Of the three subjects who discontinued the study due to injection-site reactions, one withdrew on Day 1 (Infusion 1) of the wash-in/wash-out period after a moderate injectionsite reaction and a mild headache; one withdrew on Day 22 (Infusion 4) of the wash-in/ wash-out period following severe injection-site reactions for two weeks; and one withdrew on Day 78 following a mild injection-site reaction. Local reactions decreased substantially after repeated use. Table 5 summarizes the most frequent adverse reactions (experienced by at least 3% of subjects) and considered by the investigator to be at least possibly related to Vivaglobin administration. Table 5: Incidence of Subjects With Adverse Reactions (Experienced in 3% of Subjects) and Rate* Per Infusion in the US-Canada Study Related Adverse Reactions ( 3% Subjects) Adverse reactions at the injection site† Other Adverse reactions Headache Nausea Rash Asthenia Gastrointestinal disorder Fever Skin disorder Tachycardia Urine abnormality

60 (92%)

Number (Rate*) of Adverse Reactions per Infusion (n=3656) 1787 (0.49)

21 (32%) 7 (11%) 4 (6%) 3 (5%) 3 (5%) 2 (3%) 2 (3%) 2 (3%) 2 (3%)

59 (0.016) 9 (0.002) 9 (0.002) 3 (0.001) 3 (0.001) 2 (0.001) 3 (0.001) 2 (0.001) 3 (0.001)

Number (%) of Subjects (n=65)

* Rate, number of adverse reactions per infusion. † Includes injection-site inﬂammation.

manufacturing company, but it’s going to take time, and their deadlines keep getting pushed back.” As for Teva, “we don’t know if [the company is] back in production yet. Some [generic chemotherapy drugs are] trickling out, but we can’t tell if that’s

Europe-Brazil Study In a clinical study conducted in Europe and Brazil, the efficacy and safety of Vivaglobin were evaluated for 10 months in 60 subjects with PI. Subjects were treated weekly with Vivaglobin at a mean dose of 89 mg/kg body weight (range: 51 to 147 mg/kg), which was 101% of their previous weekly IGIV or IGSC dose (see Clinical Studies [14.2]). Study subjects received a total of 2,297 infusions of Vivaglobin. The AEs and their rates reported in this study were similar to those reported in the USCanada study, with two exceptions: no episodes of headache were reported; and 18 (a rate of 0.008 per infusion) episodes of fever were judged to be related to the administration of Vivaglobin. One subject discontinued due to repeated local reactions of moderate severity. 6.2 Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. Vivaglobin Adverse reactions identified during worldwide postmarketing use of Vivaglobin for treatment of PI are allergic-anaphylactic reactions (including dyspnea, pruritus, urticaria, rash, edema and other cutaneous reactions, wheezing, syncope, hypotension, and throat swelling), generalized reactions (including flu-like symptoms, myalgia, chills, fever, tachycardia, arthralgia, nausea and vomiting, diarrhea, gastrointestinal cramping, stomach pain, back pain, headache, headache possibly caused by increased blood pressure, and chest tightness), migraine, and injection-site reactions. General The following adverse reactions have been identified and reported during the postmarketing use of IGIV products11: Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test General/Body as a Whole: Pyrexia, rigors Musculoskeletal: Back pain Gastrointestinal: Hepatic dysfunction, abdominal pain 7 DRUG INTERACTIONS 7.1 Live Virus Vaccines The passive transfer of antibodies with immunoglobulin administration may interfere with the response to live virus vaccines such as measles/mumps/rubella and varicella (see Patient Counseling Information [17.2]). 7.2 Serological Testing Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Vivaglobin. It is also not known whether Vivaglobin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Vivaglobin should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers Vivaglobin has not been evaluated in nursing mothers. 8.4 Pediatric Use In the US-Canada study, Vivaglobin was evaluated in 6 children (ages 5 through 11) and 4 adolescents (ages 13 through 16). In the Europe-Brazil study, Vivaglobin was evaluated in 16 children (ages 3 through 11) and 6 adolescents (ages 13 through 16). The safety and efficacy of Vivaglobin were not studied in pediatric subjects under 2 years of age. There were no differences in the safety and efficacy profiles as compared with adult subjects. No pediatric-specific dosing requirements were necessary to achieve the desired serum IgG levels. For recommendations on the number of simultaneous injection sites for pediatric patients who weigh less than 45 kg (99 pounds), see Administration (2.4). 8.5 Geriatric Use The clinical studies of Vivaglobin did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. For recommendations on the number of simultaneous injection sites for geriatric patients, see Administration (2.4). Manufactured by: CSL Behring GmbH Marburg, Germany US License No. 1765

Distributed by: CSL Behring LLC Kankakee, IL 60901 USA Based on April 2010 Revision.

because it’s so medically necessary that the FDA is allowing it to go out, or if they have started back into production. Teva won’t say, and the FDA can’t say.” For its part, Bedford Laboratories, now the sole manufacturer of leucovorin (although the FDA has reported that Teva plans to return to the market in April 2011), and one of three manufacturers of doxorubicin and cisplatin, issued a statement to Pharmacy Practice News. “Bedford Laboratories is committed to providing pharmaceutical products that improve the health and quality of life of patients. In April 2010, Bedford moved from 40% to 100% market share for leucovorin when the only other available supplier exited the market, making Bedford the sole provider of this criticalcare product,” the statement reads. “Due in part to this fact, we are currently facing manufacturing constraints that are resulting in back orders. We are working diligently to expedite manufacturing for all current orders and to anticipate future demands so that the patients and physicians who depend on this product as part of treatment have access to it.” Meanwhile, a response from Hospira noted that the company hopes to resume manufacture of bleomycin late in the first quarter of 2011, and that it is doing what it can to meet the demand for vincristine with tight supplies after another manufacturer left the market. “The situation highlights how fragile our supply chain is,” Dr. Fox said. “Of course, it’s good business practice to have a lean inventory and just-in-time manufacturing and no redundancies. But then, when one glitch happens it impacts patients all over the country. And it’s not like there’s not enough peanut butter on the shelves—people can die as a result of this.” A broader public health response to the growing drug shortage crisis is needed, Dr. Neuss says. “Somebody needs to step in and say that these drugs are a vital interest to society. We, as a society, have to decide how we’re going to be sure that the people who stand to benefit most from a drug are going to get it.” —Gina Shaw

Pharmacy Practice News • January 2011

Clinical 13

Practice Pearls

PEARLS ROUNDUP continued from page 1

pearls session. “The more automated we become, the more catastrophic the failures can be.” With all its benefits, the shift to automated systems has some disadvantages relative to paper-based systems, she said. For example, in the paper system, if the wrong profile is pulled and a patient is discharged erroneously, the nurses caring for the patient still have paper charts and paper medication administration records to alert them to the error so it can be rectified quickly. In contrast, in highly automated systems, “sweeping updates, transactions, etc.” can go unnoticed and cause multiple unintended alterations in a patient’s treatment. Accidental discharge of patients can cause a host of problems. The error can deactivate records in multiple departments, causing patients to miss medications, meals, procedures and so on. Errors also can be made when patient records are merged. Ms. Burkhardt recommend that hospitals look closely at “who’s doing the merge and who’s verifying that they are merging the right patient.” Attaching electronic files to the wrong patient record is another potential error. Additionally, she said, “it’s not uncommon to see workarounds because of brittle information systems.” Against this backdrop, the admission of newborns can pose a particularly dangerous situation, warned Ms. Burkhardt. In some hospitals, she explained, newborns are not “preadmitted,” so they are not recognized under a separate profile from their mother until after they are born. When a newborn requires drugs quickly, this can lead to the “unsafe practice of drawing out medication for the newborn under the profile of the mother. That is really dangerous,” she said, “because the records can become commingled” and drugs intended for the mother may end up being given to the baby. She noted that bar-coding systems “will not catch this because the records match.” Other examples of situations that pose errors are when admitting does not “move” a patient to the operating room when they are having surgery, “so STAT orders for OR patients accidentally go to the inpatient unit,” and when a neuromuscular blocking agent is not electronically and physically discontinued when a patient goes from the intensive care unit to a step-down unit, where they may not have ventilator support. Ms. Burkhardt urged attendees to evaluate their systems for these potential problems. She suggested that hospitals need to think prospectively about these risks, conduct failure mode and effect analyses, and “plan for failures

use of paralytic agents in their patients, according to medication safety expert Jeannell Mansur, PharmD, FASHP, practice leader at Joint Commission Resources, in Oak Brook, Ill. After a local newspaper reported that a patient died after being given succinylcholine by a nurse who mistakenly took the drug from a refrigerator on a floor, Dr. Mansur and her colleagues decided to evaluate the medication safety process for paralytic agents at the hospital where they practiced at the time, the University of Chicago Medical Center.

beyond the ordinary.” Noting that all staff should understand their rights and responsibilities in implementing automated systems, she concluded, “we should learn from other industries, and insist on best practices, even if it’s inconvenient for admitting or finance.”

Planning, Procedures Help Ensure Safe Use Of Paralytics

ospitals can take specific precautions and steps to ensure the safe

•

see Pearls ROUNDUP, page 14

Only Available from American Health Packaging!

Amlodipine Besylate and Benazepril HCl and Losartan Potassium Unit Dose! American Health Packaging is pleased to announce the launch of additional SKUs to our expanding unit dose line. Amloidpine Besylate and Benazepril HCl capsules and Losartan Potassium tablets are now available. Both items join our growing line of cardiovascular and circulatory unit dose products and are EXCLUSIVE to American Health Packaging.

All of our unit dose items are bar coded to the dose level and are stability tested to support extended shelf life. In addition, our color-coded labels and use of “tall man” lettering aids in selecting the correct product for dispensing.

800.707.4621 americanhealthpackaging.com

ABC Item #

Cardinal Health Item #

McKesson Item #

Morris Dickson Item #

NDC

Product Description

Strength

Size

Orange Book Rating

023349

4345195

1831783

085399

68084-0349-21

Amlodipine/Benazepril HCl Caps

5mg/10mg

30UD

023358

4345237

1834118

085407

68084-0350-01

Amlodipine/Benazepril HCl Caps

5mg/20mg

100UD

023287

4345245

1837053

085415

68084-0351-21

Amlodipine/Benazepril HCl Caps 10mg/20mg

30UD

028555

4351177

1183573

086454

68084-0346-01

Losartan Potassium Tablets

25mg

100UD

028579

4351201

1185149

086462

68084-0347-01

Losartan Potassium Tablets

50mg

100UD

028589

4351243

1186428

086470

68084-0348-01

Losartan Potassium Tablets

100mg

100UD

14 Clinical

Pharmacy Practice News • January 2011

Practice Pearls

PEARLS ROUNDUP continued from page 13

During the safety and quality pearls session, Dr. Mansur described how they developed a policy that addressed the various steps in the process, including ordering, storage and administration, to improve safety and try to prevent such errors from occurring. The recommendations include limiting who can prescribe paralytics and where they can be stored (not including rapid-sequence intubation kits). Dr. Mansur noted that it is important

to limit access to these drugs to those with expertise and to areas where they can be safely used. To avoid mix-ups, one of the main strategies that the team recommended was to create tackle boxes for vials and prepared infusions of paralytics clearly labeled with warnings in “plain language” on the proper use of these agents. For example, the outside of the tackle boxes has a sticker that reads, “WARNING! PARALYZING AGENT! PATIENT MUST BE INTUBATED!” Additionally, the compounded admixtures have stickers on the bag that

read, “WARNING: Paralyzing agent. Causes Respiratory Arrest.” She said it is important to consider both floor stock as well as pharmacy-prepared doses of these agents and storage of these items in both clinical care areas as well as within the pharmacy. Making caregivers aware of the risk associated with these agents was an important component of the redesign process. In that regard, educating nurses, anesthesia providers and pharmacy delivery staff about the risks associated with these agents and the new strategies is beneficial, suggested

The commitment to

ZOSYN ( p i p e ra c i l l i n /

tazobactam) continues with Pﬁzer Injectables

Whether your needs call for premixed frozen bags, bulk vials, or single-unit vials, you can count on Pfizer Injectables for a dependable supply of ZOSYN. It’s one more way Pfizer Injectables is dedicated to helping your business thrive with our heritage of quality, reliable manufacturing, and customer-focused flexibility. Visit www.pfizerinjectables.com for the solutions you need. USI00167

Printed in USA/June 2010

www.pfizerinjectables.com

Dr. Mansur. “It is important to make our frontline caregivers aware of these problems.”

Check Potassium In TMP-SMX Patients Or Risk Hyperkalemia

any clinicians do not realize that t r i m e t h o p r i m - s u l f a m e t h oxazole (TMP-SMX) can cause hyperkalemia in at-risk patients, according to Patrick McDonnell, PharmD, associate professor of clinical pharmacy at Temple University School of Pharmacy, in Philadelphia. During the clinical pearls session, Dr. McDonnell noted that he reviewed data from Temple University Health Care System’s internal adverse drug reaction (ADR) reporting program for the fiveyear period between 1999 and 2004. During that time the primary (85%) indication for TMPSMX, also known as cotrimoxazole, that was associated with ADRs was urinary tract infecti o n . Th e re we re 12 reports of cotrimoxazole-induced hyperkalemia. Dr. Mc D o n n e l l t h e n looked at the subsequent five-year period (2005-2009), during which the primary indication associated with ADRs had shifted to cellulitis secondary to community-acquired methicillin-resistant Stapylococcus aureus (77%), which requires higher doses of the drug for longer durations. He found that during this time, there were 63 reports of TMP-SMX-induced hyperkalemia. Dr. McDonnell described several patient populations at higher risk for this adverse drug effect: patients receiving a higher dose of the drug for a longer duration, such as those being treated for cellulitis; patients with renal impairment, particularly elderly patients; patients who are taking other drugs that increase the risk for hyperkalemia, such as angiotensinconverting enzyme inhibitors, angiotensin II receptor blockers and potassium-sparing diuretics; and patients who eat a diet high in potassium-rich foods, such as tomatoes, bananas, cantaloupe, mangos, pears, raisins and figs, etc. Dr. McDonnell said that “prescribers and pharmacists need to be aware of the risk for hyperkalemia from trimethoprim-[sulfamethoxazole].” He stressed the need for “careful, patient-specific dosing of this antibiotic,” as well as “increased monitoring for patients at risk, and that equates to prevention.”

Pharmacy Practice News • January 2011

Clinical 15

Practice Pearls Pharmacists Can Help Bring Dangerous Sodium Levels Back to Normal

nother electrolyte abnormality, hyponatremia, can be a serious medical emergency, and pharmacists should be aware of appropriate methods to rapidly correct this condition, according to a presentation during the emergency medicine pearls session. Presenter Mona Shah, PharmD, BCPS, clinical specialist in emergency medicine at Inova Fairfax Hospital in Virginia, noted that hyponatremia is considered severe if serum sodium is less than 115 mEq/L. Patients can quickly progress from disorientation to seizures and coma if they are not treated. Dr. Shah explained that patients become hyponatremic due to excess intake of water or hypotonic fluids (e.g., alcohol) or when there is increased secretion of antidiuretic hormone (ADH) secondary to hypovolemia, syndrome of inappropriate diuresis, thiazide diuretics or renal failure. In hyponatremia, there is excessive water in relation to sodium. This results in decreased serum osmolality and water shifts into the cells until a new osmotic equilibrium is reached. Severe hyponatremia can be acute or chronic. In acute hyponatremia, immediate and rapid administration of hypertonic saline may be necessary to pre-

Calculating Rate Of Correction for Hyponatremic Patients Using 3% Saline 1. Calculate the total body water (TBW). men: 0.6 × lean body weight in kg; women: 0.5 × lean body weight in kg 2. Estimate the change in serum sodium needed. If you know the hyponatremia is chronic, ∆PNa, in mEq = 10-12 mEq/L per day Or If you don’t know the hyponatremia is chronic, ∆PNa, in mEq = (120–patient’s serum sodium) = ___ mEq/L per day 3. Calculate the amount of sodium needed. Na, in mEq = ∆PNa, in mEq x TBW in L 4. Calculate the volume of infusate (3%) needed. Volume of 3% saline = (Na, in mEq/513 mEq/L) × 1,000 5. Calculate the rate of correction. Rate in mL/h = Volume in mL/__h In acute hyponatremia, may correct rapidly over 4-8 h; in chronic hyponatremia, do not correct more than 12 mEq/L per 24 h 6. Check serum Na every 2-4 h when infusing 3% saline. 7. If patient’s symptoms resolve, may switch from 3% to 0.9% saline.

vent cerebral edema whereas in chronic hyponatremia, rapid over-correction of hyponatremia can result in osmotic demyelination syndrome since the brain cells have already adapted to their new hypotonic environment. Dr. Shah said that even though hypertonic saline is the recommended treatment for both acute and chronic severe hyponatremia, the rate of correction used may be different. She recommended the steps in the box below to calculate the rate of correction using 3% saline. The maximum rate of correction should be less than 12 mEq/L per day especially

if the hyponatremia is chronic, she said, adding that it is important to check the sodium levels every two to four hours while infusing 3% saline. Additionally, she said that once the patient’s symptoms resolve or when the serum sodium reaches 120 mEq/L, the rate of sodium correction should be recalculated to ensure that the change in serum sodium does not exceed 12 mEq/L per day (in chronic cases) or the infusate may be changed from 3% to 0.9% saline. Dr. Shah warned that it is critical not to raise the sodium level up too high because over-correction can cause osmotic demyelination syndrome in

patients with chronic hyponatremia. For more information, go to pharmacypracticenews.com for our educational review on Contemporary Management of Hyponatremia. Or scan the 2-D bar code above.)

—Sarah Tilyou Next month: Our series continues with pearls on automating baseline INRs, reducing the impact of medication shortages, managing interactions with oral chemotherapy drugs, and more.

16 Clinical

Pharmacy Practice News • January 2011

Medication Safety

Yet Again, Patients Unaware of Risks of Supplement Use M ‘Warfarin accounts for more [ER] visits than any other drug.

any patients with atrial fibrillation (AF) who are prescribed warfarin do not realize that the “natural” supplements that they take could have negative, and even potentially deadly, interactions with their prescription medications, according to a new study from researchers at the Intermountain Medical Center Heart Institute in Murray, Utah. “Our previous research has shown that nine of the 10 top-selling supplements in the U.S. have negative interactions

Supplement use may be one factor ... it may be contributing to an increased risk for bleeding or medication failure.’ —Jennifer Strohecker, PharmD with warfarin,” said lead author Jennifer Strohecker, PharmD, assistant professor

of pharmacy practice at the University of Southern Nevada, Henderson, and clinical pharmacist at Intermountain Medical Center. “So since the potential for interactions is high, we wanted to know what the level of supplement use is in this very high-risk patient population, and whether or not doctors are talking to their patients about it.” The results were worrisome, she said. In a group of 100 patients with AF who were prescribed warfarin, 69% were taking some type of supplement (most commonly vitamins), and most of them were unaware of the potential interactions. Only one-third of the patients had been asked about supplement use by a medical provider; information about supplement use was absent from the medical record in 73% of patients who said that they took supplements. According to Dr. Strohecker, supplements that are risky to take with warfarin include: • Soy, multiherbal supplements and coenzyme Q10. These combinations can lower the international normalized ratio (INR), raising the risk for clots and stroke. • Cranberry, melatonin, antioxidants, fish oil, and the joint supplements glucosamine and chondroitin, which can have the opposite effect, increasing the risk for bleeding.

Ending Up in the ER “Warfarin accounts for more emergency room visits than any other drug,” she said. “Supplement use may be one factor that explains this; it may be contributing to an increased risk for bleeding or medication failure.” Although much attention is focused on the role of the physician in educating patients about possible risks associated with supplements and their interactions with prescribed medications, Dr. Strohecker said that pharmacists should be front and center on this issue. “Unfortunately, most pharmacy programs do not require a pharmacist’s education to include [detailed instruction on] supplements. Many have elective courses on alternative medicine, but only a few have a required course in supplements. We need to have pharmacists who are comfortable and educated in discussing the risks and

Pharmacy Practice News • January 2011

Clinical 17

Medication Safety benefits of these products.” S i m p l y s ayi n g “they’re not regulated by the FDA, so don’t use them,” isn’t enough, Dr. Scan for more Strohecker information on stressed. “We know dietary supplement t h e y a re u s i n g risks. See p. 3 for them. Pharmacists instructions. should take a stand that we are going to be our patients’ source of information on supplements, instead of the clerk at the health food store or the chiropractor or the Internet. We have to equip ourselves with the necessary knowledge to be that resource.” One new source of information for pharmacists and other health care professionals (as well as the public): beginning Dec. 1, 2010, PubMed has a new subset, “Dietary Supplements,” a joint project between the National Institutes of Health (NIH) National Library of Medicine and the NIH’s Office of Dietary Supplements (ODS). This subset was created using a search strategy including terms provided by ODS, and selected journals indexed for Medline that include significant dietary supplement-related content. It replaces the International Bibliographic Information on Dietary Supplements database, which was a collaboration between the ODS and the U.S. Department of Agriculture National Agricultural Library.

‘Many health care professionals would agree that supplements act like drugs, even though they are regulated like foods, and need to be reviewed by the pharmacist.’ —Cathy Rosenbaum, PharmD, MBA, RPh the pharmacist is used as the admitting medication reconciliation dietary supplement consultant to help attending physicians navigate and manage any supplement-related issues while their patients are hospitalized,” she suggested. “The pharmacist is in a pivotal place professionally to address supple-

ment usage from both a safety and efficacy perspective. Many health care professionals would agree that supplements act like drugs, even though they are regulated like foods, and need to be reviewed by the pharmacist.” This is not the first study to document a disregard for the risks posed by dietary

supplements. In fact, several researchers have shown that patients are so unconcerned, they often fail to disclose to their physicians that they are taking the OTC products. A 2004 study found that of 318 outpatients receiving cancer treatment at London’s Royal Marsden Hospital, 164 (51.6%) used complementary and alternative medicines. However, fewer than half of these patients had discussed their use of supplements with a health care professional involved in their treatment (Br J Cancer 2004;90:408-413). —Gina Shaw

You spoke. We listened. And together, we are prepared to move healthcare forward.

Taking a More Active Role At Bethesda North Hospital, an acute and tertiary care hospital in Cincinnati, Cathy Rosenbaum, PharmD, MBA, RPh, clinical effectiveness and safety officer, serves as a consultant to care teams in managing the issue of supplement use. “Referrals can come from a physician, bedside nurse, nurse practitioner or another pharmacist,” Dr. Rosenbaum said. “When requested, I go into the patient’s room to interview the patient and write up a list of all the supplements she/he is on. Then, I share my opinion with the patient as to whether or not the supplements should be continued,” based on potential for side effects, drug–supplement interactions, evidence of efficacy and so on. Dr. Rosenbaum’s recommendations are recorded in the progress note in the patient’s chart. She discusses her written progress note with the attending physician, and her notes can be read by any member of the care team. “This process is not common in many hospitals, but it’s an encouraging model for the future,” she said, adding that her patient consults usually take between 30 and 45 minutes, with another 30 minutes to write up the progress note. “Hospitals could set up a system where

Hospira is investing in new ways of Advancing Wellness™ by driving costs out of the system. At Hospira, we realize that one of our greatest assets is the thoughts and opinions of our customers. Your feedback has helped us develop unique drug delivery systems, such as ADD-Vantage™, Carpuject™ and iSecure™, which promote efﬁciency and patient safety. It enables us to help you reduce costs with more generic injectable pharmaceutical options—allowing you to reinvest in the

most critical areas of your facility. And it inspires us to continue expanding our global generic leadership beyond small-molecule drugs into developing one of the largest biosimilar pipelines in the industry. As we look to the future, we will continue to seek out your valuable insights to help us

develop smarter products, generate greater value and, most importantly, improve patient safety. Advance with us. Share your vision of the future with us at www.HospiraAdvanceWithUs.com. WE LISTEN.

WE THINK.

WE DISCOVER.

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

W E C R E AT E .

P10-2809B

W E A D V O C AT E .

W E I N V E S T.

18 Clinical

Pharmacy Practice News • January 2011

Case Report

NEW FEATURE!

Drug Interaction Between Warfarin and Arnica Chetak Jain, BS, PharmD, CGP Clinical Pharmacist NYU Langone Medical Center New York, NY

he use of herbal remedies in the United States is widespread and increasing dramatically.1 Many patients feel that herbal products are safe, primarily because the remedies are derived from natural plants. Due to this belief, patients often will fail to disclose the herbal products they are taking to their physician.2 These factors, coupled with a lack of rigorous regulatory oversight of herbal products, have increased the risk for potentially serious adverse reactions when herbs and drugs are taken together. The herb–drug interaction discussed in this case report is between warfarin and arnica, resulting in a supratherapeutic international normalized ratio (INR). Although there is a theoretical potential for such an interaction, our case appears to be the first of its kind reported in the literature.

Case Presentation Chief Complaint: Nosebleeds in the setting of a high INR. History of Present Illness: The patient is an 81-year-old woman who presented to her doctor’s office for a recall INR that came back at 29. She was immediately sent to the emergency department (ED). The patient reports an oozing nosebleed for the past day and noticed some blood streaks in her undergarments but otherwise is in her usual state of health with no other complaints. She has no headaches, no focal weakness, no chest pain, no shortness of breath, no bruising, no abdominal pain, and no rectal bleeding. Past Medical and Surgical History: • Rheumatic fever and rheumatic heart disease • 1977: bladder tumor surgery • 1981: bilateral femoral artery embolectomy while off warfarin prior to heart surgery • 1981: mitral valve replacement (MVR) with porcine valve • 1984: atrial fibrillation; begins taking warfarin • 1996: reoperation of MVR with St. Jude’s mechanical valve • 2009: mitral valve paravalvular leak–surgical repair • 2009: aortic valve replacement

Table 1. Medications on Admission Medication

Dose

Frequency

Action

Aspirin (enteric-coated)

81 mg

Daily

Held

Calcium carbonate

500 mg

Twice daily

Continued

Darbepoetin alfa

100 mcg

Every other week

Held

Digoxin

0.125 mg

Daily

Continued

Folic acid

1 mg

Daily

Continued

Furosemide

40 mg

Daily

Continued

Levothyroxine

50 mcg

Daily

Continued

Lorazepam

0.5 mg

Daily as needed

Continued

Potassium SR

40 mEq

Daily

Continued

Simvastatin

40 mg

Bedtime

Continued

Warfarin

4 mg

Monday-Saturday

Held

Warfarin

3 mg

Sunday

Held

with tissue valve • 2009: sick sinus syndrome– permanent pacemaker • Hypertension • Hyperlipidemia • Hypothyroidism • Peripheral vascular disease • Pulmonary hypertension • Gastroesophageal reflux disease • Osteoarthritis Social History: • The patient lives by herself and is able to perform activities of daily living, including driving on her own and walking up flights of stairs to her apartment. • No smoking, no alcohol, and no drug use Allergies: • No known drug allergies (Tables 1 and 2). Hospital Course/Notes From Patient Record: Day 1: Patient presents to ED with elevated INR; phytonadione administered. Day 2: Phytonadione continued. Would like to observe INR in hospital for next 2 days to see need for heparin if the INR falls under 2.5, because patient has very high embolic risk with metal MVR and history of atrial fibrillation. Day 3: Patient doing well. Needs heparin until INR returns to at least 2. Given warfarin 5 mg in evening. Day 4: No acute events overnight. Urine cultures came back positive for Escherichia coli; patient started on ciprofloxacin 250 mg orally twice daily for 3 days. Team is aware of the drug–drug interaction with warfarin and the antibiotic but not con-

to the mountains of Europe and Siberia and is cultivated in North America. The fresh or dried flowers are used for medicinal purposes.3 Arnica is used mainly for its analgesic and anti-inflammatory properties. Oral use is not considered to be safe because it can cause abdominal pain, diarrhea, vomiting, and dyspnea. There are unconfirmed reports of arnica ingestion causing cardiac arrest and death. The topical preparation is used for muscle inflammation, sacroiliac pain, and other joint pain.4 Warfarin sodium is an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors, which include factors II, VII, IX, and X, and the anticoagulant proteins C and S.

With the multitude of agents available to treat pain, arnica should really be reserved as a last resort in patients on warfarin. sidered contraindication because patient is in a monitored setting. Given warfarin 7.5 mg in evening and continued on heparin. Plan is to send home when INR is over 2 so patient can resume regular warfarin of 4 mg Monday through Saturday and 3 mg on Sunday. Day 5: Patient doing well. No active signs of bleeding and hemodynamically stable. Day 6: Patient has elevated INR. Plan for discharge tomorrow. Day 7: Discharge today. Give 2 mg tomorrow and get INR every other day. Slowly transition patient back to previous warfarin regimen. (See Table 3 for more details on INR values.)

Discussion Arnica montana is an herb that grows to a height of 1 to 2 feet with yellow-orange flowers. It is native

Proposed Mechanism of Drug Interaction: Arnica contains 2 coumadin derivatives, scopoletin and umbelliferone, which may potentiate the effect of anticoagulants.4 This effect has not been documented in humans. Shroder et al isolated 2 further compounds from arnica: helenalin and 11α,13dihydrohelenalin. They concluded that these 2 compounds inhibit platelet activation via an interaction with cellular sulfhydryl groups.5 In this case, the likelihood that the patient’s supratherapeutic INR was caused by an interaction between warfarin and arnica was strengthened by the fact that the patient’s son bought the arnica online and there is no standardization regarding concentration of the herbal product. Also, the recommended dose of topical arnica is a 2- to 4-cm long

•

see INTERACTION, page 44

Table 2. Medications Initiated During Hospital Stay Medication

Dose

Frequency

Date(s), Time

Ciprofloxacin

250 mg

Twice daily

6/11-6/14

Heparin drip

25,000 units/250 mL

Continuous

6/10-6/14

Phytonadione

10 mg

Once

6/8 17:28

Phytonadione

5 mg

Once

6/8 19:46

Phytonadione

5 mg

Once

6/9 00:50

Phytonadione

5 mg

Once

6/9 11:39

Phytonadione

5 mg

Once

6/9 17:37

Switch to Privigen

Guarantee your IVIg supply

Choose the IVIg therapy that is:

Simple. Ready-to-use 10% liquid IVIg 36-month room temperature storage Guarantee your IVIg supply for up to 5 years

Sophisticated.

Minimize your hospital’s supply risk

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

Safe.

Ensure your patients’ needs are met

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

In clinical trials, 97% of related adverse events were non-serious; 95% of 1038 infusions were administered without premedication. The most common adverse reactions were headache, pain, nausea, pyrexia/hyperthermia, fatigue, and chills 3-step virus inactivation/removal process, including nanoﬁltration to 20 nanometers, reduces the risk of pathogen transmission

Important Safety Information Privigen is indicated for the treatment of patients with primary immunodeficiency (PI) associated with defects in humoral immunity, including but not limited to common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. WARNING: Renal dysfunction, acute renal failure, osmotic nephrosis, and death may be associated with the administration of Immune Globulin Intravenous (Human) (IVIg) products in predisposed patients. Administer IVIg products at the minimum infusion rate possible. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIg products containing sucrose. Privigen does not contain sucrose. See full Prescribing Information for complete Boxed Warning.

In patients at risk for developing renal failure, monitor urine output and renal function, including blood urea nitrogen and serum creatinine. Thrombotic events have been reported with Privigen and other IVIg treatments. Monitor patients with risk factors for thrombotic events, including a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity. Aseptic meningitis syndrome (AMS) may occur infrequently with Privigen and other IVIg treatments; AMS may occur more frequently with high doses and/or rapid infusion of IVIg. Hemolysis, hemolytic anemia, and pulmonary adverse events have also been reported. There have been reports of noncardiogenic pulmonary edema in patients administered IVIg. If transfusion-related acute lung injury is suspected, test product and patient for antineutrophil antibodies.

Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin, in patients with hyperprolinemia, and in IgA-deﬁcient patients with antibodies to IgA and a history of hypersensitivity.

Privigen is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.

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

Please see brief summary of full Prescribing Information on following pages.

In clinical studies, the most common adverse reactions with Privigen were headache, pain, nausea, pyrexia/hyperthermia, fatigue, and chills.

20 Opinion

Pharmacy Practice News • January 2011

Leadership in Action

Mind-reading and Other Mentoring Pitfalls H ave you ever felt as though you had to read your boss’s mind to understand what he or she wanted you to do? How often have you gotten to the end of a project, only to find that this is not exactly what your boss had in mind? You then have to retrench, regroup and try it again. Sadly, this is not uncommon. Poor communication often results in unclear expectations. When this occurs between a boss and a subordinate, it causes mutu-

al frustration, further breakdowns of communication and an erosion of trust. I would suggest that we cannot afford to operate this way any longer. New financial constraints require us to work smarter and more efficiently. We need new systems that encourage efficiency. This efficiency not only adds to a company’s (or hospital’s) bottom line, it also promotes a team-like atmosphere and greater employee satisfaction. So, how do we get there?

One approach is “accountability leadership.” Although accountability leadership is often associated with assigning blame to people, this is a mistaken impression. Assigning responsibility (ownership) is a far cry from handing out blame. Knowing what we are being held accountable for brings certainty and confidence. Over the next few months of this column, I’d like to demonstrate how. At the same time, with the use of a

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Caritas Christi, Boston. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ caritaschristi.org.

Ernest R. Anderson Jr., MS, RPh

framework shaped by the principles in the book “Accountability Leadership,” by Gerald Kraines (Pompton Plains, NJ: Career Press; 2001), I will show you how to create this type of environment in your own workplace. Kraines defines accountability as “the

Pharmacy Practice News • January 2011

Opinion 21

Leadership in Action obligation of an employee to deliver all elements of the value that he or she is being compensated for delivering, as well as the obligation to deliver on specific output commitments with no surprises.” A worthy goal, but how can we make it happen? One of the first steps is to set goals with employees—encouraging their buy-in—then stepping back and allowing them to execute. The manager must give authority commensurate with the accountability. This gives the employee the opportunity to make creative decisions to get the job completed. In turn,

Setting goals with employees and encouraging their buy-in can go a long way toward ensuring a project’s—and staffer’s—success. this results in feelings of ownership (within the bounds of parameters of the project) and freedom.

LEAD People Kraines suggests that managers use the acronym LEAD as a formula for building a culture of accountability: Leverage. The manager’s role is to leverage the creative capabilities of their employees to maximize their contribu-

tions to the overall goals of the organization. When people are recognized for their expertise in particular areas and use that expertise to influence others and accomplish significant objectives, the result is a high level of satisfaction. This includes playing to people’s individual strengths to create a complementary team of professionals. This also acknowledges that you as a manager could not accomplish these goals on your own.

Rather, you need a team of people who have diverse abilities and expertise that you don’t possess in order to get the job done. When the manager can engage people and align their expertise with the stated goals, it is sure to result in employee success and personal development. Engagement. I have stated in this column many times, the wise manager seeks to win the minds and the hearts of his or her employees through engaging their full commitment. Coercion and autocratic rule are ineffective. There is often an unwritten contract between the effective manager and the employees when the employees know the manager has their best interest at heart and will help them accomplish the goals. By engaging the employees, the commitment becomes a two-way street. Alignment. When employees understand the significance of their roles in the organization (and “have permission” to act on that understanding), there is alignment. The employee also needs to understand how his or her position relates to the others in the department and organization as well. I have often encouraged pharmacists to think about their role as it aligns with broader national goals and institutional goals within health care. Health care reform provides opportunities for pharmacists to help patients improve their health and reduce costs. By understanding the incentives and determining how pharmacists can play a key role, we align ourselves. Institutionally, it is the managers’ responsibility to help their employees and upper management understand this alignment. Development. As Kraines states, “Managers must be held accountable for effectively developing their people.” As Ken Blanchard, author of “The Servant Leader” (Nashville, TN: J. Countryman; 2003) says, two marks of a servant leader are how he or she handles feedback and succession planning. Developing others shows an interest in the employee and helps to develop a mutual sense of trust and loyalty. Mentoring others must be intentional and not just “when you get around to it.” A great example of an opportunity to see others grow in their leadership abilities and have a part in making that a reality is through the ASHP Foundation Pharmacy Leadership Academy (PLA). The PLA is a year-long program taught remotely to prospective leaders. Credits earned during the PLA are applicable to further education toward a degree program at specified academic sites. Applications are accepted annually for the program. The application requires the identification of a mentor for the candidate. This is a great opportunity for the manager to be involved in one-on-one mentoring to develop pharmacy’s future leaders.

The bookstore division of

MCMAHONMEDICALBOOKS.COM ORDER BOOKS ONLINE

An Online Bookstore

THE BOOK PAGE

PUBLISHER’S TOP PICKS OF THE MONTH ON MCMAHONMEDICALBOOKS.COM These books and thousands more...

Anticoagulation Therapy: A Point-of-Care Guide William E. Dager; Michael P. Gulseth; Edith A. Nutescu

In the setting where anticoagulation therapy is necessary, clinicians are faced with the challenge of using agents that inherently have a small therapeutic window and the ability for medication mishaps when not used appropriately. This risk is balanced against the need to prevent against or treat thrombosis, which also can have life-altering consequences. This is an excellent resource for pharmacists who want to build expertise in caring for inpatients on anticoagulants.

Scan for easy ordering. Instructions, page 3

ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com. We can supply any medical book in print, so if you don’t find the book you want, e-mail your request with billing information to RMcMahon@ McMahonMed.com. If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@ McMahonMed.com.

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

Applied Clinical Pharmacokinetics

Assuring Continuous Compliance with Joint Commission Standards: A Pharmacy Guide: Eighth Edition

Larry A. Bauer

The most current, hands-on book in the field, Applied Clinical Pharmacokinetics provides clear and useful coverage of drug dosing and drug monitoring that no other text can match. It offers the latest standardized techniques and approaches to patient-specific dosing plus new information on more recently monitored drugs.

John P. Uselton; Patricia C. Kienle; Lee B. Murdaugh In today’s complex and changing world of compliance, you can’t afford to be left behind. This new edition of Assuring Continuous Compliance with Joint Commission Standards: A Pharmacy Guide can help keep you on target with all standards and goals. It’s the only book to cover all the latest major accreditation standards, including the Joint Commission.

Comprehensive Pharmacy Review NAPLEX® Preparation CD-ROM: Sixth Edition

Leon Shargel; Alan Mutnick; Paul Souney Designed to assist pharmacy students with preparation for their NAPLEX pharmacy board examination, this interactive CD-ROM contains all the review questions from the bestselling Comprehensive Pharmacy Review and Comprehensive Pharmacy Review Practice Exams. Its advanced functionality helps students target their strengths and weaknesses for more effective self-study and review. Complete explanations of answers are available for each question on the CD-ROM.

Encyclopedia of Clinical Pharmacy

Handbook on Injectable Drugs: 16th Edition

Instant Clinical Pharmacology, Second Edition

Pharmacy Technician Certification Review and Practice Exam: Third Edition

Joseph T. DiPiro

Providing ready access to summaries of primary literature, hard-to-find research and consensus results, the Encyclopedia of Clinical Pharmacy discusses health service delivery models.

Lawrence A. Trissel

This is still the world’s premiere guide to injectable drugs and the most trusted resource. All 349 monographs have been updated, including six all-new monographs: doripenem, someprazole sodium, ibuprofen lysine, insulin lispro, hydroxyethylstarch130/0.4 in sodium chloride 0.9% and moxifloxacin HCI. For each monograph, compatibility, stability, storage and preparation data have been painstakingly referenced and clearly presented, as you’ve come to expect and rely on in the Handbook on Injectable Drugs.

Evan J. Begg

Instant Clinical Pharmacology presents essential information about the core topics in clinical pharmacology in a concise, accessible dip-in format and aims to bridge the gap between basic pharmacology and the therapeutic use of drugs in humans. Each topic is concisely displayed in a double-page spread to aid learning and revision.

Barbara Lacher

The Pharmacy Technician Certification Review and Practice Exam comes packaged with the new TechPrep CD, which contains more than 1,000 review questions to help readers prepare for national technician certification exams. A robust practice session feature allows users to create custom quizzes by setting topic area, time and number of questions. The simulated exam function lets readers practice their test skills by providing a 90-minute, 120-question test, with questions weighted to mimic national certification exams. Students receive instant scoring and can quickly identify areas they have mastered. PPN0111

Pharmacy Practice News • January 2011

Clinical 23

Educational Review

Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations Scan for PDF of this review; see p. 3 for instructions

Jerry Siegel, PharmD, FASHP Clinical Associate Professor The Ohio State University College of Pharmacy Columbus, Ohio

hoosing an immune globulin (Ig) product is now more challenging because all products are available and in good supply. When Ig shortages were commonplace, it was

often a matter of seeing what product you could get, with less concern paid to the best product for your patient.

For the past several years, the availability of Ig products has been very good, so product shortages have not played a major role in product choice. This gives clinicians the opportunity to match the best product to the patient based on the patient’s clinical condition and comorbidities. In the future, it is expected that some of the lyophilized products will be discontinued, but additional liquid products will be coming to the market, providing more treatment options. For example, there are now 3 Ig products indicated for subcutaneous use. The recently approved Gamunex-C (Talecris), formerly Gamunex, comes in a 10% concentration and can be administered subcutaneously or intravenously. The product is expected to be available by early January. A second subcutaneous product, Hizentra (CSL Behring), has a 20% concentration and the third one, Vivaglobin, (CSL Behring), comes in a 16% concentration. Other than Gamunex-C, these subcutaneous preparations

should not be given intravenously, and their bioavailability is not the same as with preparations intended for intravenous use; thus, dosing adjustments are required when these agents are used. Another area of change for Igs is the use of these products for various new indications. One product, Gamunex-C, has received approval for use in patients with chronic inflammatory demyelinating polyneuropathy (IV only). In addition, there is ongoing research in many other potential indications, including Alzheimer’s disease and complex regional pain syndrome. The most common question regarding Ig products relates to whether they all are the same. Even though clinicians have considered all Ig products to be clinically equivalent, they are not pharmaceutically equivalent. It is imperative that Ig products not be interchanged without full consideration of the pharmaceutical differences. The reasons for switching

products may be clinical in nature and related to tolerability; they may be fiscal and based on contracting issues, or they may be due to product availability. It is best to consider product changes as if the patient is naïve to Ig use, with increased monitoring and conservative infusion times. Whereas Tables 1 to 5 may help facilitate these decisions, it is important to understand the clinical impact of changing products. Although all of the products contain primarily IgG, there are trace amounts of other Igs—IgA and IgM—as well as widely different stabilizing agents, which may affect tolerability. The differences in salt, sugar, and overall osmolarity of these products are particularly important when patients have various comorbidities, such as renal dysfunction, diabetes mellitus, vascular disease, or heart failure. Differences between lyophilized and liquid products may result in changes in product concentration and infusion rate, as well as tolerability.

The tables may be helpful in providing optimal care for patients receiving Ig products. They should be used as a general guide to help determine the product that is best suited for a particular patient population. Because there is considerable variation from batch to batch, the exact numbers represent averages of selected batches; any one batch of any Ig product may have ranges outside these average numbers. When comparing administration rates, clinicians need to keep in mind that each patient has a maximum tolerated rate. This rate is based on patient tolerability and may be different for each product. It is imperative that Ig be administered slowly initially and titrated as tolerated. The rate should be adjusted based on comorbidities as well. The infusion should be slowed or stopped if adverse events become evident during the infusion. (See the full prescribing information for each agent for more information about adverse reactions.) Tables appear beginning on page 24

24 Clinical

Pharmacy Practice News • January 2011

Educational Review Table 1. Therapeutic Considerations

Producta

Manufacturer

FDAApproved Indications

IgA Content

pH (After Reconstitution)

Plasma Source

Halflife, db

Viral Inactivation/ Removal

Intravenous Immune Globulin Carimune NF

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com

ITP, PID

720 mcg/mL (~2%)

6.4-6.8

>16,000 donors

pH 4.0/pepsin, nanofiltration, TSE removal

Flebogamma 5% DIF, 10% DIF

Instituto Grifols SA Barcelona, Spain Customer service: (888) GRIFOLS www.grifols.com

PID

2.9±0.1 mcg/mL (5%),d <6 mcg/mL (10%)d

5.6±0.1 (5%),b 5.5±0.1 (10%)b

US source IQPP-certified plasma from FDA-registered donor sites

4-week dosing: 32±5 (5%), 37±13 (10%)

Pasteurization (60°C, 10 h), SD, dual nanofiltration (35+20 nm) Fraction I and fraction II+III precipitation, 4% PEG precipitation, pH 4.0 treatment, TSE removal

Gammagard Liquid 10%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

PID

37 mcg/mL

4.6-5.1

Plasma from FDA-registered donor sites

SD, low pH, nanofiltration

Gammagard S/D 5%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

CLL, ITP, KS, PID

<2.2 mcg/mL, <1 mcg/mLe

6.4-7.2

Plasmapheresis, 10,000 donors

37.7±15

Gammaplex 5%

Bio Products Laboratory (distributed by FFF Enterprises) Customer service: (800) 843-7477 www.fffenterprises.com

PID

<10 mcg/mL

4.8-5.1

Plasma from FDA-registered donor sites

41±14

SD, nanofiltration, terminal low pH incubation

Gamunex-C 10%

Talecris Biotherapeutics Medical info: (800) 520-2807 www.gamunex-c.com

CIDP, ITP, PID

46 mcg/mL

4.0-4.5

Plasmapheresis

pH 4.2, caprylate chromatography purified, TSE removal

Octagam 5%f

Octapharma Pharmazeutika Octapharma USA Customer service: (866) 766-4860 www.octapharma.com

PID

≤200 mcg/mL

5.1-6.0

US source and recovered plasma

SD, pH 4.0

Privigen 10%

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com www.privigen.com

ITP, PID

≤25 mcg/mL

4.6-5.0

Plasmapheresis, US donors (>60,000)

36.6

pH 4.0 incubation; 20 nm virus filtration; depth filtration; TSE removal

Subcutaneous Immune Globulin Gamunex-C 10%

Talecris Biotherapeutics Medical info: (800) 520-2807 www.gamunex.com

PIDg

46 mcg/mL

4.0-4.5

Plasmapheresis

pH 4.2, caprylate chromatography purified, TSE removal

Hizentra 20%

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com www.hizentra.com

PID

≤50 mcg/mL

4.6-5.2

Plasmapheresis, US donors

pH 4.0 incubation, nanofiltration, depth filtration, virus filtration TSE reduction

Vivaglobin 16%

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com www.vivaglobin.com

PID

≤1,700 mcg/mL

6.4-7.2

Plasmapheresis, US donors

Relatively stableh

Ethanol-fatty alcohol/low pH precipitation; pasteurization

See Footnotes on page 26 and Key on page 27.

Pharmacy Practice News • January 2011

Clinical 25

Educational Review

IgG Subclass,c %

Streptococcus pneumoniae

Bacteria/Toxin Diphtheria Toxin

Escheri chia coli

IgG1

IgG2

IgG3

IgG4

60.5

30.2

6.6

2.8

3.6 IU/mL (NT)

66.6

28.5 (5%), 27.9 (10%)

2.7 (5%), 3.0 (10%)

2.2 (5%), 2.5 (10%)

60.9

32.1

Haemo philus Influ enzae Type B

Streptolysin O

HBV (Surface Antibody)

Herpes Simplex Type 1

Polio Type 2

1:64 (RIA)

1:128 (CF)

1:64 (NT)

Type 1

Type 3

1:32 (IHA)

313 (EIA)

180 (EIA)

1:60 (CF)

300 IU/mL (HAI)

1:512 (IFA); 1:348 (RIA) 1:2,560 (EIA)

5.7±0.9 IU/ mL (5%), 14.0±1.0 IU/mL (10%)

15±1 mg/L (5%)

30±6 PEI units/ mL (5%), 69±16 IU/ mL (10%)

21±4 IU/mL (5%)

48±27 IU/g Ig (5%), 42±13 IU/g Ig (10%)

2.1

4.0 units/ mL (NT)

21.2 mcg/mL (EIA)

1:2,320 (EIA)

68 PEI units/mL (EIA)

16.4 IU/mL (RIA)

≥0.20 IU/mL (EIA)

V-Z: 32 units/ mL (NT)

Type 1: 1:190 mIU/mL (NT)

2-5 IU/mL (NT); J5 lipid A 1:273

J5 LPS 1:46; 0111B4 LPS 1:12

17.5 mcgAbN/ mL (EIA)

8.5 mcg/mL (EIA)

11 mcg/mL (EIA)

1,150 IU (HH)

37 PEI mcg/mL (EIA), 1:2,480 (NT)

1:267 (RIA)

820 mIU/mL (RIA)

1:1,000 (EIA)

1:305 (NT)

2.2 IU/mL

2.3 mcg/mL

791 mcg/ 185 IU/mL mL

431 U/mL

20 IU/ mL

4.7 IU/ mL

5,129 AU/mL

65±4

26±2

5.6± 0.6

2.6± 0.2

≥2 AU/ mL

87.4±22.2 mcg/mL

26.1±7.7 mcg/mL

13.0±2.4 mcg/mL

16,846± 13,648 Todd units/mL

57 PEI units/mL

1:139

1:944

1:22 ±0 .35

5-30 IU/ mL

600-800 IU/mL

33-40 IU/mL

21-25 IU/mL

51 IU/g

1:8,192

1:1601:320 (NT)

67.8

28.7

2.3

1.2

4.9 (3.8-7.3) IU/mL

36.1 (26.445.0) IU/mL

1,746 (1,310-2,010) IU/mL

76.4 (51.2116.8) IU/mL

NA 5.3 (3.0-10.1) IU/mL

65±4

26±2

5.6± 0.6

2.6± 0.2

≥2 AU/ mL

87.4±22.2 mcg/mL

26.1±7.7 mcg/mL

13.0±2.4 mcg/mL

16,846± 13,648 Todd units/mL

57 PEI units/mL

1:139

1:944

1:22 ±0.35

68.7

26.6

2.7

≥2.5 IU/ mL

≥1,000 IU/mL

≥0.4 IU/mL

30-50 IU/mL

CMV

HAV

26 Clinical

Pharmacy Practice News • January 2011

Educational Review Table 2. Pharmaceutical Considerations

Producta

Method of Preparation

Form

Gamma Globulin, %

Monomers, %

IgM Content

<20 mcg/mL

Intravenous Immune Globulin Carimune NF

Kistler-Nitschmanni; pH 4.0 + trace pepsin; nanofiltration

Lyophilized

≥96

Flebogamma 5% DIF, 10% DIF

Cohn-Oncleyi; ion-exchange chromatography; acid pH treatment; PEG precipitation; pasteurization; SD; dual nanofiltration (35+20 nm)

Liquid

99.6±0.2 (5%),d 99.4±0.1 (10%)d

<2 mcg/mL (5%), >99.8 monomers <6 mcg/mL (10%) + dimers (5%),d >99.9 monomers + dimers (10%)d specification value: ≥95 monomers + dimers

Gammagard Liquid 10%

Cohn-Oncleyi SD treatment; anion-exchange chromatography; nanofiltration; ultrafiltration; low pH incubation

Liquid

≥98

≥95 monomers + dimers

Trace

Gammagard S/D 5%

Cohn-Oncleyi; ultrafiltration; anion-exchange chromatography; SD treatment

Lyophilized

≥90

96.4

Trace

Gammaplex 5%

Cold ethanol fractionation; ion-exchange chromatography; SD treatment; nanofiltration (20 nm); ultrafiltration; terminal low pH incubation

Liquid

>99

≥99 monomers + dimers

<0.02 mcg/mLj

Gamunex-C 10%

Cold ethanol fractionation; anion-exchange chromatography; caprylate chromatography purified; low pH incubation

Liquid

≥98

100 monomers + dimers

Trace

Octagam 5%f

Kistler-Nitschmanni; ultrafiltration; anionexchange chromatography; SD treatment

Liquid

≥96

>99 monomers + dimers

≤0.1 mg/mL

Privigen 10%

Cold ethanol fractionation; octanoic acid fractionation; anion-exchange chromatography; pH 4.0 incubation; depth filtration, nanofiltration (20 nm)

Liquid

≥98

≥98 monomers + dimers

3 mg/L

Subcutaneous Immune Globulin Gamunex-C 10%

Cold ethanol fractionation; anion-exchange chromatography; caprylate chromatography purified; low pH incubation

Liquid

≥98

100 monomers + dimers

Trace

Hizentra 20%

Cold ethanol fractionation; octanoic acid ractionation; anion-exchange chromatography

Liquid

≥98

≥90 monomers + dimers

≤10 mg/L

Vivaglobin 16%

Cold ethanol fractionation; pasteurization

Liquid

>96

FOOTNOTES a— A ll agents are contraindicated for IgA deficiency with antibodies to IgA. b— V aries with disease state, immune status, and age of the patient. c— A verage of sample lots; variable range in all IgG c lasses. d— Average of sample lots. e— F or patients with known reactions to IgA or IgA deficiency with antibodies; special request only. f—

ctagam was voluntarily withdrawn O from the US market in September 2010, pending investigation into the cause of increased thrombotic events associated

with the product.

k— Under appropriate storage conditions.

g— D O NOT USE Gamunex-C subcutaneously for ITP.

l—

h— I n contrast to serum IgG levels observed with monthly IVIG treatment (rapid peaks followed by decline), the serum IgG levels in subjects receiving weekly SQ Vivaglobin were relatively stable in 2 studies.

m— M altose may cause false elevations in blood glucose testing with glucose dehydrogenase-pyrroloquinolone quinone enzyme test strips; may cause problems with patients allergic to corn. See package insert for complete details.

i—

j—

imit infusion rate to <3.3 mg IgG/kg per L minute (2 mL/kg/h) for 10% solutions.

istler-Nitschmann is the specific cold K ethanol fractionation method used by the manufacturer (CSL Behring); C ohn-Oncley is the original method of cold ethanol fractionation.

n— L og reduction factor values obtained through prescribing information; most are available on respective Web sites.

Data on file at Bio Products Laboratory.

p— Some infusion rates were converted from

o— Data on file at Octapharma.

those listed in the prescribing information for consistency and reader convenience. q— C ertain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly. r— U nless specific compatibility information is available, do not mix with other drugs or solutions. s— P atients at high risk for thromboembolic events include patients who are elderly, overweight, or immobilized; patients with a history of hypertension, cardiovascular disease, thrombotic disorders, >65, or are dehydrated also are at increased risk.

Pharmacy Practice News • January 2011

Clinical 27

Educational Review

Sodium Content (5% Concentration)

Stabilizer

Osmolality/Osmolarity

Shelf Lifek

Reconstitution Time

0% water; 0.9% saline

5% sucrose

In sterile water: 3%, 192 mOsm/kg; 6%, 384 mOsm/kg; 12%, 768 mOsm/kg In NS: 3%, 498 mOsm/kg; 6%, 690 mOsm/kg; 12%, 1,074 mOsm/kg

24 mo

Several minutes

Not detectable

Trace

5% sorbitol (polyol)

240-370 mOsm/kg

24 mo RT

Not applicable (liquid solution)

Not detectable

Glycine

240-300 mOsm/kg

36 mo refrigerated; 12 mo RT

Not applicable (liquid solution)

<3 mg/mL

<2 mg/mL

0.85%

2% glucose

636 mOsm/L (5%), 1,250 mOsm/L (10%)l

24 mo

<5 min at RT; >20 min if cold

30-50 mmol/L

Sorbitol, glycine

480 mOsm/kg

24 mo

Not applicable (liquid solution)

<20 mcg/mL

Trace

Glycine

258 mOsm/kg

36 mo refrigerated; 6 mo RT

Not applicable (liquid solution)

10% maltosem

310-380 mOsm/kg

24 mo

Not applicable (liquid solution)

Trace

Proline

240-440 mOsm/kg

36 mo RT

Not applicable (liquid solution)

<20 mcg/mL

Trace

Glycine

258 mOsm/kg

36 mo refrigerated; 6 mo RT

Not applicable (liquid solution)

≤2%

≤10 mmol/L

Proline

380 mOsm/kg

18 mo RT

Not applicable (liquid solution)

0.3%

Glycine

24 mo refrigerated

Not applicable (liquid solution)

Albumin

PEG

<2 mcg/mL(5%), <5 mcg/mL(10%)

KEY BEV bovine enterovirus (RNA model)

FDA Food and Drug Administration

IgA immune globulin A

MEV mouse encephalomyelitis virus

PRV pseudorabies virus

BVDV bovine viral diarrhea virus

GPA guinea pig assay

IgG immune globulin G

RIA radioimmunoassay

IgM immune globulin M

MMV mice minute virus (model for nonlipid DNA virus) NA information not available

RSS reduced space symbology

normal saline

neutralization test

complement fixation

CIDP chronic inflammatory demyelinating polyneuropathy CLL chronic lymphocytic leukemia CMV cytomegalovirus CPV canine parvovirus (model for parvovirus B19) D5W dextrose 5% in water

headache

HAI hemagglutination inhibition assay HAV hepatitis A virus HBV hepatitis B virus HCV hepatitis C virus HH

inhibition of hemolysis

EIA enzyme immunoassay (formerly ELISA)

HIV human immunodeficiency virus

EMCV encephalomyocarditis virus (RNA model)

IFA immunofluorescence assay

IHA indirect hemagglutination assay IQPP International Quality Plasma Program ITP idiopathic thrombocytopenic purpura IU

international units

PEG polyethylene glycol PEI Paul Ehrlich Institute International Units

IVIG intravenous immune globulin

PEV porcine enterovirus (model for HAV)

PID primary immunodeficiency

Kawasaki syndrome

LPS lipopolysaccharide

PPV porcine parvovirus

room temperature

SBV Sindbis virus SD

solvent detergent

subcutaneous

TSE transmissible spongiform encephalopathy VZV varicella zoster virus

28 Clinical

Pharmacy Practice News • January 2011

Educational Review Table 3. Cost Consideration Criteria Producta

Supply

24-Hour Service

Storage

Distribution

Return Policy Warranty

Packaging/Labeling Enhancements

≤30°C

Wholesaler or direct

Shipping error; defective or damaged product; will NOT accept out-of-date products

Free

Tamper-evident seal, RSS bar code, peel-off label with lot number and expiration date

Intravenous Immune Globulin Carimune NF

3, 6, 12 g

Flebogamma 5% DIF, 10% DIF

2°C-25°C 2.5, 5, 24 mo; 10, 20 g do not freeze (5%), 5, 10, 20 g (10%)

Wholesaler or direct from Grifols USA (888) GRIFOLS

Shipping error; defective or damaged product; will NOT accept out-of-date products

Free

Tamper-evident seals, including hologram and recognition of prior handling, integral suspension band, laser-etched vials with unique identifier number, bar-coded, 2 peel-off labels with product and lot number information

Gammagard Liquid 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 12 mo; do not freeze

Direct from Baxter

Free

Tamper-evident cap, RSS bar code, peel-off label with lot number and expiration date

Gammagard S/D 5%

2.5, 5, 10 g ≤25°C; do not freeze

Direct from Baxter

Free

Tamper-evident cap, peel-off label with lot number and expiration date

Gammaplex 5%

5, 10 g

2°C-25°C, 24 mo; do not freeze

Wholesaler

Shipping error; defective or damaged product; will NOT accept out-of-date products

Latex-free, single-use vial, tamper-evident cap, peel-off label with lot number and expiration date

Gamunex-C 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 6 mo; do not freeze

Wholesaler or direct

Limited

Free

Tamper-evident packaging, peel-off label with lot number and expiration date

Octagam 5%f

1, 2.5, 5, 10, 25 g

2°C-25°C, 24 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; will NOT accept out-of-date products

Cost

Tamper-evident packaging, latex-free packaging, peel-off label with lot number and expiration date

Privigen 10%

5, 10, 20 g

≤25°C, 36 mo

Wholesaler or direct

Shipping error; defective or damaged product; will NOT accept out-of-date products

Free

Latex-free, single-use vial, tamper-evident seal, RSS bar code, peel-off label with lot number and expiration date

Subcutaneous Immune Globulin Gamunex-C 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 6 mo; do not freeze

Wholesaler or direct

Limited

Free

Tamper-evident packaging, peel-off label with lot number and expiration date

Hizentra 20%

5, 10, 20 mL

≤25°C, 18 mo

Wholesaler or direct

Shipping error; defective or damaged product; will NOT accept out-of-date products

Free

Latex-free packaging, single-use tamper-evident vials, peel-off label with lot number and expiration date

Vivaglobin 16%

3, 10, 20 mL

2°C-8°C; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; will NOT accept out-of-date products

Free

Latex-free packaging

See Footnotes on page 26 and Key on page 27.

Pharmacy Practice News • January 2011

Clinical 29

Educational Review Table 4. Log Reduction Factor Comparisonsn Enveloped Viruses HIV Producta

Models for HCV

Model for Large DNA

SBV

BVDV

PRV

Nonenveloped Virus

TSE (Prion)

Intravenous Immune Globulin Carimune NF

≥26

≥19

≥9

≥25

≥19 (BEV)

Flebogamma 5% DIF, 10% DIF

≥20.30

≥6.49

≥16.61

≥23.15

≥15.04 (PPV), ≥13.33 (EMCV)

≥11.64

Gammagard L iquid 10%

≥14.8

≥16.8

≥16.9

≥5.7 (HAV), ≥7.7 (EMCV), ≥5.1 (MMV)

Gammagard S/D 5%

≥18.3 (HIV-1), ≥5.7 (HIV-2)

≥5.1

≥6.2

≥12.3

≥8 (HAV)

Gammaplex 5%

>12.9

>20.2

>11.7

>5.9 (HAV), >7.5 (EMCV)

Gamunex-C 10%

≥14

≥16.3

≥12.2

≥5.0 (HAV)

≥6.6

Octagam 5%f

≥14.6

≥16.7

≥21.1

≥6.2 (MEV), ≥9.2 (PPV)

≥6.7o

Privigen 10%

≥16.0

≥11.8

≥17.7

≥9.6 (EMCV), ≥7.8 (MMV)

≥14.8

Gamunex-C 10%

≥14

≥16.3

≥12.2

≥5.0 (HAV)

≥6.6

Hizentra 20%

≥16.0

≥11.8

≥17.7

≥9.6 (EMCV), ≥7.8 (MMV)

≥14.8

Vivaglobin 16%

≥12.7

≥14.0

≥14.1

≥10.4 (PEV), ≥9.0 (CPV)

Subcutaneous Immune Globulin

Table 5. IVIG Administration Ratesp Initial Infusion Rate

Maintenance Infusion Rate

Maximum Infusion Rateq

Carimune NF 6%

0.5 mL/kg/h

1-2 mL/kg/h

3 mL/kg/h

No filter required; compatible with NaCl, D5W; increased risk for renal and thrombotic adverse effectss

Flebogamma 5% DIF, 10% DIF

0.6 mL/kg/h

Increase gradually as tolerated to: 6 mL/kg/h (5%), 4.8 mL/kg/h (10%)

6 mL/kg/h (5%), 4.8 mL/kg/h (10%)

15-20 micron in-line filter recommended (5%); no filter required (10%); for patients >65 and those at risk for renal failure or thrombotic events, administer at the minimum infusion rate practicals

Gammagard Liquid 10%

0.5 mL/kg/h for 30 min

4 mL/kg/h; increase gradually as tolerated

5 mL/kg/h

No filter required; compatible with D5W but not NaCl; patients at risk for renal dysfunction or thrombotic events should be gradually titrated up to a more conservative maximum rate <2 mL/kg/hs

Gammagard SD 5%

0.5 mL/kg/h for 30 min

1-2 mL/kg/h; increase rate every 15 min as tolerated

4 mL/kg/h (5%), 8 mL/kg/h (10%)

15-micron filter required and supplied with administration set; compatible with sterile water

Gammaplex 5%

0.6 mL/kg/h

Increase gradually as tolerated every 15 min to: 4.8 mL/kg/h

4.8 mL/kg/h

15-20 micron in-line filter recommended; for patients at risk for renal dysfunction or thrombotic events, administer at minimum infusion rate practicals

Gamunex-C 10%

0.6 mL/kg/h 1.2 mL/kg/h (CIDP)

4.8 mL/kg/h

No filter required; avoid NaCl even in evacuated containers; for patients >65 or at risk for renal or thrombotic events, administer at minimum infusion rate practicals

Octagam 5%f

0.6 mL/kg/h for 30 min

1.2 mL/kg/h for 30 min then 2.4 mL/kg/h

<4 mL/kg/h

No filter required or supplied; if an in-line filter is used, the pore size should be 0.2-200 microns; for patients at risk for renal dysfunction or thrombotic events, administer at the minimum infusion rate practical, not to exceed 0.07 mL/kg/mins

Privigen 10%

0.3 mL/kg/h

2.4 mL/kg/h (ITP) 2.4 mL/kg/h (PID)

2.4 mL/kg/h (ITP), 4.8 mL/kg/h (PID)

No filter required; for patients at risk of renal dysfunction or thrombotic events, administer at minimum infusion rate practicals

IVIG

Commentsr

Flebogamma 10%DIF 速

Immune Globulin Intravenous (Human)

Hem/Onc Pharmacy

Pharmacy Practice News • January 2011

In Focus

FERTILITY continued from page 1

beyond the more traditional platinumbased chemotherapy agents. “I think we are just on the frontier of discovering what the issues are that will surface,” said Dr. Cuellar, who moderated a cancer treatment session at the recent annual meeting of the American College of Clinical Pharmacy (ACCP), and subsequently reflected on her own clinical experience in an interview with Pharmacy Practice News. “It’s such a tough area to research—there is such limited data.” Although doctors clearly play the primary role in discussing treatment options and related side effects, pharmacists also can be influential, according to clinicians interviewed by Pharmacy Practice News. As they educate patients about treatment-related side effects, pharmacists can reinforce details related to fertility preservation, and even pregnancy prevention during the course of treatment. Another possibility is that a pharmacist might encounter a patient who hasn’t been fully counseled about his or her fertility preservation options. Slightly less than half of oncologists— 47%—routinely refer cancer patients of childbearing age to a reproductive oncologist, according to a 2009 study involving 516 oncologists (J Clin Oncol 27:5952-5957). Gwendolyn Quinn, PhD, one of the researchers involved, said that she would like to incorporate feedback from pharmacists, as well as reproductive endocrinologists, in future surveys related to fertility preservation. Dr. Quinn, associate professor at the University of South Florida and a member of the Moffitt Cancer Center, both in Tampa, added that when pharmacists check the patient’s medical record, it’s sometimes unclear whether infertility risks have been discussed along with other potential side effects. In some cases, the issue may be one of documentation rather than a lack of counseling, she said. “I’ve heard the physicians push back and say, ‘We don’t have the time to go into all of the detail of what we did and didn’t say.’ ”

Educating Patients Although the time delay prior to treatment for men is relatively negligible, given the speed involved in sperm banking, the fertility preservation logistics are more complex for women, particularly if they don’t have a long-term partner at the time they are diagnosed, clinicians say. In 2006, the American Society of Clinical Oncology (ASCO) issued guidelines, recommending that the oncologist raise the option of fertility preservation at the earliest possible opportunity, including

referring interested patients to a reproductive endocrinologist (J Clin Oncol 24:2917-2931). The literature reviewed available options, citing “a paucity” of large randomized studies. Sperm bank and embryo freezing remain standard practice and other preservation methods are experimental, the authors wrote. More recent review articles have been

published, including a 2009 overview for female patients cited at the ACCP meeting (in vivo 23:123-130). Another recent overview explored fertility preservation options for both men and women (N Engl J Med 2009;360:44-53). At the University of Texas M.D. Ander-

‘It’s hard to predict who is going to have complete ovarian failure. Sometimes it is reversible and patients do regain fertility after chemotherapy.’ —Judith Smith, PharmD, FCCP, BCOP

Post-Hodgkin’s Baby Boots

ika Gylys Bursua, PharmD, was working as a pharmacy practice resident in April 2006, when she felt a lump in her neck. Within days, the 25-year-old had learned her diagnosis: stage II Hodgkin’s lymphoma. She and her fiancé, also a pharmacist, were in the midst of planning their wedding for later that year. So during that first oncology appointment, the couple was quick to ask about fertility preservation. “We knew that we wanted to have children,” Dr. Bursua said. That question led to an appointment with a fertility specialist. They discussed various options, including freezing embryos, but decided instead to try a GnRH analogue, leuprolide (Lupron, Abbott). “This was the one that she thought was best in our situation because we didn’t have a lot of time before I started chemotherapy,” Dr. Bursua said. By year’s end, Dr. Bursua had completed her chemotherapy regimen and was looking forward to her wedding, rescheduled for the following spring. In retrospect, the monthly leuprolide injections and rapid descent into temporary menopause were, in some ways, worse than the treatment’s side effects, she said. Among her symptoms: multiple daily hot flashes and weight gain. But her cancer remains in remission, four years and counting. And her daughter arrived in September 2010. She got pregnant pretty much immediately, Dr. Bursua said, adding that they’ll never know for sure if the medication helped. “It’s hard to tell,” said Dr. Bursua, an inpatient clinical pharmacy specialist at the Jesse Brown VA Medical Center in Chicago. “But I’m glad that I did something because if I wouldn’t have, I would have never known if the Lupron made a difference.” —C.H.

son Cancer Center, in Houston, pharmacists work closely with the cancer physicians in teams and typically touch base about what type of fertility issues have been covered, before meeting with the patient for additional education prior to chemotherapy, said Judith Smith, PharmD, FCCP, BCOP, associate professor in the Department of Gynecologic Oncology and Reproductive Medicine at the cancer center. “In most agents that we use, there is a fertility risk,” Dr. Smith said. “It’s hard to predict who is going to have complete ovarian failure. Sometimes it is reversible and patients do regain fertility after chemotherapy.” To better assist patients, pharmacists should also read whatever literature the oncologists are handing out about fertility-related side effects and preservation techniques, Dr. Quinn said. “So if they get any questions, they know where they originated,” she said. She also stressed that, for some younger patients, there might be another fertility preservation window that isn’t always highlighted. Younger patients, such as those treated for leukemia in their teens or early 20s, might want to consider fertility preservation techniques soon after treatment ends, she said. Although the treatment might not make them infertile, it might increase their likelihood of early menopause. “The point we try to sell here is that there is no bad time to see the reproductive endocrinologist.” Besides freezing eggs or embryos, female cancer patients may have another path, one explored in the ASCO guidelines and in the more recent in vivo review, involving the use of gonadotropinreleasing hormone (GnRH) analogues.

Some pharmacists interviewed said that physicians at their centers sometimes provided the option prior to initiating treatment, in the hope of suppressing the patient’s ovarian function and thus protecting them from treatment’s toxic effects. But using the GnRH analogues, which include agonists or antagonists, for ovarian suppression remains “highly controversial,” according to the ASCO guidelines, which cited the need for large-scale randomized trials. Another literature review published 2008 in Human Reproduction Update cited some studies showing benefits, but said any randomized trials involved were too small to be definitive, describing their overall effectiveness as debatable (14:553-561). Preventing Pregnancy

All of this discussion about temporary sterility can trigger an undesired side effect, according to pharmacists interviewed. Patients can mistakenly

•

see FERTILITY, page 36

www.BioOncology.com

A pioneer in cancer innovation — exploring new directions

At Genentech BioOncology, we’re leading the ﬁght against cancer with innovative science and are working to transform cancer treatment. A family of ﬁrsts — Our proven therapeutics are standards of care in 5 of the 6 leading causes of cancer mortality in the United States. A robust pipeline — Our molecules in development target the fundamental mechanisms of cancer growth and include a HER dimerization inhibitor, a Hedgehog pathway inhibitor, an antibody–drug conjugate, and antibodies targeting cancer cell-surface antigens. A commitment to patients — We actively pursue ways to ensure patient access to therapeutics through a variety of patient support programs so healthcare providers can remain focused on patient care. Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.

Hem/Onc Pharmacy

Pharmacy Practice News • January 2011

In Focus

FERTILITY continued from page 34

think that they can’t become pregnant while on chemotherapy and other cancer drugs. Dr. Smith said one of her roles is to discuss contraception options and to stress that patients “don’t have a green flag” to engage in unprotected sex. Dr. Cuellar said that she also has held up chemotherapy treatment, when she discovered that a pregnancy test hadn’t been added to the standard laboratory workup. She prefers to repeat a pregnancy test monthly in women of childbearing age, even if they are in their early 40s. To date, none of her patients have become pregnant. “Thank God, knock on wood,” she said. Moffitt Cancer Center, where Dr. Quinn works, also is in the process of developing a policy regarding the treatment of patients either diagnosed with cancer while pregnant, or who become pregnant during cancer treatment. Kelly Markey, PharmD, BCOP, a Moffitt clinical oncology pharmacist on the committee developing the policy, has contacted roughly 20 U.S. cancer centers to learn if they have developed similar policies. By late 2010, eight had responded, she said. Only two reported such policies, including M.D. Anderson Cancer Center. Along with educating patients, a hospital pharmacist can provide helpful information for clinician colleagues, said Laura Bobolts, PharmD, also a Moffitt clinical oncology pharmacist. She described a scenario a few years ago, when the center’s clinicians were treating a pregnant patient who had a gynecologic malignancy and who had chosen to pursue chemotherapy and continue the pregnancy, rather than undergo an abortive hysterectomy. Dr. Bobolts not only helped to research the short- and long-term risks of various chemotherapy agents, she also educated colleagues involved with the selected treatment, including nurses and those technicians mixing the chemotherapy drugs. “To make sure they were ethically OK with doing this,” she said. “I didn’t want anybody to do something that might regret later on if something should happen to the fetus.” Not all such stories have happy endings, Drs. Bobolts and Markey cautioned. But this one did—the woman delivered a healthy baby.

Uncertain Outcomes At the University of Illinois Medical Center, besides discussing sperm banking and freezing eggs or embryos, patients also are counseled regarding GnRH analogues, Dr. Cuellar said. The center has seen at least some anecdotal evidence of success; she knows of at least two women who subsequently had

‘The point we try to sell here is that there is no bad time to see the reproductive endocrinologist.’ —Gwendolyn Quinn, PhD a baby (see sidebar). “Other than the side effects like [those associated with menopause], especially now that we’ve seen [a positive] outcome, we feel like it’s something we continue to do and continue to recommend,” she said. But frequently it’s unknown wheth-

er fertility preservation options were helpful, Dr. Cuellar said. She described another recent patient, a man with acute promyelocytic leukemia who was worried about the fertility impact of all-trans retinoic acid, which she subsequently researched. “He definitely was

the driver in that whole conversation with the physician and subsequently me,” she said. “He was bringing it up.” The man did decide to bank his sperm. Clinicians advised him to wait at least a year before trying to conceive and, if he had further concerns about effects, to get his sperm analyzed in advance for quality. But, as with many other patients who pursue fertility preservation, Dr. Cuellar likely will never know if those shortterm interventions eventually do pay off in the delivery room. —Charlotte Huff

Step up to a range of insulin delivery options.

As part of Eli Lilly and Company’s ongoing commitment, we provide healthcare facilities with a choice of vial sizes. Humalog® (insulin lispro injection [rDNA origin]), Humulin® R U-100 (regular insulin human injection, USP [rDNA origin]), and Humulin® N (NPH human insulin [rDNA origin] isophane suspension) are available in a smaller vial size.* The smaller vials are designed to give healthcare facilities ﬂexibility when evaluating insulin storage and distribution (ﬂoor stock vs individual patient supply), in addition to the 10 mL vial and Humalog® KwikPen™. • Humalog NDC Number - 0002-7510-17 • Humulin R U-100 NDC Number - 0002-8215-17 • Humulin N NDC Number - 0002-8315-17 * Smaller vials contain 3 mL of insulin in a 5 mL vial.

Humalog Indication Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control of hyperglycemia. Humalog should be used with longeracting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.

HI66337

0810 PRINTED IN USA

Humalog Important Safety Information Contraindications Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients. Warnings Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of action. Therefore, when used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an insulin pump). Glucose monitoring is recommended for all patients with diabetes. The safety and effectiveness of Humalog in patients less than 3 years of age have not been established. There are no adequate and well-controlled clinical studies of the use of Humalog in pregnant or nursing women.

Hem/Onc Pharmacy 37

Pharmacy Practice News • January 2011

In Focus

Avastin Breast Cancer Indication in Peril Rockville, Md.—The FDA has started the process of removing the breast cancer indication for bevacizumab (Avastin, Genentech), saying the drug is too toxic and confers no survival benefit for women with HER2-negative metastatic breast cancer (MBC). The FDA’s decision was based on four clinical trials: E2100, AVADO and RIBBON-1, which studied bevacizumab as first-line, and AVF 2119 g, which studied it as second-line treatment. Bevaci-

zumab was originally granted accelerated approval in 2008 on the basis of the E2100 results. In the E2100 trial, the addition of bevacizumab to paclitaxel resulted in a 5.5-month increase in median progression-free survival (PFS) but no statistically significant improvement in overall survival (OS). The tumor response rate also was higher with bevacizumab plus paclitaxel as compared with paclitaxel alone (48.9% vs. 22.2%).

However, there was a 20.2% increase in grade 3 to 5 toxicity in the bevacizumab plus paclitaxel arm over paclitaxel alone. The major toxicities included hypertension, thromboembolic events, left ventricular dysfunction, myocardial infarction, gastrointestinal and nasal perforations and proteinuria. Additionally, the death rate attributed to bevacizumab was 1.7% (six of 363 patients). There were no deaths in the

Humalog Important Safety Information, continued

Warnings, continued Starting or changing insulin therapy should be done cautiously and only under medical supervision.

Other Side Effects, continued in action of Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those who are fasting, have autonomic neuropathy or renal impairment, are using potassiumlowering drugs, or taking drugs sensitive to serum potassium level).

Hypoglycemia Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia can happen suddenly, and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening. Other Side Effects Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and hypersensitivity. Systemic allergy is less common, but may be life-threatening. Because of the difference

Please see reverse side for Brief Summary of full Prescribing Information. Please see full user manual that accompanies the pen. Humalog® and Humalog® KwikPen™ are registered trademarks of Eli Lilly and Company and are available by prescription only. Humulin® is a registered trademark of Eli Lilly and Company.

paclitaxel-alone arm, which comprised 348 patients.

No Disruptions in Treatment “[This] announcement is the first step in a process and will not have immediate impact on use of Avastin to treat breast cancer, or the drug’s availability,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press briefing. “For

•

see AVASTIN, page 38

Hem/Onc Pharmacy

Pharmacy Practice News • January 2011

In Focus

AVASTIN continued from page 37

patients, this means no disruption in treatment. Their access to Avastin will not be affected.” She added that oncologists currently treating patients with bevacizumab should use their judgment in deciding whether to continue with the drug or explore other treatment options. Dr. Woodcock said the FDA’s decision did not take into account the cost of bevacizumab, which is estimated at about $100,000 per year per patient.

Meanwhile, as the FDA was announcing its decision, the European Medicines Agency (EMA) declared that bevacizumab in combination with paclitaxel remained a valuable treatment option for women with MBC, claiming that the benefits of the combination outweighed the risks.

‘I Will Miss the Drug’ “I think this is actually a good drug,” said Steven Vogl, MD, an oncologist in private practice in White Plains and Bronx, New York. “I don’t know why it doesn’t prolong survival and it both-

ers me that it doesn’t [do so], but at least in my limited experience, I’ve had some extraordinarily long remissions in some patients I have treated with Avastin and weekly paclitaxel.” Dr. Vogl recalled that the first patient he treated with weekly paclitaxel and bevacizumab had a two-year remission, and the next several patients had remissions that lasted more than a year. “I think these are wonderful results,” he said. As for side effects, “most of my patients tolerate bevacizumab. Their biggest problem is actually headache.”

HUMALOG®

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

animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted. Nursing Mothers—It is unknown whether Humalog is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both. Pediatric Use—In a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf life may be reduced (see DOSAGE AND ADMINISTRATION). Geriatric Use—Of the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were 65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed. ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a difference in frequency of adverse events between the 2 treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Whole—allergic reactions (see PRECAUTIONS). Skin and Appendages—injection site reaction, lipodystrophy, pruritus, rash. Other—hypoglycemia (see WARNINGS and PRECAUTIONS). OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent premeal hyperglycemia. When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longer-acting insulin being given may need to be adjusted when using Humalog. The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin preparations, the time course of action of Humalog may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques. Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30, and Humulin® R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted Humalog may remain in patient use for 28 days when stored at 5°C (41°F) and for 14 days when stored at 30°C (86°F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump. Parenteral drug products should be inspected visually before use whenever the solution and the container permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be refilled with insulin. External Insulin Pumps—Humalog was tested in MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. HOW SUPPLIED: Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each presentation containing 100 units insulin lispro per mL [U-100]): 10 mL vials NDC 0002-7510-01 (VL-7510) 3 mL vials NDC 0002-7510-17 (VL-7533) NDC 0002-7516-59 (VL-7516) 5 x 3 mL cartridges3 5 x 3 mL prefilled insulin delivery devices (Pen) NDC 0002-8725-59 (HP-8725) ® ™ 5 x 3 mL prefilled insulin delivery devices (Humalog KwikPen ) NDC 0002-8799-59 (HP-8799) 1 2 3

MiniMed® and Polyﬁn® are registered trademarks of MiniMed, Inc. Disetronic®, H-TRONplus®, D-TRON®, and Rapid® are registered trademarks of Roche Diagnostics GMBH. 3 mL cartridge is for use in Eli Lilly and Company’s HumaPen® MEMOIR™ and HumaPen® LUXURA™ HD insulin delivery devices, Owen Mumford, Ltd.’s Autopen ® 3 mL insulin delivery device, and Disetronic D-TRON ® and D-TRONplus ® pumps. Autopen® is a registered trademark of Owen Mumford, Ltd. HumaPen®, HumaPen® MEMOIR™ and HumaPen® LUXURA™ HD are trademarks of Eli Lilly and Company. Other product and company names may be the trademarks of their respective owners.

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

Thus, for Dr. Vogl, the ratio between bevacizumab’s efficacy and toxicity is actually quite acceptable. Given these patients’ extent of disease, that’s significant, he stressed. “Remember, we’re talking about metastatic breast cancer. These are [women] with relatively limited life expectancy and if you can control their cancers for an extra six months, that’s a lot, even if they don’t live longer.” If those six months are better, in terms of quality of life, he noted, “that’s a lot. So I will miss the drug, and my patients will miss it because I think they’ll have shorter remissions.” Dr. Vogl added that the FDA’s action will probably cause insurance companies to stop paying for the drug. “This is a pity. In my view, most treatment for metastatic cancer is to relieve symptoms because most of the time, the longevity benefits are very limited. The lung cancer doctors get all excited about extending life eight weeks. I do not. Especially if those are eight miserable weeks.” Dr. Vogl said he emphasizes these trade-offs to his patients, telling them that “a cure is worth a lot of suffering, but if you’re not going to cure somebody, then you worry about their quality of life. If I have a symptomatic patient who is short of breath from lung metastases or pleural effusion, or her bones hurt, or she is yellow from liver metastases, and you make that better with Avastin, then some mild degree of headache from the drug is justified.” Given those considerations, he added, “Avastin is not a bad drug at all.” Dr. Vogl predicted that bevacizumab will continue to be used in patients with MBC. “Of course, good doctors will use it off-label. We always do, provide someone will pay for the drug. The FDA was never mandated, nor is it equipped, to dictate or determine best medical practice. Its narrow job is to regulate marketing and determine safety.” Whether insurance companies will continue to cover bevacizumab depends on two factors, Dr. Vogl added. “One is the quality of the computer programs of payers and prescription plans. Some are quite poor and fail to distinguish unlabeled indications—thank goodness!” he said. “The other is whether some of the compendia and the National Comprehensive Cancer Network guidelines continue to support the use of bevacizumab against breast cancer.”

Oncology Pharmacist’s Take Sara K. Butler, PharmD, BCOP, clinical pharmacist for medical oncology at Barnes-Jewish Hospital, St. Louis, gave a somewhat wry view of the drug approval process. “It’s interesting to see how drugs get fast-track FDA approval up front, but then, when additional

Hem/Onc Pharmacy 39

Pharmacy Practice News • January 2011

In Focus trials come out, [the agency] looks at what the differences are between the early and later trials and reflects on their clinical significance,” she said. The latest action by the FDA will discourage clinicians from starting new courses of bevacizumab therapy, she predicted. “Some physicians will still use bevacizumab off-label, but some will not prescribe it at all. For patients who are already on bevacizumab and responding, I can see where the oncologist and patient may want to try to continue therapy.” But she echoed Dr. Vogl’s caveats on reimbursement. “Making sure drugs are going to be reimbursed is a huge ordeal, especially in the outpatient setting. Oftentimes we don’t know up front when we give the drug whether or not it’s going to be reimbursed.” In the case of Avastin, “certainly if we’re using it off-label, for an indication that no longer exists, we run the risk of not being reimbursed.” Dr. Butler added that there is no way to tell at this point whether insurance companies will continue to pay for bevacizumab. “I think the most important thing is for the oncologist and pharmacy to check with the insurance company prior to giving bevacizumab to make sure that it is covered.” The absence of bevacizumab from the breast cancer scene is not likely to have much of an impact on pharmacy practice, she said. “Avastin is still going to have the indications for colon cancer and other [malignancies], so the drug is not going to go away by any means.” Although bevacizumab has the same side effects when it is used for other cancer indications, such as colon cancer, non-small cell lung cancer, kidney

cancer and glioblastoma, the who will have a benefit. That improvement in PFS and/or might be a future avenue for OS makes the current risk– [Genentech] to explore.” benefit ratio more favorable The FDA’s decision about in those cancers, she said. bevacizumab had been loomBevacizumab may turn Scan for NCCN’s ing ever since the Oncology out to be of particular ben- stance on Avastin Drugs Advisory Committee efit in a certain subgroup of payments. See p. 3 voted 12 to 1 to recommend for instructions. patients with MBC, Dr. Butler removing its MBC indication suggested. “Some of the patients who I in July 2010. have seen have responded, so certainly Richard Pazdur, MD, director of the it’s not a cut-and-dried issue. It makes FDA’s Office of Oncology Drug Prodyou wonder which subset of patients ucts, who led the accelerated approval High alert 7.625x9.375_F:Layout 1 5/22/09 9:47 AM Page 1 actually would benefit, or is there a process for bevacizumab in 2008, admitsubset of patients that we could predict ted that the FDA’s recommendation is a

Innovative 3-part piggyback label design. Just peel & apply!

Epidural Heparin • Insulin • Chemo • Narcotic • IV Nutrition • Oxytocin • Paralytic • Magnesium Sulfate • Blank • •

New Product Advertisement Cactus SMART SINK™ he Cactus SMART SINK™ is designed to be a secured alternative to a sink, toilet, or waste bin when unneeded raw pharmaceuticals are disposed of. This innovative and compact system helps bring medical facilities into compliance by eliminating the negative impact to our environment, and prevents the unauthorized use of unused or waste drugs. The SMART SINK™ system automatically secures and renders unused drugs acutely “un-usable and un-recoverable.”

For more information, contact Dave Maness, CEO, Cactus, LLC. Email: dmaness @cactusLLC.net. Phone: Cell: 843-693-1512

disappointment for patients with breast cancer, as well as for the agency itself. For its part, Genentech has already indicated that it will request a hearing with the FDA to appeal its decision. In a statement released the day of the FDA’s announcement, the company reminded U.S. patients and physicians that until these proceedings with the FDA are concluded, bevacizumab “remains approved for use in combination with paclitaxel for the first-line treatment of metastatic HER2-negative breast cancer in the United States.” —Fran Lowry

Choose our stock line tracing labels or easily customize your own for any medication with our exclusive MILT ® software.

EPS , INC. ®

Simplicity by Design...from EPS. A Member of The Medi-Dose® Group.

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

www.medidose.com

1 3-part Line Tracing Label is placed on infusion container.

2 Line Tracing Label is easily removed and placed at the top of the line.

3 Second Tracing Label is placed at the bottom of the line.

40 Policy

Pharmacy Practice News • January 2011

FDA Watch

After Half a Century, a New Lupus Drug Nears Approval A

fter more than 50 years without any additions to the short lineup of approved treatment options for lupus, an FDA advisory panel voted 13-2 to recommend approving a new drug, Benlysta, for the disease. A final decision is expected from the agency by March 10, 2011. More than 1.5 million Americans suffer from the chronic autoimmune disorder, with symptoms ranging widely in type and severity. Some patients may experience only occasional fatigue or a skin rash, while others will develop lifethreatening kidney and heart disease. An arsenal comprised primarily of steroids, antimalarial and immune-suppressing drugs—only three of which are FDAapproved for lupus—helps keep symptoms and flare-ups in check. But the toxic side effects of these drugs often can present even worse problems. “For people who have bad lupus, it’s a very, very serious disease,” said Geoffrey C. Wall, PharmD, associate professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences, in Des Moines, Iowa. “Up to this point, these people just don’t have a lot of options.” “Even though efficacy data for Benlysta may be a bit marginal and there were a few safety concerns, the benefits appear to outweigh the risks,” he added. “Any drug that has some data for efficacy should make rheumatologists happy.” Systemic lupus erythematosus shares many characteristics with rheumatoid arthritis (RA), another autoimmune disease. However, the two diseases are not similar enough for the far larger array of RA drugs to be FDA-approved to treat lupus. Although some of them may be used off-label in lupus patients who are very ill, insurance coverage for their application to non–life-threatening disease, which can cause painful and disabling symptoms, is hard to find. Benlysta, also known as belimumab, targets a molecule that helps to regulate the immune system: B lymphocyte stimulator (BlyS). The BlyS molecule helps to promote the survival and maturation of B cells, which play a critical role in the body’s defense against infections. In lupus, there can be too much BLyS; this causes excessive inflammation, and eventually, damage to various organs in the body. “This drug basically starves B cells of an essential growth factor, so that over time you see a reduction in certain types of B cells,” said Richard A. Furie, MD, chief of rheumatology at North Shore-LIJ Health System, in Lake Success, N.Y. (Dr. Furie has received funding from both Human Genome Sciences and GlaxoSmithKline, co-developers of the new drug.)

If the FDA approves Benlysta, the price tag for the monthly intravenous infusions is expected to be in the $30,000-per-year range, analysts note. Although many critics contend that studies have shown Benlysta results in only marginal improvement, Dr. Furie thinks otherwise. He pointed out that “the placebo was not just a placebo,” potentially blunting the treatment effect in the two Phase III trials included in the Biologics License Application (BLA) submitted to the FDA. About 80% of the patients studied were already on two or more lupus therapies. “The better the background therapy, the harder it is to show a difference,” added Dr. Furie.

‘Up to this point, [lupus patients] just don’t have a lot of options.’ —Geoffrey C. Wall, PharmD The average relative improvements for patients on a 10-mg/kg dose of Benlysta compared to placebo at week 52, the primary end point, were 32% and 26% in the two Phase III trials (P<0.05 for both). Absolute improvements over placebo were 14% and 9%. Inconsistencies

between the studies raised some questions, however, including the fact that 1 mg/kg provided a greater treatment effect than 10 mg/kg in some analyses. In an earlier Phase II study of 449 patients, filed as part of the initial New Drug Application to the FDA (and included in the BLA), researchers failed to find any significant differences in either of two primary end points: percentage change in disease activity at week 24 and time to flare up over 52 weeks. But again, Dr. Furie offered an explanation. The Phase II study failed to find a significant effect because of suboptimal patient selection and study endpoints, he suggested. The Phase III studies not only enrolled patients with more active disease, but also incorporated a novel end point created with guidance issued by the FDA and an exploratory analysis of Phase II data, according to Dr. Furie. The earlier end point scored the presence or absence of symptoms the same regardless of severity and could not account for the worsening of symptoms that had been present at baseline. “By combining outcome measurements of both improvement and worsening, they got a more clinically meaningful end point,” said Joan Merrill, MD, medical director of the Lupus Foundation. Both Dr. Merrill and

B lymphocyte

Belimumab receptor activity There are several B lymphocyte-specific therapeutic targets in systemic lupus erythematosus; here, the area of activity of belimumab (Benlysta) is shown.

Dr. Furie agreed that the more complex measure makes sense. Another obstacle to Benlysta’s approval has been evidence that the drug may not be effective in AfricanAmericans with lupus. The disease is four times more common in people of African-American descent than in whites. Dr. Merrill brushed off this concern. “There is no evidence that AfricanAmericans did worse,” she said. “The African-American subgroup was a small minority of the patients in each trial [submitted to the FDA].”

Side-Effect Profile The new drug isn’t without toxicities. Although the FDA would not comment on the specifics of what it would include on a safety label until it takes regulatory action, Dr. Wall predicted the warnings will be very detailed. Dr. Merrill agreed that it is appropriate for detailed discussions of safety and efficacy to be on a package insert for all drugs. However, she pointed out that “there is no evidence that this treatment is less safe than other biologics on the market, or any less safe than the current unapproved standard of care that is being used in these patients.” Studies have shown that Benlysta’s side effects can include infusion reactions, infections and neuropsychiatric events. Yet overall, the FDA panel agreed that the side effects were fewer and milder than those of the standard lupus treatments. Across the Phase II and III studies, about the same numbers of patients experienced an adverse event on Benlysta as on placebo (plus any background therapies): 93% and 92%, respectively. Further, the difference in the rates of psychiatric events (15% vs. 12%) and infusion reactions (17% vs. 15%) were not significant, although there was a trend toward additional infections with Benlysta (70% vs. 67%; P<0.05). The 0.8% death rate with Benlysta was also slightly higher than the 0.4% rate with placebo, although this difference too did not reach statistical significance. “I think it’s a safe drug,” Dr. Furie said. “And I think the overall benefit is there. So, I would use it, particularly when patients are not responding to their other treatments and we don’t want to increase their steroid use.” “The drug could be even more beneficial over the long term,” he added. “The name of the game is to prevent damage from the disease or from the drugs. A lot of the damage that accrues over time is not solely from lupus itself but from the steroids or other drugs.” —Lynne Peeples

Built on data

42 Policy

Pharmacy Practice News • January 2011

Pain Medicine

Clinicians: Eliminate Codeine for Pediatric Pain Relief T

he chorus of voices against the use of codeine in pediatric patients is getting louder throughout the United States and Canada. In an editorial published in the Canadian Medical Association Journal (CMAJ) two physicians suggested that codeine—which has been a standard of pain care long before rigorous clinical testing was required—should no longer be used and that its active metabolite, morphine, be used instead (CMAJ 2010; Oct. 4 [Epub ahead of print]).

Noni MacDonald, MD, MSc, section editor of Public Health for the CMAJ, and Stuart MacLeod, MD, PhD, professor of pediatrics at the University of British Columbia, Vancouver, Canada, wrote that “Professional associations and health care institutions should warn physicians of the potential for serious harm by modifying guidelines on pain control, especially for newborns and children.” In the editorial, Drs. MacDonald and MacLeod observed that codeine has

poor analgesic properties, explaining, for example, that the drug is no more effective than ibuprofen at reducing pain in children (Pediatrics 2007;119:460-467). They also noted that physicians have linked the death of three infants to an ultrarapid metabolism of codeine. These children had polymorphisms in the genes coding for the CYP2D6 isoenzyme, which transforms codeine into morphine (N Engl J Med 2009;361:827-828). The Canadian duo posited that the ultra

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Humate-P® Antihemophilic Factor/von Willebrand Factor Complex (Human) Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. 1 INDICATIONS AND USAGE 1.1 Hemophilia A Humate-P, Antihemophilic Factor/von Willebrand Factor Complex (Human), is indicated for treatment and prevention of bleeding in adults with hemophilia A (classical hemophilia). 1.2 Von Willebrand Disease (VWD) Humate-P is also indicated in adult and pediatric patients with von Willebrand disease (VWD) for: (1) treatment of spontaneous and trauma-induced bleeding episodes, and (2) prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin (DDAVP) is known or suspected to be inadequate. Controlled clinical trials to evaluate the safety and efﬁcacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects (see Clinical Studies [14]). 3 DOSAGE FORMS AND STRENGTHS Humate-P is a sterile, lyophilized powder for intravenous administration. Each vial of Humate-P contains the labeled amount of VWF:RCo and FVIII activity expressed in International Units (IU). The average ratio of VWF:RCo to FVIII is 2.4:1. Approximate potencies are shown below; check each carton/vial for the actual potency prior to reconstitution: VWF:RCo/vial 600 IU 1200 IU 2400 IU

FVIII/vial 250 IU 500 IU 1000 IU

Diluent 5 mL 10 mL 15 mL

IU = International Units.

4 CONTRAINDICATIONS Humate-P is contraindicated in individuals who have had an anaphylactic or severe systemic reaction to antihemophilic factor or von Willebrand factor preparations. 5 WARNINGS AND PRECAUTIONS 5.1 Thromboembolic Events (VWD Patients) Thromboembolic events have been reported in VWD patients receiving Antihemophilic Factor/von Willebrand Factor Complex replacement therapy, especially in the setting of known risk factors for thrombosis.3,4 Early reports indicate a higher incidence may occur in females. Endogenous high levels of FVIII have also been associated with thrombosis, but no causal relationship has been established. Exercise caution and consider antithrombotic measures in all at-risk VWD patients who are receiving coagulation factor replacement therapy. 5.2 Monitoring for Intravascular Hemolysis Humate-P contains blood group isoagglutinins (anti-A and anti-B). When doses are very large or need to be repeated frequently (for example, when inhibitors are present or when pre- and post-surgical care is involved), monitor patients of blood groups A, B, and AB for signs of intravascular hemolysis and decreasing hematocrit values and treat appropriately. 5.3 Monitoring VWF:RCo and FVIII Levels Monitor the VWF:RCo and FVIII levels of VWD patients receiving Humate-P using standard coagulation tests, especially in cases of surgery. It is advisable to monitor trough VWF:RCo and FVIII:C levels at least once a day in order to adjust the dosage of Humate-P as needed to avoid excessive accumulation of coagulation factors (see Dosage and Administration [2.2, 2.3]). 5.4 Transmission of Infectious Agents Humate-P is made from human plasma. Products made from human plasma may contain infectious agents (e.g., viruses and theoretically, the Creutzfeldt-Jakob disease [CJD] agent) that can cause disease (see Description [11] and Patient Counseling Information [17.1]). The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing (see Description [11.1] for virus reduction measures). Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Thus the risk of transmission of infectious agents cannot be eliminated completely. Report all infections thought by a physician possibly to have been transmitted by this product to CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800FDA-1088 or www.fda.gov/medwatch.

rapid metabolism of codeine might be contributing to the deaths of others who have genetic variations in CYP2D6. They believe, however, that these cases may be under-reported because the test for polymorphisms is not widely available. They suggested that perhaps the most effective strategy for preventing problems with codeine is to stop using it altogether. In fact, “at least one leading pediatric hospital—Toronto’s Hospital for Sick Children—has already removed

Some viruses, such as Parvovirus B19 virus (B19V) or hepatitis A (HAV), are particularly difficult to remove or inactivate. B19V may most seriously affect pregnant women and immune-compromised individuals. Although the overwhelming number of B19V and HAV cases are community acquired, reports of these infections have been associated with the use of some plasma-derived products. Therefore, physicians should be alert to the potential symptoms of B19V and HAV infections (see Patient Counseling Information [17.1]). Symptoms of B19V may include low-grade fever, rash, arthralgias, and transient symmetric, nondestructive arthritis. Diagnosis is often established by measuring B19V-specific IgM and IgG antibodies. Symptoms of HAV include low-grade fever, anorexia, nausea, vomiting, fatigue, and jaundice. A diagnosis may be established by measuring specific IgM antibodies. Physicians should strongly consider administration of hepatitis A and hepatitis B vaccines to individuals receiving plasma derivatives. Potential risks and benefits of vaccination should be weighed by the physician and discussed with the patient. 6 ADVERSE REACTIONS The most serious adverse reaction observed in patients receiving Humate-P is anaphylaxis. Thromboembolic events have also been observed in patients receiving Humate-P for the treatment of VWD (see Warnings and Precautions [5.1]). Reports of thromboembolic events in VWD patients with other thrombotic risk factors receiving coagulation factor replacement therapy have been obtained from spontaneous reports, published literature, and a European clinical study. In some cases, inhibitors to coagulation factors may occur. However, no inhibitor formation was observed in any of the clinical studies. In patients receiving Humate-P in clinical studies for treatment of VWD, the most commonly reported adverse reactions observed by >5% of subjects are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, and edema. For patients undergoing surgery, the most common adverse reactions are postoperative wound and injection-site bleeding, and epistaxis. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Treatment of Bleeding Episodes in VWD Allergic symptoms, including allergic reaction, urticaria, chest tightness, rash, pruritus, and edema, were reported in 6 of 97 (6%) subjects in a Canadian retrospective study (see Clinical Studies [14.1]). Four of 97 (4%) subjects experienced seven adverse events that were considered to have a possible or probable relationship to Humate-P. These included chills, phlebitis, vasodilation, paresthesia, pruritus, rash, and urticaria. All were mild in intensity with the exception of a moderate case of pruritus. In a prospective, open-label safety and efficacy study of Humate-P in VWD subjects with serious life- or limb-threatening bleeding or undergoing emergency surgery, seven of 71 (10%) subjects experienced nine adverse reactions. These were one occurrence each of mild vasodilation and mild pruritis; two occurrences of mild paresthesia; and one occurrence each of moderate peripheral edema and extremity pain and severe pseudothrombocytopenia (platelet clumping with a false low reading). Humate-P was discontinued in the subject who experienced the peripheral edema and extremity pain. Prevention of Excessive Bleeding During and After Surgery in VWD Among the 63 VWD subjects who received Humate-P for prevention of excessive bleeding during and after surgery, including one subject who underwent colonoscopy without the planned polypectomy, the most common adverse events were postoperative hemorrhage (35 events in 19 subjects with five subjects experiencing bleeding at up to three different sites), postoperative nausea (15 subjects), and postoperative pain (11 subjects). Table 5 presents the postoperative hemorrhagic adverse events. Table 5: Hemorrhagic Adverse Events in 63 Surgical Subjects Adverse Event

Wound/injection site bleeding Epistaxis Cerebral hemorrhage/ subdural hematoma Gastrointestinal bleeding Menorrhagia Groin bleed

Surgical Procedure Category

Number of Subjects/ Events

Major Minor Oral Major Minor

8/11 2/2 2/6 4/4 1/1

Major

1/2

Major

1/3

Major Oral

1/1 1/1

Onset* Severity (Number of (Number of Events) Events) On Post Mild Mod Severe 7 4 9 – 2 2 – 1 1 – – 6 3 3 – 2 2 3 1 – 1 – 1 – – 2† 3‡ 1 –

–

– 1

1 –

– –

Pharmacy Practice News • January 2011

Policy 43

Pain Medicine codeine from its formulary. Others would do well to follow its lead,” they wrote. In a comment posted online, G. Allen Finley, MD, the Dr. Stewart Wenning Chair in Pediatric Pain Management at IWK Health Centre in Halifax, Nova Scotia, supported the call to stop using codeine (http://www.cmaj.ca/cgi/eletters/cmaj.101411v1#596265). He added that a subset of people—including 7% to 10% of whites—are poor metabolizers of codeine and hence receive little or no analgesia from the drug. “In children, the issue is even more pernicious,” wrote Dr. Finley. “Children

Adverse Event Ear bleed Hemoptysis Hematuria Shoulder bleed * † ‡ §

Surgical Procedure Category Major Major Major Major

Number of Subjects/ Events 1/1 1/1 1/1 1/1

Onset* (Number of Events) 1 – 1 – 1 – 1 –

may have difficulty communicating their pain, and thus will suffer in silence from our failure to provide effective analgesic drug levels.” Amy Drendel, DO, MS, assistant professor of pediatric emergency medicine at the Medical College of Wisconsin, Milwaukee, agreed and added that “there are a number of drawbacks that might affect [codeine] compliance, including bad taste and side effects. Currently, there are alternative analgesics and opioids available that have efficacy and safety profiles that are superior to that of codeine. For these reasons, I don’t use

1 1 1 1

Severity (Number of Events) – – – – – – – –

On = on-therapy; onset while receiving Humate-P or within 1 day of completing Humate-P administration. Post = post-therapy; onset at least one day after completing Humate-P administration. Reported as serious adverse events following intracranial surgery. Two of these events were reported as serious adverse events following gastrojejunal bypass. Reported as a serious adverse event requiring hysterectomy following hysteroscopy and dilation and curettage.

Table 6 lists the non-hemorrhagic adverse events reported in at least two subjects, regardless of causality, and the adverse events that were possibly related to Humate-P. Pulmonary embolus considered possibly related to Humate-P occurred in one elderly subject who underwent bilateral knee replacement. Table 6: Non-Hemorrhagic and Possibly Related Adverse Events in 63 Surgical Subjects

Body System

Body as a whole

Cardiovascular

Digestive Hemic and lymphatic system Metabolic/ nutritional Nervous Skin and appendages Urogenital * †

Adverse Event (AE)

Pain Fever Abdominal pain Infection Surgery Back pain Facial edema Chest pain Pulmonary embolus† Thrombophlebitis† Nausea Constipation Vomiting Sore throat Anemia / decreased hemoglobin

Number of Subjects With an AE Possibly Related to Humate-P – – – – – – – –

Number of Subjects With an AE Regardless of Causality* 11 4 3 3 3 2 2 3

1 1 – 1 –

1 15 7 3 2

–

Increased SGPT

Dizziness Headache Increased sweating Insomnia Pruritus Rash Urinary retention Urinary tract infection

1 1 – – – 1 –

5 4 3 2 3 1 4

–

Events occurring in two or more subjects. Events occurring in separate subjects.

Eight subjects experienced 10 postoperative serious adverse events: one with subdural hematoma and intracerebral bleeding following intracranial surgery related to an underlying cerebrovascular abnormality; one with two occurrences of gastrointestinal bleeding following gastrojejunal bypass; and one each with sepsis, facial edema, infection, menorrhagia requiring hysterectomy following hysteroscopy and dilation and curettage, pyelonephritis, and pulmonary embolus. 6.2 Postmarketing Experience The following adverse reactions have been identiﬁed during postapproval use of Humate-P. Because these reactions are reported voluntarily from a

codeine in my clinical practice.” Kimberley Sutters, RN, PhD, also agreed that the evidence shows that codeine is not beneficial in the pediatric population. Her own team has found that acetaminophen and codeine are not effective for managing children’s pain at home following a tonsillectomy, but alternative analgesics such as acetaminophen with hydrocodone are (Pain 2004;110:49-55; Clin J Pain 2010;26:95-103). Dr. Sutters noted, however, that clinicians and legislators will need to be educated and formulary revisions will be required to facilitate the move away

population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Humate-P exposure. Adverse reactions reported in patients receiving Humate-P for treatment of VWD or hemophilia A are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock), development of inhibitors to FVIII, and hemolysis. Additional adverse reactions reported for VWD are thromboembolic complications, chills and fever, and hypervolemia. 7 DRUG INTERACTIONS None reported. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Humate-P. It is also not known whether Humate-P can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Humate-P should be given to a pregnant woman only if clearly needed. 8.2 Labor and Delivery It is not known whether Humate-P can cause harm to the mother or the fetus when administered during labor and delivery. Humate-P should be given during labor and delivery only if clearly needed. 8.3 Nursing Mothers It is not know whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Humate-P is administered to a nursing woman. 8.4 Pediatric Use Hemophilia A Adequate and well-controlled studies with long-term evaluation of joint damage have not been done in pediatric subjects. Joint damage may result from suboptimal treatment of hemarthroses. VWD The safety and effectiveness of Humate-P for the treatment of VWD was demonstrated in 26 pediatric subjects, including infants, children, and adolescents, but have not been evaluated in neonates. The safety of Humate-P for the prevention of excessive bleeding during and after surgery was demonstrated in eight pediatric subjects (ages 3 to 15) with VWD. Of the 34 pediatric subjects studied for either treatment of bleeding episodes in VWD or prevention of excessive bleeding during and after surgery, four were infants (1 month to under 2 years of age), 23 were children (2 through 12 years), and seven were adolescents (13 through 15 years). As in adults, pediatric patients should be dosed based on body weight (kg) (see Dosage and Administration [2.2, 2.3]). 8.5 Geriatric Use Clinical studies of Humate-P did not include sufﬁcient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation. 15 REFERENCES 3. Mannucci, PM. Venous Thromboembolism in Von Willebrand Disease. Thromb Haemostas. 2002;88:378-379. 4. Markis M, Colvin B, Gupta V, Shields ML, Smith MP. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemostas. 2002;88:387-388. Manufactured by: CSL Behring GmbH 35041 Marburg, Germany US License No. 1765 Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

Based on January 2010 revision.

Mix2Vial is a trademark of West Pharmaceuticals Services, Inc.

from codeine. “Some state health plans do not cover the liquid formulation of acetaminophen with hydrocodone. With the increasing number of children on state insurance plans, this impacts a lot of children,” said Dr. Sutters, a clinical nurse specialist at Children’s Hospital Central California in Madera. “And although morphine and other Schedule II oral narcotics may be suitable alternatives, these medications are associated with additional regulations for analgesic prescription in the outpatient setting. In addition, many health professionals do not view morphine as an acceptable home treatment of moderate, short-term pain.”

Pharmacist’s Take “The evidence against codeine is certainly starting to build,” said David S. Craig, PharmD, clinical pharmacist specialist and director of the Pain and Palliative Care Pharmacist Residency Program at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla. But he said there should be limits to the regulatory actions brought against the drug. “I don’t think it should necessarily be withdrawn from the U.S. market, as was done recently with propoxyphene,” he said. Rather, “it will likely have precautions/contraindications related to CYP P450 polymorphisms added to labeling.” As for alternatives to codeine, he agreed that oral morphine is a possibility, but should be used with caution. “Morphine is much more potent than codeine, so there would have to be a culture change in the way that children were prescribed opioid analgesics,” Dr. Craig stressed. “The risk to patients would be that prescribers may not recognize the potency of oral morphine, which could eliminate the whole purpose of using morphine over codeine in the first place.” Additional opioid alternatives to oral codeine could be oxymorphone or hydromorphone, he added, “but these drugs would likely require additional safety studies in pediatric patients.” —Rosemary Frei, MSc

44 Clinical

Pharmacy Practice News • January 2011

Case Report

INTERACTION

drug interaction. In this continued from page 18 case, a drug–food interaclayer of ointment applied tion does not appear to twice daily. The patient be the culprit because the stated that she applied a patient stated that she was “large amount” to her back, aware of food interactions which may have increased Do you have a case and did not change her report you’d like absorption. diet in any way. In fact, the to share? Scan this patient had been on warfabarcode to contact Conclusion rin for more than 25 years, the editor. See p. 3 A supratherapeutic INR and thus was well aware of for instructions. with warfarin can involve a problematic foods to avoid. drug–food interaction, an accidental As for an accidental overdose, that overdose of warfarin, or a drug– possibility was very remote because

the patient was cognitively intact. All of those considerations make a drug–drug interaction the likely cause, and the only medication the patient added to her treatment regimen was the arnica topical cream. This appears to be the first reported case of a patient developing a supratherapeutic INR while on warfarin and arnica. It provides confirmation of what has been theoretically discussed. Patients should be counseled to not use arnica with warfarin. If for

Table 3. INR Values And Administration Of Warfarin Date

Time

INR

6/8/10

17:45

25.75

6/8/10

23:14

25:24

6/9/10

07:55

13.44

6/9/10

16:45

8.71

6/10/10 05:35

2.36

6/10/10 22:00

6/11/10

06:05 1.34

6/11/10

13.50

6/11/10

22:00

6/12/10 05:45

Warfarin (mg)

1.60 7.5 2.25

6/12/10 22:00

6/13/10 06:00 3.85 6/13/10 14:55

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

at www.pharmacypracticenews.com

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

4.59

6/14/10 06:20 4.41

some reason the patient must be on arnica and warfarin, it is strongly advised that the dose of warfarin be substantially reduced and INR testing done at least once weekly, if not more frequently. With the multitude of agents available to treat pain, arnica should be reserved as a last resort in patients on warfarin. The patient should be advised to look for any signs and symptoms of bleeding. This case report highlights the importance of obtaining a complete and thorough medication history. Medications can include prescription drugs, over-the-counter items, vitamins, dietary supplements, and herbal preparations. Once a thorough medication history is obtained, a pharmacist should crosscheck all of the medications for drug interactions, drug–food interactions, as well as drug–disease interactions. This is an area where the pharmacist is sorely needed and can further the profession’s role in optimizing patient care.

References 1. Tachjian A et al. Use of herbal products and potential interactions in patients with cardiovascular disease. J Am Coll Cardiol. 2010;55:515-525. 2. Werneke U, Earl J, Seydel C, Horn O, Crichton P, Fannon D. Potential health risks of complementary alternative medicines in cancer patients. Br J Cancer. 2004;90:408-413. 3. www.umm.edu/altmed/articles/arnica-000222.htm. Accessed Jan. 3, 2011.

4. Arnica. In: AltMedDex System [Internet database]. Greenwood Village, CO: Thompson Reuters Healthcare. 5. Schroeder H et al. Helenalin and 11-alpha, 13-dihydrohelenalin, two constituents from Arnica montana L., inhibit human platelet function via thiol-dependent pathways. Thromb Res. 1990;57:839-845.

Pharmacy Practice News • January 2011

Technology 45

Practice Pearls

Effective Leadership Facilitates Implementation Of Computerized Prescriber Order Entry Systems Tuan Huynh PharmD Candidate

Meredith Moy PharmD Candidate University of Maryland School of Pharmacy Baltimore, Maryland

Larry Siegel, PharmD Director of Pharmacy

Herbert Mathews, PharmD Pharmacy Operations Manager Carroll Hospital Center Westminster, Maryland

ntegration of new technologies has become a widely accepted solution in addressing the ongoing problem of medical errors in hospitals. In fact, the U.S. government is investing billions of dollars in improvements to the health care system, including funding for health information technology systems such as computerized prescriber order entry (CPOE).1,2

Such CPOE programs provide legible medication orders and clinical decision support, and have been shown to reduce serious medication errors and adverse patient outcomes by 55% to 80%.2-5 Additionally, these programs have been shown to enhance provider performance by 66% and reduce prescription order time by 28%.6,7 Despite these improvements to medication safety, only 4% to 10% of the nation’s hospitals have fully implemented CPOE.8 To expand these implementation numbers and effectively adopt CPOE, hospitals must assess costbenefits, overcome internal barriers by adequately planning and training, and address post-implementation problems.

Cost–Benefit Evaluation One of the major obstacles to incorporating CPOE into hospital systems is the high up-front cost of the technology. A large Massachu-

To overcome many of the internal barriers to CPOE, administrative leaders must strategically assess the needs of the hospital and staff. setts hospital calculated the cost of developing and implementing its CPOE system to be approximately $1.9 million in 1992, with an annual maintenance fee of $500,000.9 In

Please complete the following CPOE evaluation form. Information provided will be used to evaluate the success of CPOE and to clarify areas of improvement. Your opinions are important and will help advance the use of this technology. Please circle the number that best represents your opinion. PARAMETER

STRONGLY DISAGREE

DISAGREE

SOMEWHAT AGREE

AGREE

STRONGLY AGREE

CPOE has improved my daily workflow.

CPOE has improved my ability to choose the most appropriate medication therapy for my patients.

CPOE has improved my ability to select medications from the hospital formulary.

I feel that CPOE reduces medication errors.

I feel that CPOE improves patient safety.

I think that CPOE is user friendly.

I can customize CPOE to meet my needs and the needs of my patients.

I am satisfied with CPOE’s functionality.

I do not have concerns about using CPOE as part of my daily patient care activities.

I do not think that CPOE needs improvement.

I do not have suggestions for changing CPOE.

I feel that action will be taken by my administration based on my suggestion(s).

Comments/Suggestions ———————————————————————————————————————————————————————————————————————————————————————— ———————————————————————————————————————————————————————————————————————————————————————— ————————————————————————————————————————————————————————————————————————————————————————

Figure. Computerized prescriber order entry satisfaction survey form.

addition to the concrete costs of such systems, there also are intangible costs that must be considered, such as training time and workflow changes for physicians, pharmacists, and nurses that may lower hospital productivity initially after CPOE is implemented. Although the expense of new technology systems and products is substantial, it is important to consider the long-term savings from improved operations that lead to decreased medication errors and legal liability. Return on investment from CPOE implementation is estimated to save hospitals between $5 and $10 million annually.9 These savings are in part due to the reduced amount of redundant laboratory tests and the selection of more clinically appropriate and cost-effective formulary medications.10 In addition to the projected annual savings from implementing CPOE, hospitals also can benefit from U.S. government funding created specifically for health information technology as part of the American Recovery and Reinvestment Act of 2009. An estimated $26 billion has been designated to promote, expand, and increase the adoption of health information technology and provide grants to help health care systems plan and implement these technologies.1 However, to be eligible for available government financial aid, hospitals must demonstrate “meaningful use” of these technologies based on established criteria from the Centers for Medicare & Medicaid Services.2 Third-party payers also may reward hospitals that

•

see IMPLEMENTATION, page 46

46 Technology

Pharmacy Practice News • January 2011

Practice Pearls

IMPLEMENTATION continued from page 45

have implemented CPOE with higher re i m b u r s e m e n t rates because of the overall savings that result from prevented drug Scan for more tips adverse on avoiding CPOE events.11 Despite missteps. See p. 3 the high initial for instructions. cost and temporary loss in productivity, there are greater incentives for hospitals to move ahead to integrate CPOE with their other systems. Hospital leaders must communicate this benefit to all affected personnel through meetings, discussions, presentations, handouts, and e-mail.

Overcoming Internal Barriers Even with enhanced communication efforts, there may be internal barriers that slow the full implementation of these health information technologies. Opposition from physicians, pharmacists, nurses, and other internal customers can greatly delay the integration of CPOE. This resistance often stems from fear of change to current work practices, disparities in technological literacy, and concerns about product maturity.10,11 To overcome many of the internal barriers to CPOE, administrative leaders must strategically assess the needs of the hospital and staff. The following are 10 essential steps that can help abate staff concerns: 1. Create a vision for integrating CPOE into the hospital and set goals that will help move the hospital toward this vision. Share goals with all staff members and describe the benefits and address possible concerns. 2. Involve all affected departments, staff, system vendors, and stakeholders in the initial assessment of implementing CPOE. This can be achieved through organized meetings to solicit personnel concerns and suggestions. Also, have

feedback boxes or mechanisms available throughout the hospital that capture issues not brought up during meetings. Address all the concerns raised and individualize responses to the department or personnel to determine if the hospital is ready to consider implementing CPOE. Solicit feedback from staff members to evaluate and assess their needs and the hospital’s needs when choosing and/or adopting a CPOE system. It is critical that the selected vendor is able to effectively address concerns and tailor the system to the needs of hospital staff. For example, pharmacists should be able to view a patient’s full medical profile before processing a medication order sent from a physician. Provide mandatory training sessions, especially for physicians, pharmacists, and nurses. An initial training session is necessary to collect suggestions for improving the hardware and software. Follow-up training sessions will allow the staff to track the progression of CPOE. These sessions will address any CPOE literacy gaps and will increase acceptance as the system improves. Have CPOE experts available in all affected departments to help staff navigate, use, and customize CPOE applications. These can be either specially trained hospital staff or an external support group. Remind employees of the purpose and importance of the CPOE system. The staff should feel that they are making a difference by using this new system. Always maintain communication between physicians, pharmacists, nurses, informatics personnel, and administrators. Although CPOE provides clinical decision support, it does not negate the expertise of professionals in specific fields. Incorporate routine daily administrative rounding that includes assessment from employees

on how CPOE is working, what changes can be done to better the system, and whether there are any tools or equipment that can be provided to improve the use of the system. 10. Recognize when goals for implementing CPOE are achieved and celebrate. Reward the staff for improving patient safety by effectively incorporating the system into their daily workflow.

Addressing PostImplementation Problems Although careful planning and using the above 10 steps can guide hospitals toward successful CPOE use, there still can be issues that arise after integrating new technologies. It is important to confront these problems and have contingency plans to address issues as they arise. Administration and affected department leaders should routinely meet with their employees to discuss any ongoing matters regarding CPOE usability and integration into the hospital workflow. Additionally, creating a CPOE Satisfaction Survey and using feedback mechanisms can help garner employees’ opinions to evaluate the success of the new technology and determine if changes are necessary to meet the needs of the users. An example of a survey form is illustrated in the Figure. As changes and improvements are made, it is important to recognize those who suggested the change. By continuously gathering staff responses about the CPOE system and efficiently handling problems, hospitals can increase user acceptance and employee satisfaction.

The Bottom Line Assessing, planning, integrating, and continually improving a CPOE system is a challenge for many hospitals. Implementation is not always successful. Nevertheless, the use of such health information technology can drastically improve patient safety, reduce legal liability, and decrease health care costs. Long-term financial gains and government funding also

provide hospitals with greater incentive to invest in these computerized systems. By using the key concepts discussed above, administrators have a framework to lead their staff, vendors, and stakeholders in implementing CPOE in a way that meets the needs of the hospital and its patients.

References 1.

Recovery Programs: Health Information Technology. United States Department of Health and Human Services Web site. http:// www.hhs.gov/recovery/programs/#Health. Accessed December 14, 2010.

Bates DW. CPOE and clinical decision support in hospitals: getting the benefits: comment on “Unintended effects of a computerized physician order entry nearly hard-stop alert to prevent a drug interaction.” Arch Intern Med. 2010;170(17):1583-1584.

Nerich V, Limat S, Demarchi M, et al. Computerized physician order entry of injectable antineoplastic drugs: an epidemiologic study of prescribing medication errors. Int J Med Inform. 2010;79(10):669-706.

van Doormaal JE, Mol P, Zaal RJ, et al. Computerized physician order entry (CPOE) system: expectations and experiences of users. J Eval Clin Pract. 2010;16(4):738-743.

Bates DW, Leape LL, Cullen DJ, et al. Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA. 1998;280(15):1311-1316.

Hunt DL, Haynes HR, Hanna SE, Smith K. Effects of computer-based clinical decision support systems on physicians performance and patient outcomes: a systematic review. JAMA. 1998;280(15):1339-1346.

No authors listed. University health network achieves over 85% CPOE with Misys CPR, improves accuracy and saves time. Healthc Q. 2006;10:74-76.

Ash JS, Gorman PN, Seshadri V, Hersh WR. Computerized physician order entry in U.S. hospitals: results of a 2002 survey. J Am Med Inform Assoc. 2004;11(2):95-99.

Kelly WN, Rucker TD. Compelling features of a safe medication-use system. Am J Health Syst Pharm. 2006;63(15):1461-1468.

10.

Foster RA, Antonelli PJ. Computerized physician-order entry: are we there yet? Otolaryngol Clin North Am. 2002;35(6):1237-1243.

11.

Poon EG, Blumenthal D, Jaggi T, Honour M, Bates D, Kaushal R. Overcoming barriers to adopting and implementing computerized physician order entry systems in U.S. hospitals. Health Aff (Millwood). 2004;23(4):184-190.

This article was written by the authors in their private capacity. No official support or endorsement by Carroll Hospital Center is intended or should be inferred.

We Want Your Pearls Do you have an interesting practice pearl you’d like to share? If so, send it to smtilyou@mcmahonmed.com. Pearls should: •F ocus on a clinical or operational problem at your institution, with tips (“tricks of the trade”) on how to manage the problem via an innovative system or strategy • Offer insights that are not widely known, understood or published • Explain why the pearl should be implemented on a widespread basis • Not exceed 1,000 words

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

Available from Otsuka America Pharmaceutical, Inc. Choose from 2 dosing strengths To place your order, call your wholesaler or distributor today.

NDC

Dosage

Size

59148-020-50 59148-021-50

15 mg QD* 10-count blister pack 30 mg QD 10-count blister pack

*Usual starting dose.

Oral administration of tablets without regard to meals 15 mg

30 mg

• Titrate at intervals of ≥24 hours, up to a maximum of 60 mg/day • Fluid restriction during the first 24 hours of therapy with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium and should be avoided – Fluid restriction with SAMSCA may increase risk of dehydration and hypovolemia • Patients can and should drink in response to thirst

SAMSCA® (tolvaptan), the first and only oral vasopressin V2-receptor antagonist that increases free water clearance and serum sodium concentrations Indication and important limitations • SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA. It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients

Important safety information SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients. • Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors • Co-administration with hypertonic saline is not recommended • Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium Commonly observed adverse reactions: (SAMSCA vs placebo) thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%). For more information about SAMSCA, visit samsca.com or call 1-877-726-7220.

Please see BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the previous page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. US Patent Nos: 5,258,510 and 5,753,677. Samsca is a trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

June 2010

0710A-0776A