The December 2010 Digital Edition of Pharmacy Practice News by McMahon Group

Bo In O PI nn de NI ie fe Ki ns O rs e o N Se ch f en RE e pa b M ge au S: 14 m, M S

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The Pharmacist’s Pharmacy News Source Edition Hematology/Oncology Section begins after page 22

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Optimal Vancomycin Use Elusive Despite New Rx Guidelines Initial dosing among key points of debate Austin, Texas—Despite guidance provided by 2009 updated consensus recommendations, the precise doses and timing for vancomycin continue to pose a clinical challenge, according to research presented at the American College of Clinical Pharmacy (ACCP) meeting. “As pharmacists, we really spend a lot of time dosing vancomycin,” said Christopher Giuliano, PharmD, assistant clinical professor at Wayne State University’s Eugene Applebaum College of Pharmacy and Health Sciences, Detroit. “We don’t even know what the correct dose is for vancomycin—I think we’re still trying

•

see VANCOMYCIN, page 30

in this issue Clinical

Practice Pearls Tips for safer hazardous drugs handling.

•

see HIV DRUG ERRORS, page 31

McMahon Publishing

Patients Remain the Focus For Change at PPMI Summit

Opinion Wanted: Comparative Effectiveness Pharmacist.

Clinical

Transplant Medicine Managing the switch to generic immunosuppressants.

Infectious Disease Debating the merits of oral antibiotics in colectomy patients.

Operations & Mgmt

Exclusive Interview

Austin, Texas—An “alarming” number of HIV medication errors were documented in a retrospective study at Henry Ford Hospital in Detroit, triggering several practice changes geared to improving the safety of antiretroviral therapy. Errors in prescribing comprised slightly more than half of the identified errors, according to the data, presented at the American College of Clinical Pharmacy annual meeting. The retrospective analysis found a total of 116 errors, involving 50 adult patients

Medical center targets insulin to improve patient safety.

ASHP’s Henri Manasse Jr., on making PPMI action points gain traction.

Study Sheds Light On Causes of HIV Medication Errors

Volume 37 • Number 12 • December 2010

Technology

Irving, Texas—A more patient-focused future for health-system pharmacy began to take shape during last month’s Pharmacy Practice Model Initiative (PPMI) Summit. More than 100 stakeholders, voting on an ambitious plank of practice goals, reached consensus on several objectives that could fundamentally change the profession. A majority of the voting participants agreed that pharmacy technicians should be licensed by state boards of

pharmacy—a steep upgrade from current regulations—and also gave their support to a requirement that all inpatients be given some degree of drug therapy management by a member of the pharmacy team. Pharmacist prescribing was also passed. But there was enough disagreement among the voting members to keep the crystal ball somewhat cloudy. For example, the group failed to reach consensus

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see FOCUS, page 32

Medication Tracking Tools for outsmarting drug diverters.

Bar Coding Bedside bar-coding lessons learned.

Educational Review

Despite Some Stars, Rural Hospitals Lag in EHR Adoption Critical access facilities face uphill IT battle

K IVIG Medication Safety: A Stepwise Guide to Product Selection and Use

Insert after page

anabec Hospital in Mora, Minn., may be just one small health system in the constellation of more than 1,300 critical access hospitals across the United States, but it has shone brightly among its rural peers in the race to implement advanced information technology (IT). Last year, Kanabec became the first

The Book Page

critical access hospital to be recognized by Healthcare Information and Management Systems Society (HIMSS) Analytics for attaining stage 6 out of a possible 7 in electronic health record (EHR) development. “It was a huge honor,” said Brent Thompson, PharmD, director of pharmacy. The honor

•

see EHR ADOPTION, page 39

New Product

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Pharmacy Practice News • December 2010

Up Front 3

Capsules

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DECEMBER 2010

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Comparing Pharmacists and Nurses in Med Reconciliation 2. In Emergencies, Drug Errors Common 3. A Dream (Still) Deferred 4. Panel Urges Ceftaroline Approval for Pneumonia, Skin Structure Infections 5. ASP Plus 6% Not a Done Deal Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘Until the profession embraces the necessity to get closer to the patient,

and become relevant to the integral care of the patient overall, we’re not going to see fundamental change.’

See article, page 36

—Henri R. Manasse Jr., PhD, ScD

2-D Bar Codes in PPN

Most Patients Enter Hospital At High Risk for Sleep Apnea

ight in 10 hospital patients are at high risk for obstructive sleep apnea, according to a new study by Chicago researchers who say facilities should consider screening patients for the condition. Researchers at Loyola University Health System used the STOP-BANG questionnaire to assess 195 patients at their institution. They found that 157 patients (80.5%) answered yes to at least three of the eight questions on the survey, putting them at high risk for sleep apnea. Of the patients likely to have sleep apnea, 41 (26%) had undergone a sleep study and 31 (20%) had been diagnosed with the condition. Only 18 (11%) had received treatment for the disorder, the researchers said. “Undiagnosed obstructive sleep apnea may be associated with increased risk of complications in hospitalized patients,” the researchers said in a statement. “Screening and evaluation for obstructive sleep apnea in high-risk patients should be considered as it may help reduce the burden” of the condition. The researchers reported their findings at Chest 2010, the annual meeting of the American College of Chest Physicians. The STOP-BANG questionnaire asks patients the following: 1. Do you Snore loudly? 2. Do you often feel Tired, fatigued or sleepy during daytime? 3. Has anyone Observed you stop breathing during your sleep? 4. Have you or are you being treated for high blood Pressure? 5. Is your Body mass index greater than 35 kg/m2? 6. Are you over 50 years of Age? 7. Is your Neck circumference greater than 40 cm? 8. Are you male [Gender]? —Staff

Correction

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.

CME Special Report monograph entitled, “Clinical and Pharmacoeconomic Evaluation of Thrombin-Containing Products in the Hospital Setting,” included in the November issue of Pharmacy Practice News, incorrectly referred to a comparator in a requested postmarketing safety study of recombinant thrombin. That study evaluated re-exposure to recombinant thrombin. Applied Clinical Education, cosponsor of the activity, regrets the error. To download the corrected monograph, please visit www.CMEZone.com and enter the keyword MN109. Or you can scan the 2-D bar code tag at right. (For instructions, see box at left.)

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Volume 37 • Number 12 • December 2010 • pharmacypracticenews.com

Anesthesiology/Pain Robert Barkin, PharmD, Chicago, IL Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY Biotechnology Indu Lew, PharmD, Livingston, NJ Cardiology

Internal Medicine Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP Des Moines, IA NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

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

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Robert Ignoffo, PharmD, San Francisco, CA

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

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4 Clinical

Pharmacy Practice News • December 2010

Practice Pearls

Hazardous Drugs Maintaining standards of safe pharmacy practice Tuan Huynh PharmD Candidate University of Maryland School of Pharmacy Baltimore, Maryland

Yash Jalundhwala, BPharm MS Candidate Department of Pharmacy Administration College of Pharmacy University of Illinois at Chicago Chicago, Illinois

Vaiyapuri Subramaniam, PharmD, MS Associate Chief Consultant, Pharmacy Benefits Management Department of Veterans Affairs Washington, DC Clinical Affiliate Professor Nova Southeastern University College of Pharmacy Fort Lauderdale-Davie, Florida University of Maryland School of Pharmacy Baltimore, Maryland

andling hazardous drugs is complicated, and meeting current standards and requirements outlined in the latest revision of United States Pharmacopeia (USP) Chapter <797> can be challenging. However, hospitals are legally obligated to ensure that these specific provisions are in place to prevent unsafe practices and protect workers from unnecessary exposure. Pharmacists play a fundamental role in assessing, planning, and implementing these specifications into pharmacy operations. Their involvement is crucial to the success of maintaining these standards of practice. The purpose of this article is to provide pharmacists and hospital staff with a framework to better identify hazardous drugs in the workplace, recognize their possible dangers, assess the risk for exposure, and understand the necessary measures involved in handling these potentially harmful agents.

Defining Hazardous Drugs Any drug or substance that has the potential to cause harm to a person’s health upon exposure can be said to be hazardous. The National Institute for Occupational Safety and Health (NIOSH) modified an earlier definition by the American Society of HealthSystem Pharmacists (ASHP) to define a hazardous drug as any drug having one or more of the following characteristics in humans or animals.1 These characteristics can be broadly classified as: • Genotoxicity • Carcinogenicity • Teratogenicity or other developmental toxicity

• Organ toxicity at low doses • Reproductive toxicity • Structure and toxicity profiles of new drugs that mimic existing drugs that have been determined to be hazardous by the above criteria. Therapeutic agents, including antineoplastic, biological, immunosuppressive, antiviral, and cytotoxic agents can be classified as hazardous drugs. Accidental skin contact, inhalation, ingestion, or injection is possible during preparation and/or administration of these drugs.2 Exposures may result in skin rashes, infertility, congenital defects, cancers, and acute harm.3 The frequent use of these agents in critical and life-threatening conditions presents multiple opportunities for exposure and unintended harm to various health care workers.2 Pharmacists, in particular, have a high chance of exposure because they are involved in preparing, handling, and storing these drugs. To standardize the practice of handling hazardous drugs and improve safety for pharmacists and other health care workers, government and professional health care organizations have published pharmacy practice guidelines during the past 3 decades, such as ASHP’s “Quality Assurance for PharmacyPrepared Sterile Products.”4

Addressing an Ongoing Problem Despite these efforts, NIOSH estimated hazardous drug exposures among health care workers to have increased from approximately 5.5 million to 8 million between 2004 and 2007.1,3 Furthermore, exposed personnel unknowingly can spread hazardous agents in the hospital and to their homes, making it a concern for public safety. In a study conducted by Massachusetts General Hospital, drug residues were found

‘It is the responsibility of the health care facility to ensure that all staff members understand the uses and limitations of personal protective equipment to reduce potential contamination by [cytotoxic agents] in the workplace.’ on surfaces throughout the hospital, including computer keyboards, elevator buttons and pumps sent home with patients, even on some items that were located several hundred feet away from preparation and administration areas.5 In an attempt to address this issue, the USP published Chapter <797> on Pharmaceutical Compounding— Sterile Preparations in 2004 and revised it in 2008.6,7 Pharmacists are in a prime position to ensure that health care facilities and staff members comply with USP Chapter <797> provisions as well as guidelines from the Occupational Safety and Health Administration (OSHA), NIOSH, and ASHP regarding environmental and work practice controls, personnel training, and personal protective equipment (PPE).2

Environmental and Work Practice Controls The revised standards of USP Chapter <797> include a separate category for handling hazardous agents.6,7 Pharmacists must play an active role in adhering to and enforcing these safeguards when compounding drugs to help prevent injury and illness from exposures and to ensure personnel safety. They must ensure that the compounding environment and procedures maintain a standard of quality that prevents microbial contamination of sterile products. This includes constant air changes, ventilation using HEPA filters, routine environmental testing, and appropri-

ate allocation for disposal of hazardous drugs.6 The environmental and work practice controls set by USP Chapter <797> and NIOSH are listed in the Table.1,2,4,6-10

Training on Handling Hazardous Drugs Pharmacists can ensure that all pharmacy personnel are adequately educated on all standards and regulations regarding the preparation and handling of hazardous drugs. Continuing education programs are essential to ensure that all staff members are up to date on protocols, regulations, and safe practices regarding these hazardous agents. The various guidelines also provide specific details regarding the personnel training required for handling and preparing hazardous drugs (Table).1,2,4,6-10 Given their knowledge and expertise on drugs, pharmacists should be involved in the development and implementation of these training programs. These programs should be ongoing and provide trainees with material safety data sheets (MSDS) and didactic review of hazardous drugs and their properties.6,8

Using Personal Protective Equipment The OSHA requires that PPE, including gloves, gowns, respiratory protection, eye and face protection, and sleeve, hair, and shoe coverings be used to reduce hazardous drug exposures among employees.9 It is the responsibility of the health care facility to ensure that all staff members understand the uses and limitations of PPE to reduce potential contamination by these agents in the workplace. Pharmacists should be actively involved in the ordering of and training on PPE to ensure that it is used adequately and appropriately. General practice guidelines for using PPE are provided in the Table.1,2,4,6-10

Medical Surveillance Although measures are taken to protect health care workers from dangerous drug exposures, contact with these substances is still possible in the

•

see HAZARDOUS, page 6

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6 Clinical

Practice Pearls

HAZARDOUS continued from page 4

workplace. For this reason, a medical surveillance program should be instituted to monitor staff members who work with hazardous agents. Medical surveillance collects data, interprets information, and detects health status changes among workers who are potentially exposed to hazardous drugs. Such programs are used to establish the initial baseline health of the employees and to monitor their health for future complications resulting from potential exposures to hazardous agents. Basic medical surveillance components include routine collection of reproductive and general health information, laboratory tests, physical examinations, and adequate follow-up of exposed employees. Pharmacists must be part of overseeing the medical surveillance program to ensure that all personnel actively report hazardous drug exposures as they occur. Pharmacists also can provide guidance on improving and expanding the program. Health care facilities can use the data collected via medical surveillance to determine the effectiveness of their environmental and work practice controls, training, and PPE, and can develop action plans to prevent future worker exposure.2

Pharmacy Practice News • December 2010

Table. Checklist for Hazardous Drug Controls, Handling, Training, and Medical Surveillance Environmental Controls

Written inventory, update, and review of all hazardous drugs in the workplace Storage and preparation of hazardous drugs within a negative pressure ISO Class 7 (<352,000 particles/m3) buffer area that is physically separate from other areas Preparation phase requiring ISO Class 5 (<3,520 particles/m3) BSC or CACI that vents to the outside air using HEPA filtration Adjacent ante-areas that are ISO 7 or better 12 ACPH in the compounding area Acceptable 2-tier containment protocols for preparations in facilities that prepare low volumes of hazardous drugs and do not require a buffer area Routine environmental testing, such as surface or gloved fingertip sampling and viable air sampling Pressure differential monitoring at least every work shift or by a continuous recording device Maintenance and review of all certification records by supervising employees to ensure that controlled environment complies with proper air cleanliness, room pressures, and ACPH

Work Practice Controls

Removal of all personal outer garments, cosmetics, and jewelry, and use of appropriate PPE Antiseptic hand cleaning prior to entering buffer area or segregated compounding area Disposal of hazardous drug–contaminated syringes and needles in chemotherapy sharps container Separation of hazardous waste and contaminants from other trash Cleaning and disinfecting work areas in contact with hazardous drugs before and after each activity, and at the end of each work shift Immediately cleaning hazardous drug spills using proper safety protocols, PPE, and EMS assistance

Personnel Training/ Evaluation

Provide instructional audio-visual sources, professional publications, and didactic review on: – Hazardous drugs and their properties – Packaging, handling, transporting, and storing hazardous drugs – Proper garbing and gloving – Adequate cleaning and disinfecting of compounding area – Aseptic manipulation – Maintaining ISO Class 5 environmental conditions – Proper compounding techniques within an ISO Class 5 BSC or CACI – CSTDs – Hazardous drug exposure procedures and reporting – State and local regulations on hazardous drug cleanup and disposal – CSP labeling requirements Require all compounding personnel to pass written competence assessment and media-fill test annually for low- and medium-risk level compounding, and semiannually for high-risk level compounding

PPE Use

Use 2 pairs of sterile powder-free chemotherapy gloves—1 covering the cuff of the gown— when there is a risk for hazardous drug exposure Use a lint-free, nonabsorbent, disposable gown that has a closed front and long sleeves with closed cuffs Use appropriate full-face respirator to protect against airborne particulates Use a face shield and/or goggles to protect from splashes to the eyes, nose, and mouth Use coated sleeve, hair and shoe coverings that reduce contamination Ensure that all PPE is correctly fitted

Medical Surveillance Program

Set up a comprehensive and ongoing medical surveillance program by a designated team that provides: – Initial and continuous health monitoring – Routine collection of reproductive and general health information – Physical examinations –L aboratory workup (ie, complete blood count, comprehensive metabolic panel liver enzymes, urinalysis) – Screening tests – Exposure assessment and documentation – Analysis and notification of test results – Exposure control plan – Occupational health follow-up and consultation

The Bottom Line For Pharmacists Pharmacists play a key role in developing, initiating, and expanding medical surveillance programs that monitor the health of workers who potentially may be exposed to hazardous drugs. Their skills in pharmacotherapy help to ensure safer handling of these agents. By using pharmacists in both medical surveillance and enforcement of USP Chapter <797>, NIOSH, ASHP, and OSHA standards and requirements, health care facilities can address proactively this public health safety issue in the workplace to ensure a safe environment for all staff members who handle, compound, and administer hazardous drugs to patients. These safe practices also will reduce unintended exposures of patients as a public health initiative.

References 1. Department of Health and Human Services. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings. DHHS (NIOSH) Publication. 2004;165:1-50. http://www.cdc. gov/niosh/docs/2004-165/pdfs/2004-165.pdf. Accessed November 8, 2010. 2. Power LA, Polovich M. Safe handling of hazardous drugs: reviewing standards for worker protection. Pharmacy Practice News. 2010:37(3):1-8. 3. National Institute for Occupational Safety and Health. Medical surveillance for health care

Based on references 1, 2, 4, and 6-10. ACPH, air changes per hour; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; CSP, compounding sterile preparation; CSTD, closed system transfer device; EMS, environmental management service; HEPA, high efficiency particulate air; PPE, personal protective equipment

workers exposed to hazardous drugs. Workplace Solutions. DHHS (NIOSH) Publication. 2007-117. http://www.cdc.gov/niosh/docs/ wp-solutions/2007-117/pdfs/2007-117.pdf. Accessed November 8, 2010. 4. Kastango E. The ASHP Discussion Guide for Compounding Sterile Preparations: Summary and Implementation of USP Chapter <797>. ASHP & Baxter Healthcare Corporation. http://www.ashp.org/s_ashp/docs/ files/HACC_797guide.pdf. Accessed November 8, 2010. 5. Tilyou S. Cytotoxic drug residues still lurking in health care facilities. Pharmacy Practice News. 2010;37(1):1,20-22. 6. Buchanan EC, Cassano AT. The ASHP Dis-

cussion Guide on USP Chapter <797> for Compounding Sterile Preparations: Summary of Revisions to USP Chapter <797>. ASHP & Baxter Healthcare Corporation. http://www. ashp.org/s_ashp/docs/files/discguide797-2008. pdf. Accessed November 8, 2010. 7. The United States Pharmacopeial Convention. <797> Pharmaceutical Compounding—Sterile Preparations. In USP 32—NF27. Vol 1. Rockville, MD: The United States Pharmacopeial Convention; 2008:318-355. 8. National Institute for Occupational Safety and Health. Personal protective equipment for health care workers who work with hazardous drugs. Workplace Solutions. DHHS (NIOSH) Publication. 2009;106.

http://www.cdc.gov/niosh/docs/wpsolutions/2009-106/pdfs/2009-106.pdf. Accessed November 8, 2010. 9. Occupational Safety and Health Administration. Personal Protective Equipment (OSHA 3151-12R 2003). OSHA Publications. 2003. http://www.osha.gov/Publications/osha3151. pdf. Accessed November 8, 2010. 10. Polovich M. Safe handling of hazardous drugs. Online J Issues Nurs. 2004;9(3):6.

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

WHEN CHOOSING AN IV SEDATIVE

Different situations require different solutions

Precedex : A right ﬁt ®

FOR TODAY’S SEDATION MANAGEMENT PRACTICES

FASTEST GROWING IV SEDATIVE1

DIFFERENT SITUATIONS REQUIRE DIFFERENT SEDATIVE SOLUTIONS The ﬁrst and only alpha2 agonist indicated for sedation2,3 —Nonintubated patients prior to and during surgical and other procedures2 —Intubated and mechanically ventilated patients during treatment in an intensive care setting2 Can be used alone or in combination with other sedatives or opioid analgesics to provide sedation and added patient comfort.2 Should be administered by continuous infusion not to exceed 24 hours.2 Effective for intubated patients not just before—but also during—and after extubation.2 More than 4.5 million vials administered to millions of patients since launch.4

IMPORTANT PRECEDEX SAFETY INFORMATION Clinically signiﬁcant episodes of bradycardia, sinus arrest and hypotension have been associated with Precedex infusion and may necessitate medical intervention. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex. Please see the brief summary of Prescribing Information on adjacent page.

The right ﬁt

FASTEST GROWING IV SEDATIVE1

FOR TODAY’S SEDATION MANAGEMENT PRACTICES

For step-by-step instructions on how to start using Precedex and what to expect, please visit us at www.Precedex.com. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex.2 Clinically signiﬁcant episodes of bradycardia and sinus arrest have occurred in young, healthy volunteers with high vagal tone or with different routes of administration such as rapid intravenous or bolus administration.2 Transient hypertension has been observed primarily during the administration of the loading dose. Treatment has generally not been necessary, although a reduction in loading dose infusion rate may be desirable.2

Hypotension and bradycardia can occur and may necessitate medical intervention such as —Decreasing or stopping Precedex infusion —Increasing rate of IV ﬂuid administration —Elevating lower extremities —Administering pressor agents such as atropine, ephedrine or glycopyrrolate2 Use with caution in patients with advanced heart block or severe ventricular dysfunction.2 The most common adverse effects (incidence >2%) are hypotension, bradycardia and dry mouth.2

Please see the brief summary of Prescribing Information on adjacent page. References: 1. Based on increases in weight of active ingredient sold (either mcg or mg). IMS Health National Sales Perspective 2Q 2009. US nonretail market, all channels injectables. 2. Precedex [package insert]. Lake Forest, IL: Hospira, Inc; 2008. 3. Kamibayashi T, Maze M. Clinical uses of B2-adrenergic agonists. Anesthesiology. 2000;93:1345-1349. 4. Data on file. Hospira, Inc. Hospira, Inc. 275 North Field Drive, Lake Forest, IL 60045 P10-2830 Aug., 10. Printed in the USA.

Advancing Wellness™

For more information on Advancing WellnessTM, contact your Hospira representative at 1-877-9HOSPIRA (1-877-946-7747) or visit www.hospira.com.

8 Clinical

Pharmacy Practice News • December 2010

Practice Pearls

Medical Center Targets Insulin To Improve Patient Safety I

n 2008, the staff at Saint Barnabas Medical Center (SBMC) implemented a number of hospital-wide safety initiatives in an effort to minimize medication errors involving insulin. Prompted by ongoing medication variance monitoring that consistently identified insulin as a top contributor to medication errors, the pharmacy staff reduced the number of insulin products available on the medical center’s formulary and implemented a major product conversion. The following is an account of the experiences of SBMC in implementing these initiatives.

ince discovery of this lifesaving, yet potentially lethal, hormone, seldom has a day gone by when pharmacists working in the hospital setting haven’t been exposed to the association between insulin and medication errors. Fortunately, hospital practice standards enforced by the Joint Commission, as well as numerous safety measures and ongoing alerts issued by watchdog organizations, such as the Institute for Safe Medication Practices (ISMP), have minimized catastrophic errors involving insulin dispensing and administration. However, incidents such as that of an infant receiving 1 mL of regular insulin (100 units) instead of 1 mL of a 1 unit/mL insulin dilution continue to occur. Consistently known as a top offender, insulin is associated with the most harmful and severe adverse events on the list of highalert drugs published by the United States Pharmacopeia (USP) and the ISMP.1 At SBMC, insulin consistently is at the top of the list of medication errors. According to the ISMP, common risk factors for insulin-related medication errors include lack of dose check systems; storing insulin and heparin vials in close proximity to each other on nursing units, which leads to mixups; use of “U” as an abbreviation for “units” (“U” can be confused with “O,” resulting in 10-fold overdose); incorrect rates programmed into infusion pumps; availability of too many insulin products with sound-alike names (eg, Humulin, Humulog), which may lead to mix-ups; and varying concentrations (U500, U100).2 Suggested strategies for minimizing potential errors include establishing 2 independent checks of all pump settings, taking extra precautions when writing and interpreting orders for insulin mixtures, not using slash marks to separate neutral protamine hagedorn (NPH) and regular insulin doses (eg, NPH 10/12 regular has been confused with 10 NPH and 112 regular), standardizing preparation and administration (eg, never

prepare U100 insulin doses in tuberculin syringes), not storing insulin and heparin near each other, and spelling out the word “units” instead of using “U.”2,3

Eliminating NPH Insulin Already having many of these safety measures in place, SBMC sought to further reduce the potential for insulin-related errors with additional broad-scale initiatives. Some of the major action steps involved removing insulin from floor stock and minimizing the risk for brand mix-ups by reducing the number of available insulin products. Given that NPH insulin is known to cause variability in blood glucose levels, SBMC eliminated use of NPH insulin products from all but pediatric and obstetrics-gynecology departments. Other than for IV use, regular insulin was replaced with a single rapid-acting insulin analog, NovoLog. These initiatives minimized problems of sound-alike/look-alike drug names (eg, NovoLOG, NovoLIN, HumULIN, and HumaLOG) and reduced the number of hypoglycemic episodes

resulting from meal delays. Because insulin analogs may be administered with meals, nurses were able to ensure that patients began eating at the time of injection, as opposed to relying on patients to self-initiate meals 30 minutes after injection of regular insulin. SBMC also minimized the use of sliding-scale insulin as a replacement for scheduled basal and bolus insulin because the traditional sliding-scale approach is known to carry the risk for hypoglycemia, as well as hyperglycemia. In enforcing these safety measures, pharmacists were given the authority to automatically substitute physician orders with formulary-approved insulin products and make certain that insulin orders were being written on newly implemented preprinted insulin order sets.

Insulin Pen Injectors Mightier Than Vials Another major initiative involved converting from insulin vials to insulin

Robert T. Adamson, PharmD Corporate Vice President of Clinical Pharmacy Services Saint Barnabas Health Care System Livingston, New Jersey

Scott Mathis, PharmD Director of Pharmacy Monmouth Medical Center Long Branch, New Jersey (former Assistant Director of Clinical Pharmacy Services, Saint Barnabas Medical Center)

Eric Tomasz Hola, RPh, MS, MLS Pharmacy Director Saint Barnabas Medical Center Livingston, New Jersey

Elena Beyzarov, PharmD Director of Medical Communications Livingston Services at Saint Barnabas Health Care System Livingston, New Jersey

pen injectors. Intended primarily to facilitate easy and accurate patient self-administration of insulin, pen injectors increasingly are being used in hospitals due to several advantages over vials. Each pen is already labeled by the manufacturer with the product name and strength (whereas unit-based preparation of insulin from vials can lead to unlabeled syringes) and each pen may be individually labeled with the patient’s name.4 Also, the pen provides the patient’s insulin in a form ready for administration, which lessens nursing time needed to prepare and

Pharmacy Practice News • December 2010

Clinical 9

Practice Pearls administer insulin. Finally, insulin pens reduce medication waste that may occur when full insulin vials are dispensed for each patient.4 Patients like the pens because the needles are smaller and thus less painful, and nurses are at reduced risk for needle injury because pens may be injected straight into the injection site, rather than on an angle. The conversion was widely accepted by medical staff, with the only problem being frequent loss of pens. Despite advantages of insulin pens, reports of problems have surfaced.4 Although mix-ups among insulin pens may not be more common than mix-ups among insulin vials, pens and vials are subject to similar risks, given the look-alike packaging of each manufacturer’s line of insulin products and similarities in product names. For example, numerous reports have cited dispensing mix-ups between Novolog 70/30 FlexPen and Novolog (human insulin aspart) FlexPen. Potentially fatal incidents involving administration of large doses of short-acting insulin, instead of long-acting insulin, have occurred as well.4 When nurses are unsure how to use a particular insulin pen or encounter problems when using it, they sometimes use the pen cartridge as a multipledose vial for a single patient or as floor stock for multiple patients. In these cases, they withdraw insulin from the pen cartridge using a sterile needle and insulin syringe. Such removal of insulin from the cartridge is not recommended by manufacturers unless an emergency exists and the pen is malfunctioning. Large air pockets or bubbles left behind in the cartridge after some of the insulin is aspirated with a needle may result in dosing errors or subcutaneous injection of air if the pen is used to deliver a subsequent dose.4

Insulin pens and vials are subject to similar risks, given the look-alike packaging of each manufacturer’s line of insulin products and similarities in product names. slightly. SBMC plans to conduct a more in-depth analysis, but because there have been no overt safety issues identified and medical staff and patients generally accept the pens, conversion from insulin vials to pens has been initiated throughout

other Saint Barnabas Health Care institutions.

References 1. American Society of Health-System Pharmacists. Professional practice recommendations for safe use of insulin in hospitals. http://www.

ashp.org/s_ashp/docs/files/Safe_Use_of_Insulin.pdf. Accessed October 4, 2010. 2. Institute of Medicine. To Err Is Human: Building a Safer Health Care System. Washington, DC: National Academy Press; 1999. 3. Cohen MR, Kilo CM. High-Alert Medications: safeguarding against errors. In: Medication Errors. Cohen MR, ed. Washington, DC: American Pharmaceutical Association; 1999:5.1-5.40. 4. Institute for Safe Medication Practices. Considering insulin pens for routine hospital use? Consider this… ISMP Medication Safety Alert! http://www.ismp.org/Newsletters/ acutecare/articles/20080508.asp. Accessed October 4, 2010.

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Education Critical The key to using insulin pen devices safely is a comprehensive risk management approach that involves educating nurses about proper administration technique and precautions, anticipating potential safety issues before these devices are used widely, and closely monitoring use of the pens for several months after implementation. In monitoring the impact of switching from insulin vials to pens, the pharmacists at SBMC wanted to make sure that the conversion did not worsen related outcomes. To that end, they found no increases in needlestick injuries or infectious disease incidents, and use of dextrose 50% injection for hypoglycemic episodes decreased

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10 Clinical

Pharmacy Practice News • December 2010

Research News

Fluid Paper Retracted Over Ethics, Possible Fraud Critical care pharmacist says alleged research improprieties ‘very concerning’

oachim Boldt, MD, PhD, a leading German anesthesiologist with more than 200 papers to his name, has been accused of “very serious misrepresentations” in a paper he published late last year in the journal Anesthesia & Analgesia. In a retraction notice published online Oct. 28, Steven L. Shafer, editor-in-chief of the journal, wrote that Dr. Boldt and his co-authors did not obtain approval from an institutional review board or informed consent from patients in their December 2009 article, “Cardiopulmonary bypass priming using a high dose of a balanced hydroxyethyl starch versus an albuminbased priming system.” In addition, the journal said, it has reason to suspect that data in the paper were fabricated, a possibility that is being investigated by German authorities. Indeed, the notice stated, “it is possible that the study was never performed at all.” Hydroxyethyl starch (HES) is a colloidal solution that clinicians administer to patients during surgery to keep their blood volume high, in order to maintain adequate delivery of nutrients to cells. Intraoperative fluid management remains an unsettled topic for the critical care team. Indeed, the controversy has been called the “Great Fluid Debate.” Dr. Boldt, head of anesthesia at a private hospital in Rheinland, has spent much of his career studying the safety and efficacy of colloids. “Given the number of publications by Prof. Boldt ... the finding of misconduct in a recent publication implies that clinicians should question whether modern colloids have fully addressed the safety concerns that limited the use of first-generation hydroxyethyl starch solutions,” Dr. Shafer said in an article that first appeared on the Web site of Anesthesiology News, a sister publication to Pharmacy Practice News. Efforts to reach Dr. Boldt were not immediately successful. He has disclosed receiving funding for his research from makers of hetastarch and other products including B. Braun, Baxter and Fresenius Kabi. He also has received funding from Plasmaselect and Bernburg, as well as Edwards Lifesciences, which makes devices that allow clinicians to monitor fluids in surgery patients.

Critical Care Pharmacist’s Take Tricia Meyer, MS, PharmD, director of pharmacy services at Scott & White Hospital in Temple, Texas, and an assistant professor of anesthesiology at Texas A&M University in College Station,

echoed Dr. Shafer’s concerns. “The news of the potential misrepresentation of data is very concerning,” she told Pharmacy Practice News. “As pharmacists, we utilize the literature on a daily basis to determine formulary status, dosing recommendations, appropriate indications, safety information and answers from physicians on individual patient’s medication needs. The contaminated information may be disseminated when analyzed in systematic reviews or meta-analyses.

Nine months after he first raised questions about the paper, Dr. Shafer said he heard from the board. Again, from the retraction letter: “On October 25th I received notification from LÄK about their findings. Professor Boldt’s manuscript describes IRB [institutional review board] review, written informed consent, prospective randomization, and a follow-up questionnaire. LÄK determined that there was no IRB approval, no informed consent, no randomization process, and no follow-up

‘As medication experts, we risk conveying inaccurate information when data has been misrepresented.’ —Tricia Meyer, MS, PharmD This further exacerbates the spread of false information. As medication experts, we risk conveying inaccurate information when data has been misrepresented.” Dr. Meyer added that such research improprieties “can translate into patient errors and harm. Honesty and integrity are essentials for professionals and also patient safety.”

The Retracted Paper The paper in question reported on a study of 50 patients undergoing cardiopulmonary bypass (CPB). Some were given hydroxyethyl starch and others received albumin. According to the authors, “high-volume priming of the CPB circuit with a modern balanced HES solution resulted in reduced inflammation, less endothelial damage, and fewer alterations in renal tubular integrity compared with an albuminbased priming. Coagulation including platelet function was better preserved with high-dose balanced HES CPB priming compared with albumin-based CPB priming.” However, as Dr. Shafer explained in the retraction notice, the data in the paper simply looked too good to be true: “Shortly following publication the Journal received several letters from concerned readers that the variability in the cytokine assay was too low to be believed. Upon reviewing the results, we concurred with that assessment. We also believed that the variability in blood gas results reported in the paper was too low to be believable.” Dr. Shafer said Dr. Boldt initially promised to help resolve the issue. However, the researcher soon stopped cooperating, and Dr. Shafer has been dealing with the medical board, LÄK, in Rheinland.

questionnaire as described in the study. These are very serious misrepresentations in Professor Boldt’s manuscript. As a result, the entire manuscript is compromised, and is hereby retracted.” According to Dr. Shafer’s letter, LÄK has asked for but not received research data from Dr. Boldt’s group that might help him refute allegations of fraud stemming from the retracted article. “LÄK has not reached a conclusion that the data were fabricated. This is still an open question, and LÄK is continuing its investigation,” he wrote. Even without fabricated data, the ethical lapses certainly are severe enough to get the paper pulled. But, the retraction letter continued, the issues might be far worse: “Professor Boldt has published more than 200 manuscripts in the peerreviewed medical literature. A shadow has been cast over that body of work based on a determination that the report published in Anesthesia & Analgesia is fraudulent. In the coming months and years we will work with LÄK to determine the veracity of all reports by Professor Boldt published in Anesthesia & Analgesia.” The paper was cited five times, according to Thomson Scientific’s Web of Knowledge, including an editorial that accompanied it in Anesthesia & Analgesia, and another by Dr. Boldt in the Journal of Cardiothoracic and Vascular Anesthesia. Dr. Shafer said his journal has published in the neighborhood of 40 articles by Dr. Boldt. He has notified other journals—including Anesthesiology, Critical Care and Critical Care Medicine, about the issues with the German scientist’s research and warned them to review his manuscripts. If more than a handful of

those require retracting, Dr. Boldt might eclipse the notorious Scott Reuben, MD, as the most significant fraudster yet detected in anesthesiology. Dr. Reuben, a Massachusetts pain specialist, was found to have fabricated data and committed other fraud that led to the retraction of at least 21 papers, many in Anesthesia & Analgesia, in early 2009. Dr. Reuben, who blamed his actions on mental illness, is now serving a six-month prison sentence for health care fraud. Dealing with Dr. Boldt’s body of publications “could take years,” Dr. Shafer said. Dr. Boldt “has published far more than Reuben. The data that Reuben fabricated supported the safety and efficacy of selective COX-2 inhibitors, drugs with a benign safety profile. Older colloidal solutions are known to interfere with coagulation and renal function and may contribute towards inflammation. Newer colloidal solutions appear to have addressed these limitations. However, some of that research was performed by Prof. Boldt. The safety and efficacy of modern solutions is potentially compromised by the finding of misrepresentations in his research.”

An Apology to Readers That helps explain the penultimate paragraph of Dr. Shafer’s retraction letter: “I apologize to our readership, and to the patients cared for by our readership, for the publication of a fraudulent report in Anesthesia & Analgesia. We will examine our editorial policies, the quality of our peer review, and look for ways to detect fraudulent research in the peer review process.” Dr. Shafer said the 2009 paper was reviewed by several cardiovascular anesthesiologists, none of whom caught the bogus data. Nor did he suspect anything when he reviewed the report—including the part about perioperative blood gases, which he now views as “obviously unbelievable.” That, he added, points to the difficulties reviewers and editors face in catching fraud before a manuscript is published. “Things are only obvious once they’re obvious,” he said. As for the impact on critical care pharmacy and their role in helping to ensure proper fluid management in the ICU, the verdict is still out, Dr. Meyer said. “At this point, we have not established our process,” Dr. Meyer said. “We will discuss this with our physician group, and we also will want to see how other publications are reviewing his work and their determinations.” —Adam Marcus

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

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

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

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

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

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

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

12 Opinion

Pharmacy Practice News • December 2010

Wanted: Comparative Effectiveness Pharmacist Fred J. Pane, RPh, BS Pharm, FASHP Senior Director Pharmacy Solutions The Medicines Company

ith the passage of health care reform legislation and the need to improve the quality of patient care, hospitals are evaluating their current committee structures and the role each depart-

ment plays, including pharmacy. The time is right to re-evaluate the current pharmacy model and reassess the clinical pharmacist’s place in therapeutics. The true acute care and non–acute care patient models are being eliminated in favor of accountable care organizations as payers move toward bundled payment: Hospitals and physicians will be held accountable for not only inpatient care, but readmissions, outpatient care management and preventive care.

The Centers for Medicare & Medicaid Services has already implemented a Physician Quality Review Initiative for physicians, and several private health plans have instituted value-based purchasing, value-based insurance or balanced scorecard accountability models, in which financial outcomes are tied to quality of care. In September 2008, I was fortunate to be interviewed by aides for Sen. Max Baucus (D-Mont.) and Sen. Kent Conrad (D-N.D.), who were collecting informa-

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Privigen®, Immune Globulin Intravenous (Human), 10% Liquid Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. WARNING: ACUTE RENAL DYSFUNCTION/FAILURE Use of Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death.1 Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Privigen does not contain sucrose. For patients at risk of renal dysfunction or failure, administer Privigen at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]). 1 INDICATIONS AND USAGE Privigen is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the treatment of the following conditions. 1.1 Primary Humoral Immunodeficiency Privigen is indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immunodeficiency in common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. 1.2 Chronic Immune Thrombocytopenic Purpura Privigen is indicated for the treatment of patients with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts. 3 DOSAGE FORMS AND STRENGTHS Privigen is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion. 4 CONTRAINDICATIONS Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. Because it contains the stabilizer L-proline, Privigen is contraindicated in patients with hyperprolinemia. Privigen is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Severe hypersensitivity reactions may occur (see Contraindications [4]). In case of hypersensitivity, discontinue the Privigen infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. Privigen contains trace amounts of IgA ( 25 mcg/mL) (see Description [11]). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Privigen is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction (see Contraindications [4]). 5.2 Renal Failure Ensure that patients are not volume depleted before administering Privigen. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Privigen. For patients judged to be at risk of developing renal dysfunction, administer Privigen at the minimum infusion rate practicable (see Boxed Warning, Dosage and Administration [2.3]). 5.3 Hyperproteinemia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Privigen and other IGIV product treatments. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events.2 5.4 Thrombotic Events Thrombotic events may occur following treatment with Privigen and other IGIV products.3-5 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Privigen at the minimum rate of infusion practicable (see Dosage and Administration [2.3]). Weigh the potential risks and benefits of IGIV against those of alternative therapies in all patients for whom Privigen therapy is being considered. 5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently with Privigen (see Adverse Reactions [6, 6.1]) and other IGIV product treatments. Discontinuation of IGIV treatment has resulted in remission of AMS

tion about comparative effectiveness for health care reform. They did not realize that several hospital and health systems were already looking at the difference in outcomes and costs associated with various patient treatments. Perhaps the greatest opportunity for pharmacists to expand their role lies in the profession’s comparative effectiveness as determined by comparative effectiveness research (CER). The Institute of Medicine’s June 2009 brief,

within several days without sequelae.6 AMS usually begins within several hours to 2 days following IGIV treatment. AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting (see Patient Counseling Information [17]). Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. 5.6 Hemolysis Privigen may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.7-9 Hemolytic anemia can develop subsequent to Privigen therapy due to enhanced RBC sequestration and/or intravascular RBC destruction.10 Hemolysis, possibly intravascular, occurred in two subjects treated with Privigen in the ITP study (see Adverse Reactions [6, 6.1]). These cases resolved uneventfully. Six other subjects experienced hemolysis in the ITP study as documented from clinical laboratory data. Monitor patients for clinical signs and symptoms of hemolysis (see Patient Counseling Information [17]). If these are present after Privigen infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. 5.7 Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients following IGIV treatment.11 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions (see Patient Counseling Information [17]). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient’s serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. 5.8 Volume Overload The high-dose regimen (1 g/kg/day for 2 days) used to treat patients with chronic ITP is not recommended for individuals with expanded fluid volumes or where fluid volume may be of concern (see Dosage and Administration [2.2]). 5.9 Transmissible Infectious Agents Privigen is made from human plasma. Based on effective donor screening and product manufacturing processes (see Description [11]), Privigen carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered to be extremely remote. No cases of transmission of viral diseases or CJD have been associated with the use of Privigen. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare professional to CSL Behring Pharmacovigilance at 1-866-9156958. Before prescribing Privigen, the physician should discuss the risks and benefits of its use with the patient (see Patient Counseling Information [17]). 5.10 Monitoring: Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If signs and/or symptoms of hemolysis are present after an infusion of Privigen, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. 5.11 Interference With Laboratory Tests After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test. 6 ADVERSE REACTIONS The most serious adverse reaction observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject. The most common adverse reactions observed in >10% of clinical study subjects with PI were headache, pain, nausea, fatigue, and chills. The most serious adverse reactions observed in clinical study subjects receiving Privigen for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects. Six other subjects in the ITP study experienced hemolysis as documented from clinical laboratory data (see Warnings and Precautions [5.5, 5.6]). The most common adverse reactions observed in >10% of clinical study subjects with chronic ITP were headache, pyrexia/hyperthermia, and anemia. 6.1 Clinical Trials Experience Because different clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in practice. Treatment of Primary Humoral Immunodeficiency In a prospective, open-label, single-arm, multicenter clinical study, 80 subjects with PI (with a diagnosis of XLA or CVID) received Privigen intravenously every 3 or 4 weeks for up to 12 months (see Clinical Studies [14.1]). All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. Subjects ranged in age from 3 to 69; 57.5% were male and 42.5% were female. The safety analysis included all 80 subjects, 16 on the 3-week schedule and 64 on the 4-week schedule. The median doses of Privigen administered intravenously ranged from 200 to 888 mg/kg every 3 weeks (median dose 428.3 mg/kg) or 4 weeks (median dose 440.6 mg/kg). A

Pharmacy Practice News • December 2010

“National Priorities of Comparative Effectiveness Research,” defined CER as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor a clinical condition or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers and policy makers to make informed decisions that will improve health care at both the individual and population levels.” Generally, CER can help hospitals, health-systems and physicians:

• Make formulary decisions on prescription medicines and medical devices • Enhance understanding of how CER can benefit diverse populations and engage communities in research; and • Help develop the foundation (infrastructure, training, registries, nongovernment investment, etc.) for future CER.

Taking the Next Step Pharmacists have always practiced CER when evaluating which drugs to place on a hospital or pharmacy benefit manager formulary. Efficacy, safety

total of 1038 infusions of Privigen were administered, 272 in the 3-week schedule and 766 in the 4-week schedule. Of the 1038 infusions, 435 were administered to females and 603 to males. Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related adverse events (AEs) that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered. Temporally associated AEs are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. In this study, the upper bound of the 1-sided 97.5% conﬁdence interval for the proportion of Privigen infusions temporally associated with one or more AEs was 23.8% (actual proportion: 20.8%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 397 (a rate of 0.38 AEs per infusion), reﬂecting that some subjects experienced more than one AE during the observation period. Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Privigen infusion or within 72 hours after the end of an infusion, irrespective of causality. Table 2: Adverse Events* Occurring in >5% of Subjects With PI During a Privigen Infusion or Within 72 Hours After the End of an infusion, Irrespective of Causality Adverse Event Subjects (%) [n=80] Infusions (%) [n=1038] Headache 35 (43.8) 82 (7.9) Pain 20 (25.0) 44 (4.2) Fatigue 13 (16.3) 27 (2.6) Nausea 10 (12.5) 19 (1.8) Chills 9 (11.3) 15 (1.4) Vomiting 7 (8.8) 13 (1.3) Pyrexia 6 (7.5) 10 (1.0) Cough 5 (6.3) 5 (0.5) Diarrhea 5 (6.3) 5 (0.5) Stomach discomfort 5 (6.3) 5 (0.5) *Excluding infections.

Of the 397 temporally associated AEs reported for the 80 subjects with PI, the investigators judged 192 to be related to the infusion of Privigen (including 5 serious, severe AEs described below). Of the 187 non-serious AEs related to the infusion of Privigen, 91 were mild, 81 were moderate, 14 were severe, and 1 was of unknown severity. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (29% of subjects), pain (14% of subjects), nausea (11% of subjects), fatigue (11% of subjects), and chills (11% of subjects). Sixteen subjects (20%) experienced 41 serious AEs. Five of these were related severe AEs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature) that occurred in one subject and resulted in the subject’s withdrawal from the study. Two other subjects withdrew from the study due to AEs related to Privigen treatment (chills and headache in one subject; vomiting in the other). Seventy-seven of the 80 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia. During this study, no subjects tested positive for infection due to human immunodeﬁciency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V). Treatment of Chronic Immune Thrombocytopenic Purpura In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less received a total of 2 g/kg dose of Privigen administered as 1 g/kg intravenous infusions daily for 2 consecutive days (see Clinical Studies [14.2]). Subjects ranged in age from 15 to 69; 59.6% were female and 40.4% were male. Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56.1%) subjects received premedication with acetaminophen and/or an antihistamine. Table 3 lists the temporally associated AEs that occurred in more than 5% of subjects with chronic ITP during a Privigen infusion or within 72 hours after the end of a treatment cycle (two consecutive infusions) with Privigen, irrespective of causality. Table 3: Adverse Events Occurring in >5% Subjects With Chronic ITP During a Privigen Infusion or Within 72 hours After the End of a Treatment Cycle*, Irrespective of Causality Adverse Event Headache Pyrexia/hyperthermia Nausea Epistaxis Vomiting Blood unconjugated bilirubin increased Blood conjugated bilirubin increased Blood total bilirubin increased Hematocrit decreased

* Two consecutive daily infusions.

Subjects (%) [n=57] 37 (64.9) 21 (36.8) 6 (10.5) 6 (10.5) 6 (10.5)

Infusions (%) [n=114] 41 (36.0) 22 (19.3) 6 (5.3) 6 (5.3) 6 (5.3)

6 (10.5)

6 (5.3)

5 (8.8)

5 (4.4)

4 (7.0) 3 (5.3)

4 (3.5) 3 (2.6)

Of the 183 temporally associated AEs reported for the 57 subjects with chronic ITP, the investigators judged 150 to be related to the infusion of Privigen (including the one serious AE described below). Of the 149 non-serious AEs related to the infusion of Privigen, 103 were mild, 37 were moderate, and 9 were severe. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (65% of subjects) and pyrexia/hyperthermia (35% of subjects).

and cost have driven formularies, and most hospitals, health-systems and pharmacy benefit managers have used medication use evaluations to monitor their formularies. However, the time has come for pharmacists to move beyond drugs to embrace their comparative effectiveness and evaluate the role of clinical pharmacy in therapeutics. Should there be a comparative effectiveness pharmacist and/ or committee that are responsible for value analysis, quality assurance and performance improvement? How else can health systems compare various treat-

Three subjects experienced three serious AEs, one of which (aseptic meningitis) was related to the infusion of Privigen. One subject withdrew from the study due to gingival bleeding, which was not related to Privigen. Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase, and a decrease in hemoglobin level within two days after the infusion of Privigen. Two of the eight subjects were clinically anemic but did not require clinical intervention. Four other subjects with active bleeding were reported to have developed anemia without evidence of hemolysis. In this study, there was a decrease in hemoglobin after the first Privigen infusion (median decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29. Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, 12 (21.4%) developed a positive DAT during the 29-day study period. 6.2 Postmarketing Experience Because postmarketing reporting of adverse events is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. Evaluation and interpretation of these postmarketing reactions is confounded by underlying diagnosis, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance. Privigen Postmarketing Experience Adverse reactions reported during worldwide postmarketing use of Privigen do not differ from what has been observed in clinical studies with Privigen and from what is known for IGIV products. General The following mild to moderate reactions may occur with the administration of IGIV products: headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, skin reactions, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, myalgia, arthralgia, and changes in blood pressure. Immediate hypersensitivity and anaphylactic reactions are also a possibility. The following adverse reactions have been identified and reported during the post-approval use of IGIV products.12 Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test Musculoskeletal: Back pain Gastrointestinal: Hepatic dysfunction, abdominal pain General/Body as a Whole: Pyrexia, rigors 7 DRUG INTERACTIONS Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, and rubella.13 The immunizing physician should be informed of recent therapy with Privigen so that appropriate measures may be taken (see Patient Counseling Information [17]). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Privigen. It is not known whether Privigen can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Privigen should be given to pregnant women only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.14,15 8.3 Nursing Mothers Use of Privigen in nursing mothers has not been evaluated. 8.4 Pediatric Use Treatment of Primary Humoral Immunodeficiency Privigen was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with PI. There were no apparent differences in the safety and efficacy profiles as compared to those in adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and effectiveness of Privigen have not been established in pediatric patients with PI who are under the age of 3. Treatment of Chronic Immune Thrombocytopenic Purpura Safety and effectiveness of Privigen have not been established in pediatric patients with chronic ITP who are under the age of 15. 8.5 Geriatric Use Clinical studies of Privigen did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Use caution when administering Privigen to patients age 65 and over who are judged to be at increased risk of developing renal insufficiency (see Boxed Warning, Warnings and Precautions [5.2]). Do not exceed recommended doses, and administer Privigen at the minimum infusion rate practicable. Manufactured by: CSL Behring AG Bern, Switzerland

US License No. 1766 Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

Based on November 2009 revision.

Opinion 13

ments and outcomes? The silos within hospitals must be removed if hospitals, physicians and health systems are to survive in the era of health care reform. One disease—cancer—serves as an example of CER in action. Various oncology groups identify which diagnostic methods and treatment are the best alone or in combination. These groups develop evidence-based guidelines that payers turn to when approving treatments and defining the terms of reimbursement. Payers also can track costs and outcomes. Cancer is unique in that many cancer centers already have a comparative effectiveness committee in place, and patients will meet with an oncologist, a radiation oncologist, and a surgeon before starting treatment. Pharmacoeconomics needs to evolve into “thereconomics,” or therapy plus economics, which measures both the financial and clinical outcomes associated with various treatment options, including drugs, devices and surgical/interventional procedures. Unlike pharmacoeconomics, thereconomics is all-inclusive and can be applied to any treatment. This method of analysis takes a balanced scorecard approach to all pharmaceutical operations, both clinical and financial. Thereconomics applies the principles of comparative effectiveness. As an example, pharmacists know that in some cases, drugs may replace surgery or the need for another treatment (e.g., use of erythropoietin-alfa instead of packed red blood cells to treat anemia). Yet pharmacists also know that drugs are not the only treatment for certain diseases. For example, they are aware that in acute myocardial infarction, emphasis has shifted from door-to-drug time to door-to-balloon time, in which a patient undergoes cardiac catheterization. In my former capacity as administrator of pharmacy services for Lehigh Valley Hospital in Allentown, Pa., we were able to change our Pharmacy and Therapeutics Committee to the Therapeutics Committee, so that we could also address non-drug treatments. We were able to convince our chief operating officer and chief financial officer that in some cases, a more expensive drug may be necessary not only to achieve the best clinical outcome, but also ultimately to lower costs by way of a shorter hospital length of stay. Pharmacy, in coordination with the Performance Improvement Department, tracked these outcomes and presented the data to the Performance Improvement Committee, the Medical Executive Committee and the Therapeutics Committee. Here is a new opportunity for pharmacists to become involved in CER initiatives in their hospitals, health systems or pharmacy benefits management programs. We need to step forward and seize this initiative!

14 Opinion

Pharmacy Practice News • December 2010

Safety by Design: The REMS Program Bonnie Kirschenbaum, MS, FASHP, FCSHP Healthcare Consultant Breckenridge, Colo.

he creation of Risk Evaluation and Mitigation Strategies (REMS) as part of the Food and Drug Administration Amendments Act (FDAAA) of 2007 represents an important step forward in the long history of governmental and private efforts to ensure safe medication use. Under the FDAAA, the FDA is empowered to require drug and biological product manufacturers to put REMS in place whenever the agency determines it necessary to ensure that a product’s therapeutic benefits outweigh its risks. REMS are important not only because they provide an opportunity to rebalance risks and benefits but also because they ensure patient access to medications that might otherwise be unavailable due to a high risk–benefit ratio. Additionally, they provide a method of communicating important risk information to all stakeholders, including patients. REMS are not just passive black box warnings; they require action on the part of both health care providers and patients. REMS may include any one or combination of the following components: medication guides, patient package inserts and communication plans for health care

providers, as well as one or more additional measures collectively known as elements to assure safe use (ETASU). The latter might include an implementation system requiring, for example, that a prescriber, practitioner or pharmacy be certified before ordering, dispensing or administering a drug with a high-risk safety profile (Table 1). Once a product is approved and comes to market, it does not escape the potential need for REMS. The FDA has developed criteria for considering whether a REMS is necessary both during the drug’s initial approval process and after it is marketed. Initial approval considerations include estimated population size, seriousness of disease or condition, expected benefit of the drug, anticipated or actual duration of treatment, seriousness of any known or potential adverse events and whether the drug is a new molecular entity. During the postmarketing phase, REMS may be required when the FDA becomes aware of new safety information via clinical trials or adverse drug event (ADE) reports.

Group or Class REMS REMS can apply to a group or class of products. Examples include REMS for cancer-related erythropoiesis-stimulating agents (ESAs), which became effective March 2010, and for long-acting opioids, which have been proposed and are now in an extended comment period. In the case of REMS for cancer-related

Table 1. A Closer Look at REMS Components Medication Guide: Provision of a guide listing detailed information about the benefits and risks may be required at each dispensing or administration of the drug. Communication Plan: REMS may require the drug sponsor (manufacturer) to provide educational materials to health care providers; communicate with vendors of point-of-sale clinical alert data systems; orchestrate speakers’ bureaus, symposia or presentations at major meetings of professional societies; or conduct other communication activities. Elements To Assure Safe Use (ETASU): These can include any of various activities to provide postmarketing surveillance or safety-oriented actions; for example, the patient and prescriber registries required for ambrisentan (Letairis), eltrombopag (Promacta) and romiplostim (Nplate). They also might require prescribers and practitioners to have specific training, experience or certification in the use of the products, or certification in health care settings, including pharmacies that dispense the medications. Postmarketing surveillance: Such oversight also may be required. Each patient using the drug is subject to monitoring such as laboratory tests and pregnancy screens, and the drug is dispensed to patients only with evidence or documentation confirming safe use. Additionally, a drug may be dispensed only in certain health care settings. Implementation System: FDA will sometimes require specific steps regarding REMS implementation. For example, the Onsolis REMS specifies how wholesalers and distributors may obtain certification to distribute the drug. Timetable for Submission of Assessments: Evaluations are required 18 months after REMS is initially approved, then at three and seven years. (The latter may be eliminated if after three years the risks are being adequately identified, assessed and managed.) Source: Bonnie Kirschenbaum 2010

ESAs, manufacturers are charged with ensuring that providers are fully compliant with all aspects of the REMS. ETASU apply, including medication guides, patient counseling on ESA risks and benefits, training and certification on the use of ESAs for health care professionals who administer chemotherapy as well as registration and active enrollment in the APPRISE (Assisting Providers and Patients with Risk Information for the Safe use of ESAs) program. REMS for opioid drugs remain an open issue. The FDAAA allows FDA to defer assessment of an approved REMS until one or more public meetings are called to consider possible responses; several have been held and more than 80 organizations and individuals have testified, reinforcing the need for REMS standardization and research to identify which elements mitigate risks and seeking to exempt inpatient hospital settings (Table 2). The reasons for going forward with long-acting opioid REMS are compelling. Between 1999 and 2006, the use of prescription opioid analgesics and the number of opioid-related overdose deaths increased significantly in the United States. In 2006 alone, there were 26,400 unintentional drug overdose deaths, second only to motor vehicle crash deaths among leading causes of unintentional injury death. REMS for opioids are not going away despite all the posturing that has occurred. The four new long-acting opioid products that have come to market all have REMS requirements: Onsolis (fentanyl buccal soluble film; Meda Pharmaceuticals Inc), Butrans (buprenorphine Transdermal System; Purdue Pharma), Exalgo (hydromorphone ER Tab; Mallinckrodt/Covidien) and OxyContin (oxycodone CR Tab; Purdue Pharma). The FDA’s Drug Safety and Risk Management Advisory Committee is trying hard to make this safety initiative work and is responsible for seeking input on how to standardize ETASU. The panel is responsible for evaluating the elements annually to ensure that they are not unduly burdensome on patient access as well as on the health care delivery system.

REMS in the Hospital Setting The American Society of HealthSystem Pharmacists (ASHP) has stated that REMS requirements for hospitals should depend on the nature of REMS requirements themselves. A REMS may require a drug to be dispensed only in certain health care settings (e.g., hospitals) or they may specifically exclude the hospital setting from dispensing the drug at all. ASHP is clarifying whether

Table 2. Opioids: Possible REMS Elements The Objective: Reduce misuse, abuse and accidental overdose while balancing access The Products: Extended-release opioids (n=24) Fentanyl Hydromorphone Oxycodone Oxymorphone Methadone Morphine Possible Elements: Certification and training of prescribers Certification and training of pharmacists Prescriber–patient agreements Source: Bonnie Kirschenbaum 2010

‘REMS issues do exist, but should not be a deterrent to putting this important safety mechanism into practice.’ hospitals are required to distribute medication guides in the inpatient setting (www.ashpadvantage.com/fdaaa). Health-system strategies should include education about REMS and involvement of Pharmacy & Therapeutics Committees as part of the formulary process, along with medication safety committees, risk management and pharmacy, nursing and medical staffs. Additionally, a central pharmacy resource should be appointed to coordinate REMS programs and use information technology, such as order sets, to ensure that criteria are met, perhaps modeling the system on investigational drug services. Try to incorporate REMS into medication reconciliation! REMS issues do exist, but should not be a deterrent to putting this important safety mechanism into practice. The challenges involve lack of standardization, potential use of specialty pharmacy, scary language, health care literacy levels, the need for multilingual medication guides and apathy on the part of health care practitioners and patients. Healthsystem pharmacists need to take a proactive role, press for standardization of REMS to reduce the burden on the health care system and urge a balance of risk and benefit for patient access. Tossing a medication guide into the bag with the prescription is not enough; talk to your patients and encourage them to be participants in their own safety. Additional resources and information available in an expanded, online version of article (pharmacypracticenews.com).

PRINTER-FRIENDLY VERSION AT PHARMACYPRACTICENEWS.COM

IVIG Medication Safety: A Stepwise Guide to Product Selection and Use JERRY SIEGEL, PHARMD, FASHP Clinical Associate Professor The Ohio State University College of Pharmacy Columbus, Ohio

ver the past 30 years, intravenous immunoglobulin (IVIG) has been used for the treatment

of primary immunodeficiency disorders and numerous autoimmune diseases.

During this time, manufacturers have worked to enhance the safety profile of these products, with improvements in purification and stabilization. Additionally, through observation over years of treating patients, clinicians have improved patient tolerability of IVIG therapy. Appropriate selection and use of IVIG products can reduce the rate of IVIG-associated adverse events (AEs). The IVIG safety overview shown in Figure 1, as well as the information presented in Figures 2 through 9 and Tables 1 and 2, is designed to help maximize the safe use of IVIG and to reduce the AEs associated with the infusion of these products.

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Table 1. Clinical Considerations: Matching the IVIG With the Patient Profile IVIG Characteristics Patient Risk Factors

Volume Load

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Renal dysfunction

Sugar Content

Sodium Content

Osmolality

Anti-IgA antibodies Thromboembolic risk

IgA

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tolerated. Third-line indications are restricted to when other therapies have failed, and the evidence for these indications often is limited to open-label studies, small sample sizes, or case reports. Institutions need to develop policies to approve the use of IVIG in these types of indications. Fourth-line indications have no evidence or have evidence that shows that use of IVIG either has anecdotal benefit at best, or is potentially detrimental. IVIG should not be used for these indications. Guidelines from the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology provide further information on the appropriate use of IVIG.1

Matching the Right Product To the Right Patient Clearly, various components contained in an IVIG formulation can affect patients differently. Medical history and patient risk factors, such as contraindications, age, and comorbidities, must be weighed carefully against each productâ&#x20AC;&#x2122;s criteria to ensure that an appropriate product is selected and severe AEs are avoided. Just as

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

patients receiving IVIG differ, so do IVIG products. Health care providers must make critical clinical decisions as to the appropriate product selection for each patient. Table 1 shows how various IVIG characteristics could affect specific patient risk factors.

CONTRAINDICATIONS Some patients have an immunoglobulin (Ig)A deficiency. Most often, this is caused by a failure of the bone marrow or a lack of thymus production of IgA. In more rare circumstances, IgA deficiency is caused by an anti-IgA antibody. In this situation, infusion of IgA could potentially cause anaphylaxis. Normally, this only occurs when the anti-IgA antibody is IgE-derived. Despite the rarity of this occurrence, patients need to be evaluated, and the lowest IgA-content IVIG product should be selected if the benefits of IVIG outweigh the risk associated with its use in such patients (Figure 3).

AGE CONSIDERATIONS The effects of age need to be considered when IVIG is being prescribed (Figure 4). Geriatric patients aged

65 years and older require additional monitoring and screening to prevent adverse reactions to IVIG. The increased likelihood of comorbid disease is higher in this patient population. Additionally, sensitivities to sugars, salts, and hyperosmolar infusions are more likely to cause IVIG intolerance in geriatric patients. In neonates, the infusion volume must be minimized. Additionally, the solution’s pH also must be considered. Low pH is important for stability of some products, but it can cause phlebitis in an infant’s small peripheral veins. Although the products are buffered and their pH is not of concern in adults, acidic pH may be problematic in neonates receiving IVIG. Slow infusions should resolve any concerns about metabolic acidosis. Finally, because the total blood volume in neonates is so small, the infusion of hyperosmolar, hyperviscous fluids can lead to hemolysis.

COMORBIDITIES Comorbid conditions may determine which IVIG product is most appropriate for individual patients (Figure 5).2 In patients with diabetes mellitus, the biggest concern is the stabilizer agents used to prevent IgG aggregation. Although glucose directly impacts the insulin requirement, complex sugars such as sucrose and maltose have no impact on these requirements (see Product Features Potentially Affecting Tolerability). Renal insufficiency also should be considered when IVIG products are adminstered. IVIG-induced renal insufficiency and acute renal failure were first noted with use of IVIG products stabilized with sucrose. This issue can occur with any carbohydrate-stabilized IVIG, and a related “black box” warning is part of all IVIG package inserts. Renal risk factors should be part of the standard review for all patients prior to IVIG product selection. Other safety measures called for in patients with renal insufficiency are using a slow infusion rate and using products that are close to isotonic. Finally, although the exact relationship between IVIG and thrombotic AEs is not fully understood, it is recommended that the infusion rate be slowed, the dose

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PRECAUTIONS Various other factors require clinicians to use caution when prescribing IVIG (Figure 6). Aseptic meningitis. Aseptic meningitis is a post-infusion AE. Although the patient with this disorder will exhibit a severe headache with accompanying nuchal rigidity, lumbar puncture will not show evidence of infection. If the patient does not provide information about a previous IVIG administration, the connection might not be recognized. Patient education is imperative. Switching the product may not always result in improvement of this disorder. If the benefit of IVIG therapy outweighs the risk in such patients, use of isotonic IVIG products with a lower dose and rate of administration is warranted. Hemolysis. Hemolysis is a rare AE associated with IVIG and anti-IgD administration. The exact mechanism and risk factors are not clear. Patients need to be aware of postinfusion signs of hemolysis. Hematuria may cause a darkening of the urine within a few hours of IVIG administration and can serve as an early warning sign of hemolysis.

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For more information on false-positive readings with certain monitoring devices, see reference 2.

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:\[Va\_ ]NaVR[a` S\_ ]bYZ\[N_f NQcR_`R _RNPaV\[` N[Q A?.96

=NaVR[a` dVaU A?.96 ZNf OR ZN[NTRQ b`V[T \efTR[ aUR_N]f dVaU NQR^bNaR cR[aVYNa\_f `b]]\_a

6[Sb`V\[ c\YbZR` [RRQ a\ OR PN_RSbYYf P\[`VQR_RQ V[ aUR S\YY\dV[T `RaaV[T`' ]NaVR[a` dVaU PN_QVNP P\[QVaV\[`( ]NaVR[a` dVaU ]bYZ\[N_f RQRZN( ]NaVR[a` dVaU aU_\ZO\RZO\YVP _V`X( TR_VNa_VP ]NaVR[a`( [R\[NaNY ]NaVR[a`

Figure 6. Clinical factors that call for caution when IVIG is used. TRALI, transfusion-related acute lung injury

Sodium considerations. The sodium concentration of IVIG products can vary from 0% to 1.8%. It is important to know the amount and concentration of sodium being infused. Lyophilized products that already have sodium chloride are of particular concern. The choice of diluents is a factor for reconstitution of lyophilized products. Liquid IVIG products normally do not contain sodium chloride. Transfusion-related acute lung injury (TRALI). This syndrome is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Because TRALI can be associated with significant morbidity and mortality, monitoring for it is important in patients receiving IVIG products. Volume considerations. If a patient weighing 100 kg

receives 1 g/kg of a 5% IVIG, the volume infused would be 2,000 mL. This volume of fluid, especially if hypertonic, could cause numerous problems for patients. Cardiac, pulmonary, and renal dysfunctions cause particular concern. In neonates, because the total blood volume is small, the volume of infused IV fluid can influence the neonateâ&#x20AC;&#x2122;s metabolic state. Use of higher-concentration yet isotonic solutions of IVIG are best suited for these patients.

Product Features Potentially Affecting Tolerability In addition to possible clinical efficacy and safety effects, different manufacturing steps also may affect product characteristics that affect tolerability. IVIGs

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Table 2. Pharmaceutical Aspects of IVIG: Osmolality/Osmolarity, Sodium Content, and Stabilizer Product

Osmolality/Osmolarity

Sodium Content

Stabilizer

Carimune NF, CSL Behring (lyophilized)

In water: 3%, 192 mOsm/L; 6%, 384 mOsm/L In saline: 6%, 690 mOsm/L; 12%, 1,074 mOsm/L

0%-0.9%, depending on diluent

10% sucrose at 6% concentration

Flebogamma 5% DIF, 240-370 mOsm/L Instituto Grifols (liquid 5%)

<3.2 mmol/L

5% D-sorbitol

Gammagard, Baxter Healthcare (liquid 10%)

240-300 mOsm/kg

Trace

No sugar (glycine based)

Gammagard S/D, Baxter Healthcare (lyophilized)

5%, 636 mOsm/L; 10%, 1,250 mOsm/L

0.85% at 5% concentration

2% glucose

Gammaplex, Bio Products (liquid 5%)

480 mOsm/kg

Approximately 40 mmol/L

Sorbitol, glycine

Gamunex-C, Talecrisa 258 mOsm/kg (liquid 10%)

Trace

No sugar (glycine based)

Octagam, Octapharma (liquid 5%)

<30 mmol/L

10% maltose

Trace

No sugar (L-proline based)

310-380 mOsm/kg

Privigen, CSL Behring 240-440 mOsm/L (liquid 10%) a

Gamunex-C will replace Gamunex; it is expected to be available by January 2011.

vary with respect to available formulations, concentrations, osmolalities, IgA content, pH, and sodium and sugar content (Table 2). Some IVIG preparations contain sugar as a stabilizer (Table 2 and Figure 7). Glucose, sucrose, and D-sorbitol also have been used. Other IVIG products do not contain any sugar. Even though sorbitol may not increase the glucose level in the blood, it is metabolized to fructose. Caution needs to be exercised with patients who have heredity fructose intolerance. A small population of patients may have hyperprolinemia and should not receive products stabilized with L-proline. Volume load (rate of infusion is another factor that can affect tolerability.

Dosing and Rate Considerations DOSAGE SELECTION Originally, IVIG was indicated only as replacement therapy for IgG-deficient patients with primary immunodeficiency disorders. Doses ranged from 150 to 250 mg/kg. Evaluation of outcomes and measurement of IgG serum levels revealed that this dose range was suboptimal to achieve an IgG level greater

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

than 600 mg/dL. Doses for replacement therapy usually are in the 400- to 500-mg/kg range, administered every 3 to 4 weeks. For immunotherapy, such as for idiopathic thrombocytopenic purpura and chronic inflammatory demyelinating polyneuropathy, the dosage can be much higher but is normally 2,000 mg/kg per treatment course. If the patient is able to tolerate it, a dosage of 1,000 mg/kg per day for 2 days will result in a rapid response. Some patients may need a lower dosage regimen spread out over time to minimize side effects. Volume considerations must be evaluated with regard to patient age, comorbidities, and so forth (see Figure 8).

DOSING

OBESE PATIENTS

Clinicians often are concerned with proper dosing of IVIG for patients who are morbidly obese. IVIG product registration studies used actual body weight to calculate the final dose, however, morbidly obese patients usually are excluded from study populations. In most situations, actual body weight should be used, but when the patientâ&#x20AC;&#x2122;s weight is greater than 100 kg or body mass index is greater than 30 kg/m2, an adjustment of dosing weight may be warranted.3

@aNOVYVgR_ 0\[`VQR_NaV\[`

@\_OVa\Y' Q\R` [\a V[P_RN`R TYbP\`R YRcRY V[ OY\\Q

:NYa\`R' Q\`R [\a V[P_RN`R TYbP\`R YRcRY V[ OY\\Q

0NbaV\[' @\_OVa\Y V` ZRaNO\YVgRQ a\ S_bPa\`R( Nc\VQ V[ ]NaVR[a` dVaU UR_RQVaN_f S_bPa\`R V[a\YR_N[PR

0NbaV\[' :NYa\`R V` QR_VcRQ S_\Z P\_[ `f_b] N[Q `U\bYQ OR Nc\VQRQ V[ ]NaVR[a` dVaU P\_[ NYYR_Tf

9 ]_\YV[R' Q\R` [\a V[P_RN`R TYbP\`R YRcRY V[ aUR OY\\Q

4YfPV[R' Q\R` [\a V[P_RN`R TYbP\`R YRcRY V[ OY\\Q

0NbaV\[' P\[a_NV[QVPNaRQ V[ ]NaVR[a` dVaU Uf]R_]_\YV[RZVN

Figure 7. Considerations for various stabilizers used in IVIG products.

6[VaVNY 1\`R N[Q ?NaR @RYRPaV\[ :\`a V[QVPNaV\[`' ZT XT ]R_ P\b_`R \S aUR_N]f N

1\`V[T dRVTUa QRaR_ZV[NaV\[

6[ Z\`a PN`R` b`R ./D

6S + XT \_ /:6 + XT Z PNYPbYNaR 6/D

! ZT XT \cR_ " QNf` <? " ZT XT \cR_ ! QNf` <? ZT XT \cR_ QNf`

1\`V[T _NaR QRaR_ZV[NaV\[ P 3\YY\d ZN[bSNPab_R_Âˇ` TbVQRYV[R`

.YdNf` R`PNYNaR _NaR aU_\bTU ]UN`R`

./D Â˛ 6/D e " 6/D * Q\`V[T dRVTUa O

?RQbPR _NaR VS .2` \PPb_

B`R ]_RZRQVPNaV\[` VS .2` \PPb_

@a\] V[Sb`V\[ VS .2` Q\[Âˇa `bO`VQR

1RaR_ZV[R ]NaVR[aÂˇ` ZNeVZbZ a\YR_NaRQ _NaR

Figure 8. IVIG dose and rate selection steps. a

Doses are customized per patient for maintenance dosing

For more information on dosing in obese patients, see reference 3.

See full prescribing information for each product for rate guidelines.

ABW, actual body weight; AE, adverse event; BMI, body mass index; IBW, ideal body weight

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

=NaVR[a 0\[`bYaNaV\[

1\PbZR[aNaV\[ V[ ZRQVPNY _RP\_Q ;\aR O_N[Q _NaR _V`X` N[Q a\YR_N[PR

CR_VSf ]NaVR[a X[\dYRQTR \S aUR S\YY\dV[T' @]RPVSVP 6C64 O_N[Q ORV[T b`RQ :\`a _RPR[a 6C64 Q\`R aURf _RPRVcRQ 6C64 _NaR R`PNYNaV\[ b`RQ N[Q a\YR_N[PR aURf ReUVOVaRQ ]_RcV\b`Yf =_RZRQVPNaV\[` aURf _R^bV_R ?V`X SNPa\_` aURf UNcR 6[Sb`V\[ _RYNaRQ N[Q QRYNfRQ .2` aURf UNcR Re]R_VR[PRQ

Figure 9. Patient education and documentation steps. AE, adverse event

RATE DETERMINATION Each product has a recommended rate of infusion that should be followed. Upon initiation of therapy, an initial rate that allows for observation and monitoring over a 15to 30-minute period should be used. The rate should be increased as defined and then a third escalation should be instituted to determine the patient’s maximum tolerated rate. AEs can occur at any time, and slowing the rate should be the first consideration. Additionally, the administration of antidotes may be warranted. On subsequent infusion, specific premedications may be administered to improve patient tolerability. During any situation when slowing the rate does not immediately reduce the AE, the IVIG should be stopped and treatment administered.

Conclusion Further comparisons of available IVIG products can be found in Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations.4 Because of the differing characteristics, certain products may not be well tolerated by or recommended for particular patient populations. Additionally, individual patient tolerability may differ between certain products. Therefore, much care and consideration needs to be taken when selecting a particular IVIG for a particular patient. When

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

treating patients with IVIG therapy, an important component is patient education about the brand being used, the rate escalation, risk factors they may have, their tolerance of the product, and any AEs they may have experienced. Another important component is documentation in the patient’s medical record of the IVIG brand used, infusion rate, patient risk factors, tolerance, and documentation of the brand selected (Figure 9). A stepwise approach that considers all of the components listed in the figures and tables will help foster the safe use of IVIG and reduce the adverse reactions commonly associated with the infusion of these products.

References 1.

Orange JS, Ballow M, Berger M. Work group report on the appropriate use of intravenously administered immunoglobulin (IGIV). http://www.aaaai.org/media/resources/academy_statements/practice_papers/igiv.pdf. Accessed September 1,2010.

2. Bronstein D. FDA issues warning on glucose test strips. Pharmacy Practice News. 2009;36:3. http://www.pharmacypracticenews. com/index.asp?section_id=61&show=dept&issue_id=560&article_ id=13863. Accessed September 13, 2010. 3. Siegel J. Immunoglobulins and obesity. Pharmacy Practice News. 2010;37(1):8-9. 4. Siegel J. Immune globulins: therapeutic, pharmaceutical, cost, and administration considerations. http://www.pharmacypracticenews. com/index.asp?show=pocketguide&section_id=159&article_ id=15544. Accessed August 26, 2010.

16 Clinical

Pharmacy Practice News • December 2010

Coagulation

Point-of-Care Device Improves Fibrinolysis Diagnosis Real-time assessment of coagulation function could direct therapy, save more lives Chicago—In a finding that one day may change the standard of care for severely injured trauma patients, a team of U.S. surgeons is reporting that they can successfully measure injured adults’ blood clot strength inside the operating room and then use these results to individualize blood therapy. “For the first time, with a point-of-care device right in the OR, we have the poten-

tial ability to make the diagnosis of fibrinolysis when we’re managing a patient. We can then identify the patients whom we should pretreat with antifibrinolytics,” said lead author Jeffry Kashuk, MD, currently section chief of acute care surgery and professor of surgery in the Division of Trauma, Acute Care and Critical Care Surgery at Penn State Milton S. Hershey Medical Center, in Hershey, Pa.

At the 2010 annual meeting of the American Surgical Association, Dr. Kashuk presented the study conducted at the Denver Health Medical Center in which 61 consecutive trauma patients underwent rapid thrombelastography (r-TEG, Haemonetics Inc.) in the OR. This test differs from conventional thrombelastography because tissue factor is added to the whole blood specimen, resulting in a

Immune Globulin Intravenous (Human) Flebogamma® 5% DIF For intravenous use only Rx only BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Flebogamma® 5% DIF is indicated for replacement therapy in primary (inherited) humoral immunodeficiency disorders. DOSAGE AND ADMINISTRATION The usual dose of Flebogamma® 5% DIF for replacement therapy in primary humoral immunodeficiency diseases is 300 to 600 mg/kg body weight administered every 3 to 4 weeks. An in-line filter with a pore size of 15 to 20 microns is recommended for the infusion. Antibacterial filters (0.2 micron) may also be used. Discard unused contents and administration devices after use. The infusion of Flebogamma® 5% DIF should be initiated at a rate of 0.01 mL/kg body weight/minute (0.5 mg/kg/minute). If, during the first 30 minutes, the patient does not experience any discomfort, the rate may be gradually increased to a maximum of 0.10 mL/kg/minute (5 mg/kg/minute). For patients judged to be at risk for developing renal dysfunction or considered to be at increased risk of thombotic/thromboembolic events, it may be prudent to limit the infusion rate to a maximum rate less than 0.06 mL/kg body weight/minute (3 mg/ kg/minute). Reduction in dose, concentration, and/or rate of infusion in patients at risk of acute renal failure, which includes patients over 65, has been proposed in the literature in order to reduce the risk of acute renal failure. CONTRAINDICATIONS Flebogamma® 5% DIF should not be administered to individuals with a history of severe or anaphylactic reactions to blood or blood-derived products. Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Anaphylaxis can occur using Flebogamma® 5% DIF even though it contains low amounts of IgA (typically < 50 μg/mL). Such patients should only receive intravenous immune globulin with utmost caution and in a setting where supportive care is available for treating life-threatening reactions. If patients are known to be intolerant to any component of Flebogamma® 5% DIF, such as sorbitol (i.e., intolerance to fructose), they should not receive the product. WARNINGS Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Flebogamma® 5% DIF does not contain sucrose. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure. Flebogamma® 5% DIF is made from human plasma. As with all plasma derived products, the risk of transmission of infectious agents, including viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The risk that such products will transmit an infectious agent has been greatly reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Biologicals at 888-GRIFOLS (888-474-3657). All patients, but especially individuals receiving Flebogamma® 5% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at risk for the development of inflammatory reactions characterized by fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations may reduce the risk of these types of events. Appropriate supportive care, including immediate access to epinephrine injection, should be available for the management of acute anaphylactic reactions.

faster, real-time assessment of coagulation function in the trauma setting. Until recently, thrombelastography was used primarily for cardiac and transplant patients. Dr. Kashuk and his colleagues, however, argue that r-TEG is ideal for trauma patients because it can provide point-of-care assessments of coagulation in patients who require immediate results. In a study published last year, the

PRECAUTIONS General: Any vial that has been entered should be used promptly. Partially used vials should be discarded and not saved for future use because the solution contains no preservative. Do not use if turbid. Solution that has been frozen should not be used. Ensure that patients are not volume-depleted before the initiation of the infusion of IGIV. Renal Function: Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing Flebogamma® 5% DIF at a maximum rate less than 0.06 mL/kg (3 mg/kg) body weight/minute. Aseptic Meningitis Syndrome: An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic milliliter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high-dose (e.g., > 1.0 g/kg body weight) and/or rapid-infusion IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. Hemolysis: Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration [See ADVERSE REACTIONS]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis [See PRECAUTIONS: Laboratory Tests]. Thrombotic Events: Thrombotic events have been reported in association with IGIV (See ADVERSE REACTIONS). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [See PRECAUTIONS: Laboratory Tests]. Transfusion-Related Acute Lung Injury (TRALI): There have been reports of non-cardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1 to 6 hours after transfusion. Patients with TRALI may be managed by using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum [See PRECAUTIONS: Laboratory Tests]. Information For Patients: Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians. It is recommended that the lot number of the vials used be recorded when Flebogamma® 5% DIF is administered. Laboratory Tests: Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF in patients judged to have a potential increased risk for developing acute renal failure and again at appropriate intervals thereafter.

Pharmacy Practice News • December 2010

Clinical 17

Coagulation researchers successfully used point-ofcare r-TEG as a screening tool in trauma patients to identify hypercoagulable states (Surgery 2009;146:764-772). Their new report shows that the r-TEG results can be used to aid clinical decision making in the key first hour after injury. The findings indicate that the clot strength of blood in severely injured trauma patients is strongly associated with primary fibrinolysis and mortality. Moreover, loss of clot strength can be identified within an hour of injury. “This is very important work,” said David Hoyt, MD, executive director of

‘This is very important work. It could be a potential target for intervention at a time when our traditional thinking has suggested that inhibition of fibrinolysis might be dangerous or enhance coagulopathy.’

—David Hoyt, MD

the American College of Surgeons and a nationally recognized trauma surgeon, after hearing the study presented. “It could be a potential target for intervention at a time when our traditional thinking has suggested that inhibition of fibrinolysis might be dangerous or enhance coagulopathy. As we further understand

Following infusion of Flebogamma® 5% DIF, there may be a transitory rise of various antibody titers that may result in misleading positive results in serological testing. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum. Pregnancy Category C: Animal reproduction studies have not been performed with Flebogamma® 5% DIF. It is also not known whether Flebogamma® 5% DIF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Flebogamma® 5% DIF should be given to a pregnant woman only if clearly needed. Drug Interactions: Antibodies in Flebogamma® 5% DIF may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration. Pediatric Use: The above mentioned clinical trial with Flebogamma® 5% DIF enrolled only a very limited number of children (0) and adolescents (3) with primary humoral immune deficiency, a number insufficient to fully characterize and establish the efficacy and safety in pediatric patients. Geriatric Use: Subjects over 65 are at increased risk of renal failure with IGIV treatment. For these subjects, and for any other subjects at risk of renal failure, the infusion rate of Flebogamma® 5% DIF should be limited to < 0.06 mL/kg/min (3 mg/kg/min). Adverse Reactions Increases of creatinine and blood urea nitrogen (BUN) have been observed as soon as 1 to 2 days following infusion of IGIV. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment. Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, proximal tubular nephropathy, and osmotic nephrosis. Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate [See DOSAGE AND ADMINISTRATION] must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Adverse reactions may occur more frequently when a high infusion rate is used, the treatment is the initial exposure to immunoglobulin, the immunoglobulin product has been changed to that of a different manufacturer, or there has been a long interval (more than 8 weeks) since the previous infusion. Slowing or stopping an infusion usually results in the prompt disappearance of symptoms. Post-Marketing: The following adverse reactions have been identified and reported during the postapproval use of IGIV products. Respiratory

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

Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiac arrest, thromboembolism, vascular collapse, hypotension Coma, loss of consciousness, seizures, tremor Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, bullous dermatitis Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test Pyrexia, rigors Back pain Hepatic dysfunction, abdominal pain

Because post-marketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently. Adverse events were reported in a study of 46 individuals with primary humoral immunodeficiency diseases receiving infusions every 3 to 4 weeks of 300 to 600 mg/kg body weight. Forty-three (94%) subjects experienced at least 1 adverse event

the complexity of shock and coagulation, I think this will come into perspective.” For every one-unit reduction in clot strength, measured by r-TEG, patients have a 30% increased risk for primary fibrinolysis and a 10% increased risk for death, the results showed. Of 61 patients tested by r-TEG, 11

irrespective of the relationship with the product, and these subjects reported a total of 595 adverse events. None of the 46 subjects who participated in this study discontinued the study prematurely due to an adverse experience related to the study drug. One subject had treatment-emergent bronchiectasis, mild, ongoing, after infusion #10; and one subject had recurrent moderate leukopenia after the 7th and 12th infusions. No adverse events occurred with an incidence of > 2% on a per infusion basis. Table 1. Adverse Events Occurring with an Incidence of > 15% Adverse Event

Number of AEs

Combined Bronchitis Cough and productive cough Diarrhea NOSa Headache NOS and sinus headache Nasal congestion Injection site reaction NOS Pyrexia Arthralgia Sinusitis NOS Pharyngitis Upper respiratory tract infection Wheezing and asthma aggravated

19 10 14 46 11 13 27 11 38 9 24 24

Number of Subjects with AEs 14 10 9 16 7 7 17 7 20 8 15 10

Percent of Subjects with AEs 30 22 20 35 15 15 37 15 44 17 33 22

a. NOS = not otherwise specified The total number of AEs (regardless of attribution) reported whose onset was within 72 hours after the end of an infusion of Flebogamma® 5% DIF was 216. There were a total of 709 infusions, resulting in a rate of 0.305 (95% confidence interval 0.225 to 0.412) temporally associated AEs per infusion. There were 144 infusions (20.1%, 1-sided 95% upper bound confidence interval = 24.4%) associated with 1 or more AEs that began within 72 hours after the completion of an infusion. Table 2. Summary of Infusions with Mild, Moderate, and Severe TreatmentRelated Adverse Events Severity of AE Mild Moderate Severe

No. Infusions 58 25 1

Adjusted % a with AE 7.9 3.6 0.1

Confidence Intervalb 10.4 4.9 0.3

a. Adjusted % = average of the % of infusions with a treatment-related adverse event for each individual subject. b. The 95% upper bound for the adjusted % of infusions for which at least 1 treatmentrelated adverse event was reported was derived by using the t-statistic. The number and percent of subjects with treatment-emergent rises in AST or ALT are in Table 3. Table 3. Number (%) of Subjects with Treatment-Emergent Rises in AST or ALT (N = 46) Laboratory Test AST ALT

Assessment Criteria Above 3x the ULNa Above 3x the ULN

n 3 1

% 6.5 2.2

a. ULN = upper limit of normal. None of these subjects had a concomitant treatment-emergent rise in total bilirubin. Reported adverse reactions with Flebogamma® 5% DIF and other IGIV products include: headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing, rash, arthralgia, and edema, often beginning within 60 minutes of the start of the infusion. Rarely, Immune Globulin Intravenous (Human) can induce a severe fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with IGIV. In the case of shock, the current standard medical treatment for shock should be implemented. Manufactured by INSTITUTO GRIFOLS, S.A. Barcelona - Spain U.S. License No. 1181 Distributed by GRIFOLS BIOLOGICALS INC. Los Angeles - CA 90032 Phone: 888-GRIFOLS (888-474-3657)

(18%) were found to have primary fibrinolysis, defined as more than 15% estimated percent lysis (EPL). Another 28 patients (46%) had transient fibrinolysis, defined as more than 15% EPL, and 22 (30%) had no fibrinolysis. Patients with primary fibrinolysis represented the sickest group, with 34% requiring a massive transfusion. They also had higher mortality at 64%, compared with 29% in the transient fibrinolysis group and 18% with no fibrinolysis (P=0.027).

Early Fibrinolysis Critical What might prove most significant, said the researchers, is their discovery that primary fibrinolysis sets in within an hour of severe injury. It was identified at an average of 58 minutes after injury (inter-quartile range [IQR], 18.2-95.9). Transient fibrinolysis sets in later, at 104 minutes after injury (IQR, 13-1200). The timing of fibrinolysis is likely “a very important factor that was not previously appreciated,” said Dr. Kashuk. The early onset indicates that the breakdown process that often leads to a patient’s death after trauma starts early after injury, and is a combination of coagulopathy, shock, acidosis and hypothermia, as well as other physiologic changes. By using the r-TEG test, trauma surgeons can test patients immediately for primary fibrinolysis. If the test is positive, patients can be pretreated with antifibrinolytics. Surgeons hope that pretreatment will improve chances of survival. “That could have a significant impact in survival in these patients,” Dr. Kashuk said. The trauma team from Denver Health is using the test results to select patients for antifibrinolytics. They said that they are hoping that their future studies will define optimal prophylaxis for patients with r-TEG-proven hypercoagulability. “It may well be that patients who don’t exhibit significant fibrinolysis can be resuscitated with traditional resuscitation factors. However, in patients with primary fibrinolysis, they likely require antifibrinolytics. If not, the fibrinolysis could shift to a consumptive coagulopathy—essentially a premorbid condition,” Dr. Kashuk said. Sid Patanwala, PharmD, clinical assistant professor of critical care/emergency medicine at the University of Arizona, in Tucson, called the r-TEG test “very cutting-edge.” But he stressed that widespread adoption “is still going to be debated,” in part because the assay “is complicated to administer in the trauma bay.” Dr. Patanwala also pointed out that using a test to individualize inhibition of fibrinolysis is itself controversial, regardless of what assay is used. He noted that recent studies, such as the CRASH-2 trial (Lancet 2010;376:23-32), support a far simpler approach—“giving antifibrinolytics to everyone.” —Christina Frangou

18 Clinical

Pharmacy Practice News • December 2010

Coagulation

Blood Thinner ‘Holiday’ for Surgery Patients Challenged A

small pilot study is calling into question the common practice of interrupting the administration of antiplatelet drugs in patients with coronary artery disease shortly before general surgery. The study found unexpectedly low levels of platelet inhibition in many of the 12 patients who had stopped taking aspirin and/or clopidogrel prior to general surgery. Another analysis involving a similar cohort of patients found that perioperative stress further decreases the inhibition of platelet function in these patients. Both factors potentially increase the risk for major adverse cardiac events. “If the surprisingly lower platelet inhibition found in our patients with short-term interruption of therapy is duplicated in large, randomized trials, careful re-evaluation of the generally accepted five- to seven-day interruption may be warranted to avoid undue risk of coronary stent thrombosis,” said study leader Davide Cattano, MD, PhD, assistant professor of anesthesiology and medical director of the preoperative anesthesia clinic at the University of Texas Medical School at Houston. “Patients do not respond equally to antiplatelet therapy, and the response is not predictable,” Dr. Cattano noted. “A preoperative assessment of platelet function should be done in every patient on dual therapy, especially when the type of surgery demands suspension of the medications.” Patients diagnosed with coronary artery disease commonly receive drugeluting stents and a regimen of antiplatelet medications such as aspirin and clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-aventis). Because the drugs increase the risk for bleeding, these patients usually are advised to discontinue their regimens for a short period before surgery. But stopping the medications can increase a patient’s risk for clotting, which is linked to heart attacks and other potentially life-threatening cardiac events. The rate of perioperative complications for these patients can reach 5%, Dr. Cattano said, and the rate of mortality can be as high as 40% to 80% for those who do experience adverse events.

Thrombelastograph Platelet Mapping In May 2009, Dr. Cattano and his colleagues began a preliminary observational study to assess the ability of thrombelastograph platelet mapping (TEG-PM, Haemonetics Corp.) to detect platelet inhibition by aspirin and clopidogrel in patients scheduled for general surgery. TEG-PM is a relatively new assay that measures clot strength

Table. Platelet Inhibition as Measured By Thrombelastograph Platelet Mapping Antiplatelet Drug

Preoperative Inhibition, %

Postoperative Inhibition, %

P Value

Aspirin (AA)

43±23.9

29±24.6

<0.059

Clopidogrel (ADP)

34±16.8

23±11.9

<0.024

‘Patients are receiving very potent antiplatelet drugs without any control over their efficacy.’

—Marcin Wasowicz, MD

in whole blood. It detects platelet inhibition by clopidogrel and aspirin in response to adenosine diphosphate (ADP) and arachidonic acid (AA) stimulation, respectively. Data were collected on 12 patients (age, 64±5.7 years) who arrived at the preoperative anesthesia clinic for evaluation or on the day of surgery. The duration of antiplatelet therapy for all patients was 30.2±22.5 months. Aspirin interruption lasted 0.8±1.3 days and AA inhibition was 71±30.4%. Eleven patients had short-term interruption of clopidogrel for 1.1±1.3 days, with an ADP-mediated inhibition of 64±27.8%. “In this small, preoperative surgical patient sample, incomplete platelet inhibition assessed by TEG-PM was a surprising finding,” Dr. Cattano said. “Resistance to antiplatelet therapy may be a clinically relevant problem.” Dr. Cattano said in an interview just prior to reporting on the findings at the 2010 annual meeting of the American Society of Anesthesiologists in October (abstracts A1164 and A1224). Dr. Cattano said he was planning on providing updated results, including a finding that only 13 of 21 patients who suspended clopidogrel within three days of surgery showed adequate inhibition of platelets. Marcin Wasowicz, MD, assistant professor of anesthesiology at Toronto General Hospital, in Ontario, Canada, who is also studying antiplatelet therapy during the perioperative period (Anesth Analg 2010;111:331338), said Dr. Cattano’s results “indicate that many patients coming for noncardiac surgery after previous antiplatelet therapy have inadequate platelet inhibition. The recommended percentage of platelet inhibition is 50% to 80%, and many patients

studied [by the Texas group] presented with significantly lower inhibition.” One part of Dr. Cattano’s study included the 12 original patients plus three others. Blood samples were collected preoperatively on the day of surgery and compared with those collected postoperatively in recovery. Inhibition for clopidogrel (ADP) was 34±16.8% preoperatively and 23±11.9% postoperatively (P=0.024). Inhibition for aspirin (AA) was 43±23.9% before surgery and 29±24.6% after (P=0.059; Table). “It appears that when there is partial inhibition, there is also a postoperative effect from surgery,” Dr. Cattano said. “Validation of these findings in larger analyses may have significant implications for perioperative management of these high-risk patients with potentially unanticipated antagonism of residual platelet inhibition due to the stress-induced changes of surgical stimulation.”

Ongoing Study Exploring Bleeding, Clotting Outcomes From a clinical perspective, Dr. Wasowicz added, “it potentially means that these patients are at higher risk of suffering from thromboembolic complications during the perioperative period.” Dr. Wasowicz is currently leading a multicenter observational study of up to 200 patients receiving antiplatelet therapy and who are scheduled for elective,

noncardiac surgery in order to assess the incidence of clotting or major bleeding in the perioperative setting. Dr. Wasowicz said Dr. Cattano’s findings “also indicate that patients are receiving very potent antiplatelet drugs without any control over their efficacy. As pointed out by the authors, many patients are poor responders or nonresponders to aspirin and/or clopidogrel therapy, and ... are at even higher risk of thromboembolic complications.” Jacques E. Chelly, MD, PhD, MBA, professor and vice chair of clinical research in the Department of Anesthesiology at the University of Pittsburgh School of Medicine, said that while Dr. Cattano’s studies involve a limited number of patients, the results raise important issues. For instance, the recommendation against performing blocks in a patient for whom Plavix has not been discontinued between five to seven days before surgery is based only on theory. “The methodology used by Dr. Cattano allows the clinician to determine if a patient taking Plavix is really at a higher risk of major bleeding if a block is performed,” Dr. Chelly said. “If platelet function is normal or mildly affected by Plavix, this represents an argument in favor of using regional anesthesia. It is critically important to start evaluating the clinical consequence of administering Plavix in patients before developing an anesthesia plan.”

Pharmacist’s Perspective “This is a provocative project that raises more questions than it answers,” said C. Michael White, PharmD, professor of pharmacy at the University of Connecticut, in Storrs, and director of the UCONN/Hartford Hospital Evidence-Based Practice Center, in Hartford. “In many areas of medicine, trying to apply the ‘First, do no harm’ doctrine is difficult. From one perspective, stopping an antiplatelet agent before surgery would reduce the risk of bleeding, but in doing so, raises the risk of thrombosis. So which takes precedent?” Added Dr. White: “While the severity of bleeding may be less than experiencing a coronary event, the risk of experiencing a thrombotic event over the few days of therapy interruption is likely lower than that of bleeding. I applaud the investigators for raising these issues and this is where comparative effectiveness research is needed. While investigating whether a new therapy works in a disease is very flashy, it is research gaps like this that impact many patients on a dayto-day basis.” —Ted Agres

Built on data

20 Clinical

Pharmacy Practice News • December 2010

Pediatrics

Systemic Steroids May Trigger Post-Tonsillectomy Bleeding S

ystemic steroids may do more harm than good in children undergoing tonsillectomy, according to results of a new meta-analysis by Canadian researchers. Although the drugs diminish postoperative nausea and vomiting, the findings suggest that steroids may increase the risk for reoperation resulting from bleeding after the procedure. Like many anesthesiologists, Jennifer Plante, MD, a resident at the University of Laval University in Quebec City, Canada,

and her colleagues frequently gave the misery-reducing steroids to young tonsillectomy patients. But during a recent lecture club meeting at their hospital, Dr. Plante’s group reviewed a publication in the Journal of the American Medical Association (JAMA 2008;300:2621-2630) that prompted them to reconsider the practice. The study had set out to investigate the optimum dose of dexamethasone for children undergoing tonsillectomy. It was stopped early due to a relatively

high rate of postoperative bleeding: 24% of children receiving 0.5 mg/kg of the steroid had bleeding episodes compared with 4% of those given a placebo. “The highest dose was the most effective in reducing nausea and vomiting, but on the other side, it also increased the bleeding risk,” said Christoph Czarnetzki, MD, consultant anesthetist at the University Hospitals of Geneva, in Switzerland, who led the JAMA study. “This was very astonishing to us.”

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.

The findings also surprised and concerned Dr. Plante, especially given the widespread use of dexamethasone at Laval’s hospitals. So, she led her team in conducting a systematic review of the literature to assess the association between systemic steroids and bleeding. They selected 25 randomized clinical trials, including Dr. Czarnetzki’s, covering 2,201 patients. Each study compared the use of a steroid during tonsillectomy with a placebo or another drug.

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 • December 2010

Clinical 21

Pediatrics Tripled Risk for Bleeding The meta-analysis found no differences in the rate of postoperative bleeding between the two groups. However, children given steroids were at approximately three times the risk for reintervention due to severe bleeding as those in the other group. Dr. Plante presented the results at the 2010 annual meeting of the Canadian Anesthesiologists’ Society, in Montreal (abstract 799776). Why was there such an inconsistency in comparative bleeding rates between Dr. Czarnetzki’s study and the set of studies as a whole? The key, he said, is

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 –

that his team followed patients for more than two weeks after their operations. “A typical study of nausea and vomiting in the anesthesia and operative context is stopped after 24 hours. But two-thirds

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

of the bleeding [episodes] in our study happened after the first day after the operation.” As Dr. Plante pointed out, none of the studies she included systematically mea-

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.

sured and reported the risk for bleeding. The primary focus of most trials was on postoperative nausea and vomiting (PONV), which explains why the majority followed patients for a day or two after surgery. Still, many also reported later reoperations. “The need for reintervention may be more objective and reliable than postoperative bleeding,” she said. “If you bleed that much, you can be sure you will go back to the hospital.”

Impaired Healing May Be Key Although nonsteroidal anti-inflammatory drugs are known to disrupt coagulation, and therefore are avoided in the tonsillectomy patients, the mechanism by which a steroid might induce bleeding is not well understood. Dr. Czarnetzki said the drugs may interfere with proper healing of the large scar left after tonsil removal. Dr. Czarnetzki has stopped using steroids on children during tonsillectomies. “Which is better, having nausea and vomiting or bleeding? You can die from tonsil bleeding. Without a doubt, we shouldn’t give steroids anymore.” Of course, this doesn’t mean that the more than two-thirds of children who will suffer from PONV after a tonsillectomy cannot be offered some relief, such as selective serotonin receptor antagonists, he stressed.

Caveats From Pharmacists Asked to comment on the study, Deborah Wagner, PharmD, clinical associate professor at the University of Michigan College of Pharmacy, in Ann Arbor, said, “Dexamethasone has been shown to be very effective for PONV, and we always wrestle with that [side effect of surgery] in the pediatric population.” She added that “you would expect some bleeding anyway, as tonsillectomy is a high-risk surgical procedure in kids.” Thus, “if we are going to recommend that we make a change in what has been accepted as the standard of care, we need to be sure that the benefits outweigh the risks in terms of bleeding versus increased risk of PONV. In my view, the data are not definitive enough.” Peggy Bickham, PharmD, clinical assistant professor, hospital pharmacy services at the University of Illinois Medical Center, in Chicago, offered similar words of caution. “Despite the concerns raised in this abstract, post-op vomiting may also increase the risk and/or severity of bleeding. While both the JAMA article and the meta-analysis described in this abstract raise interesting questions worthy of further study, they come to differing conclusions and do not present convincing enough evidence to justify a change in practice.” —Lynne Peeples

22 Clinical

Pharmacy Practice News • December 2010

Transplant Medicine

Managing the Switch to Generic Immunosuppressants Austin, Texas—With additional monitoring and patient education, generic immunosuppressants often can be a safe and cost-effective alternative to brandname products for transplant recipients. But the use of such generics, which is growing, still can pose some risks for patients, according to two transplant pharmacists debating the issue at the annual meeting of the American College of Clinical Pharmacy (ACCP). In interviews with Pharmacy Practice News, both pharmacists described an increasing comfort level with generic immunosuppressants, based on some research data and accumulating clinical experience. However, they expressed concerns about switch-related complications, which they try to limit by educating patients to look closely at their pills and discussing the issue with outpatient pharmacies. “I have no problem with the generic and I have no particular allegiance to the brand,” said Lisa McDevitt, PharmD, BCPS, senior clinical specialist in organ transplantation at Tufts Medical Center, in Boston. “My only concern is when patients switch from any product (brand or generic) to another product.”

mailed letters to transplant recipients, notifying them of the upcoming generic options and the importance of alerting their clinician if a medication’s appearance changed. To date, only about 40 outpatients have gotten in touch with the transplant center, out of at least 700, the vast majority of who were originally taking Prograf, said Dr. Gabardi. He noted that an additional 15 to 20 immunosuppressant switches were identified during a routine follow-up clinic visit. When the patients were questioned about their medications, “they admitted to us that they had a change in the color or the size or their shape of their [immunosuppressant].” There’s no way of knowing how many other switches haven’t been identified, he said.

Studying Conversion At the ACCP meeting, Dr. McDevitt presented data on a research project she

The projected amount ranged from less than $1 monthly for those on Medicaid, to $18 for privately insured patients and as much as $72 per month for Medicare patients (Table). For patients with limited incomes, even a difference between a $5 and a $10 monthly copay can, ove r t i m e, become substantial, Kwaku Marfo, PharmD, BC P S, clinical pharmacy manager for solid organ transplantation at Montefiore-Einstein Transplant Center, New York City, told Pharmacy Practice News. At Brigham and Women’s, transplant clinicians initially stayed with Prograf, until they started getting pushback from patients, Dr. Gabardi said. The most common scenario was a patient with private insurance, for whom the Prograf was bumped into a higher insurance copay tier. “For example, their $20 went up to $50, but they were told they could get a $5 copay if they got generic,” he said.

Table. Impact on Patient Copays N=102

Prograf Brand

Tacrolimus Generic

Average

Range

Average

Range

Savings

Educational Logistics

Medicaid

$0.93

$0 – 3.00

$0.47

$0 – 2.00

$0.47

Medicare

$123.42

$0 – 865.15

$51.13

$0 – 366.73

$72.29

Private

$27.48

$0 – 120.00

$9.79

$0 – 30.00

$18

Medicare & Private

$24.30

$0 – 64.60

$9.23

$0 – 40.00

$15

Medicare & Medicaid

$1.38

$0 – 3.00

$1.00

$0 – 2.00

$0.38

At times, Dr. McDevitt noted, patients do not realize that their drug has been switched and thus don’t get the additional laboratory monitoring they need to ensure that adequate blood levels of the new drug have been reached. Steven Gabardi, PharmD, BCPS, abdominal organ transplant specialist at Brigham and Women’s Hospital, also in Boston, had a similar take: “Right now, if I had my say, I would put everyone on a generic, if they could stay on the same version of that generic. My biggest concern is a generic-to-generic switch without us knowing.” Another problem is that patient education likely only catches some of the switches, said Dr. Gabardi, who was involved with an extensive letter writing campaign to reach patients. In 2008, when it became clear that Prograf, Astellas’ brand of tacrolimus, would go generic, Brigham and Women’s clinicians

led, involving the switch from Prograf to generic tacrolimus in 102 adult patients at four medical centers, including Tufts and Brigham and Women’s. The data, which also were presented at the American Transplant Congress earlier this year, showed that nearly 30% of patients required a dose adjustment; about half required an upward titration and half a downward one. Several side effects were reported, including mouth sores and vision changes. There were no episodes of allograft rejection, but the data still validate the need for close monitoring, Dr. McDevitt said. “They did fine on the generic, [but] it did confirm our worry about … conversion, because nearly 30% of them needed to have a dose titration.” Based on an insurance analysis of the 102 patients involved, switching from Prograf to generic tacrolimus could save patients out-of-pocket monthly costs.

versions of mycophenolate mofetil and tacrolimus to its inpatient formulary. That protects patients from first being switched to brand during hospitalization and then back to generic once discharged home, he said. Dr. Marfo had concerns about the switch early on. After all, he said, the margin involved with maintaining therapeutic levels is both narrower and more critical for such drugs used in transplant recipients than for other classes of drugs. “We are talking about patients’ lives, where they may not have a chance to get another organ. If you get that one kidney, you want to make sure you ride it as long as possible. These are not trivial decisions that need to be made.” However, he said his initial concerns about conversion risks have been eased somewhat by recent findings involving Montefiore transplant recipients. The outcomes of two groups have been studied, one involving patients switched from CellCept, Genentech’s brand of mycophenolate mofetil, to a generic version. The second, with more patients, followed patients switched from Prograf to generic tacrolimus. The results, which Dr. Marfo plans to submit for publication, didn’t identify any increase in acute organ rejection following conversion.

Dr. McDevitt said that she leaves the generic decision up to the kidney and liver patients she helps treat, after laying out the cost difference and the additional monitoring required. If they opt for a generic, she tells them that they assume the responsibility of notifying transplant clinicians any time there is a drug change when they refill their medication. When generic tacrolimus was released last year, more than 80% of those patients didn’t want to switch, she said. Now, she estimated, roughly half take a generic version.

Transition to Home Tricky As more patients take generic immunosuppressants, another switch-related concern has developed—the transition from hospitalization to home, Dr. Marfo said. For that reason, Montefiore clinicians decided this summer to add generic

Like the other pharmacists interviewed, Dr. Marfo views the generic transition as inevitable and its success highly dependent on education, of pharmacists as well as patients. Additionally, Dr. Gabardi said, “Even though the generics have been out for a year now, the education can’t stop.” At Brigham and Women’s, clinicians also talk with pharmacies they work with regularly about the potential clinical risk of an inadvertent switch, Dr. Gabardi said. Ideally, the pharmacist will call if they don’t see “brand-name only” specified on the prescription. And they will limit the number of generic immunosuppressants they stock, reducing the possibility of generic-to-generic switches. Or, if they change the generics they stock, they might provide a courtesy call to transplant clinicians. “We were a center that fought like crazy to not convert and we knew that it was a losing battle,” Dr. Gabardi said. “I think most of us [at Brigham and Women’s] realize that, ‘Yeah we fought it for a while, but this is something that no matter how much how we fight, we are going to lose.’ Now we’re focusing on safe conversion.” —Charlotte Huff

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Pharmacy Practice News • December 2010

In Focus

Everolimus Active Against Neuroendocrine Tumors Milan—Results from a Phase III trial support the use of everolimus (Afinitor, Novartis) in patients with advanced pancreatic neuroendocrine tumors (pNETs). The study, presented at the recent European Society for Medical Oncology (ESMO) Congress, showed that everolimus improved progressionfree survival (PFS) by six months when added to best supportive care (BSC) in patients with pNETs. “RADIANT-3 [RAD001 In Advanced Neuroendocrine Tumors] is the largest randomized controlled trial ever completed in patients with advanced pancreatic neuroendocrine tumors,” said J.C. Yao, MD, associate professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, who led the study. “Everolimus has demonstrated a meaningful 2.4-fold increase in median progression-free survival. Everolimus should be considered a standard of care for patients with advanced pancreatic neuroendocrine tumors.”

P<0.0001). “We saw robust mus could improve PFS in treatment benefit across all patients with advanced and subgroups,” Dr. Yao said. The progressive NETs when addmost common drug-related ed to octreotide acetate (Sanadverse events reported were dostatin LAR, Novartis), the stomatitis, rash, diarrhea, standard treatment for sympfatigue and infections, with the tom control (ESMO abstract most common grade 3/4 events Scan for abstract. LBA8). The study, RADIbeing stomatitis, anemia and Instructions, page 3 ANT-2, involved 429 patients hyperglycemia (Figures 1 and 2). with well- or moderately differentiated A second Phase III study present- advanced NETs and a history of carcinoed at ESMO tested whether everoli- id symptoms. Patients were randomized

in a 1:1 fashion to receive everolimus (10 mg per day) plus octreotide (30 mg intramuscularly every 28 days) or placebo plus octreotide. Primary tumor sites included small intestine, lung, colon, pancreas and the liver. The 5.1-month (16.4 vs. 11.3) improvement in PFS identified in patients receiving everolimus did not reach statistical significance by central radiology review. The P value was 0.026, which narrowly

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ERBITUX Increased Overall Survival in Both: Squamous Cell Carcinoma of the Head and Neck (SCCHN) in Combination With RT in Locoregionally Advanced Disease

EGFR-Expressing Metastatic Colorectal Cancer (mCRC) after Irinotecan and Oxaliplatin Failure as a Single Agent

100 Best supportive care plus everolimus

Patients, %

Best supportive care plus placebo

60 40 20 6.9

6 0

Stomatitis

Anemia

Hyperglycemia

Figure 1. Most common drug-related grade 3/4 events in RADIANT-3 trial. RADIANT Trials Neuroendocrine tumors (NETs) grow slowly and are rare; pNETs are different from pancreatic adenocarcinoma, which accounts for about 95% of all pancreatic cancers. Although the FDA has approved medications for symptom control of NETs, no drug has been approved for oncologic control. In the RADIANT-3 trial, 410 patients in 18 countries with advanced low- or intermediate-grade pNETS were randomized to everolimus (10 mg per day) plus BSC or placebo plus BSC. At progression, which was determined by RECIST (Response Evaluation Criteria In Solid Tumors), patients were unblinded and could cross over to the everolimus arm from the placebo arm. The median PFS was 4.6 months in the control arm and 11 months in the everolimus arm (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.27-0.45;

ERBITUX Indications Head and Neck Cancer ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck

Metastatic Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX EGFR=epidermal growth factor receptor; RT=radiation therapy.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

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Pharmacy Practice News • December 2010

In Focus 100

RADIANT missed the prespecified boundary of 0.0246 that adjusted for two interim analyses. Still, the lead investigator, Marianne Pavel, MD, from Charite University in Berlin, said the study results were clinically meaningful. Currently, there is no approved drug for the oncologic control of carcinoid tumors.

Go Slow or Attack Mode? Primarily, there are two schools of thought when it comes to treating NETs.

Patients, %

continued from page H1

Best supportive care plus everolimus

Best supportive care plus placebo 64

31 23

0 Stomatitis

Rash

Diarrhea

Fatigue

Infections

Figure 2. Most common drug-related adverse events in RADIANT-3 trial.

One advocates for an initial “watch-andwait” approach to the slow-growing tumors that aims to individualize care and treat people only when needed. The other advocates for aggressive treatment at diagnosis. Oncologists’ reactions to the RADIANT trials seem to be based on which school they belong to. Run Yu, MD, PhD, co-director of the Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, Los Angeles, belongs to the aggressive-treatment camp. He said that some doctors already use everolimus off-label for NETs and thinks that most doctors will probably

ERBITUX Signiﬁcantly Increased SCCHN

in Combination With RT in Locoregionally Advanced Disease Survival in Combination With RT (N=424)*1,2 ERBITUX (cetuximab) + RT (n=211)

Median overall survival 49.0 months

RT alone (n=213)

29.3 months

45%

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year overall survival rate 55%

19.7

month improvement

P=0.05 RT=radiation therapy; HR=hazard ratio; CI=conﬁdence interval. multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information for SCCHN ■ The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

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Pharmacy Practice News • December 2010

In Focus try everolimus for pNETS based on RADIANT-3. “The results are impressive. The design is appropriate for real-world experience,” Dr. Yu said. “The bottom line is that we can probably use everolimus in advanced pancreatic neuroendocrine tumors and may try it for carcinoid in a subgroup of patients and expect a meaningful prolongation of progression-free survival.” According to Dr. Yu, the aggressive treatment approach comprises tumor resection, locoregional treatment of liver metastases, systemic therapy with somatostatin analogs and prevention and man-

‘The real question is, how will this drug regimen affect overall survival? Because as these studies show, it will definitely cause some toxicity, which raises quality-of-life issues.’ —Cindy O’Bryant, PharmD, BCOP agement of symptoms. For patients with unresectable tumors, treatment options include interferon-α, low-toxicity chemotherapy and targeted therapy. “The natural history of neuroendocrine tumors is that they always grow and can cause problems,” Dr. Yu said. “Unless in a select group of patients such as those

with genetic syndromes, comorbidities, contraindications to treatment, patient refusal, etc., the aggressive approach should be taken.” Leonard Saltz, MD, professor of medicine at Memorial Sloan-Kettering Cancer Center, in New York City, belongs to the traditionalist “watch-and-wait” school.

Overall Survival in Both: EGFR-Expressing mCRC

after Irinotecan and Oxaliplatin Failure as a Single Agent Median Overall Survival, All Patients (N=572)†1 6.14 months ERBITUX + BSC (n=287)

4.57 months BSC alone (n=285)

34%

improvement

HR: 0.77; 95% CI: 0.64-0.92; P=0.0046

BSC=best supportive care. CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome measure of the trial was overall survival.1

† NCIC

■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1

ERBITUX Safety Information for EGFR-Expressing mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/ desquamation (12%), and other-gastrointestinal (10%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

“I have many patients who I have followed for many years without the need to intervene,” said Dr. Saltz, who sees a large number of patients with NETs in his practice. “If a person is going to do well for years without therapy, why expose them to the risk and toxicity [of treatment] until they really need it and clearly have the potential to benefit from it?” Dr. Saltz said more information is needed about the chronicity, or lack thereof, of the toxicities. “Grade 1 or 2 stomatitis, rash, diarrhea or fatigue would be trivial if they lasted for a few days, but quite

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Hem/Onc Pharmacy

Pharmacy Practice News • December 2010

In Focus

RADIANT continued from page H3

problematic if they last for many weeks or months,” he said. “Most people would rather have one day of a grade 4 toxicity than a month of grade 2.” He also argued that PFS should more accurately be called progression-free interval, since it measures the amount of time from when a treatment starts until it is no longer working, and doesn’t measure survival. “In a tumor for which survival is measured in many years, how likely is it that a six- to eight-month

improvement in progression-free interval is going to translate into a longer survival? How likely is it that it matters if we do the treatment now, or several years from now, when—and if—the patient is symptomatic?” Dr. Saltz asked. “We do not have evidence that these prolongations of PFS extend survival, and I would not necessarily make that assumption given the nature of these tumors.”

Pharmacist’s Perspective “Having everolimus on board does give us another option for these patients that we just didn’t have before,” said

Cindy O’Bryant, PharmD, BCOP, associate professor, Department of Clinical Pharmacy, University of Colorado School of Pharmacy, Aurora. “For years, we’ve been limited to surgery, other nondrug modalities or octreotide to manage symptoms in these patients, or we’ve had to rely on other chemotherapy agents that don’t really have a lot of strong evidence to support them.” But Dr. O’Bryant echoed Dr. Saltz’s concern about the indolent nature of NETs. “A majority of these patients can live with the disease for a very long time—often up to 15 years—with

minimal or no treatment,” she said. “So the real question is, how will this drug regimen affect overall survival? Because as these studies show, it will definitely lead to increased toxicity, which raises quality-of-life issues.” Thus, “we may want to reserve this therapy for patients with the severest disease and poorest survival. Yet as the RADIANT-2 trial demonstrated, the drug response in patients with more aggressive disease didn’t quite reach statistical significance.” Thus, “the option of watchful waiting still may be viable.” —Kate O’Rourke

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 ( 0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

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Pharmacy Practice News • December 2010

In Focus

T-DM1 Makes Big Splash at European Cancer Meeting Milan—A new type of drug that combines trastuzumab and chemotherapy, called trastuzumab-DM1 (T-DM1, ImmunoGen/Roche), may prove to be a “super Herceptin,” if preliminary results from a Phase II trial are any indication of the drug’s potential. The results showed the drug produces slightly higher response rates in patients with HER2positive metastatic breast cancer than does trastuzumab with docetaxel treatment, but with significantly fewer side

effects. The study was pregreater adverse events (AEs) sented at the European Society in the T-DM1 arm which is for Medical Oncology (ESMO) half [of ] what is seen in the Congress (abstract LBA3) held more traditional arm,” said in October. Edith Perez, MD, deputy “T-DM1 appears to have a director of Mayo Clinic Canfavorable overall safety profile cer Center, Mayo Clinic, in compared to the older, more Scan for abstract. Jacksonville, Fla. Dr. Perez, traditional trastuzumab [and] Instructions, page 3 the study’s principal investidocetaxel regimen as first-line therapy gator, said data on the primary trial end for HER2-positive metastatic breast point, progression-free survival (PFS), cancer, with an incidence of grade 3 or were not yet mature.

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2010, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ, 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US10AB08604

10/10

T-DM1 is an antibody drug conjugate that combines the biological HER2positive targeted properties of trastuzumab (Herceptin, Genentech) with a targeted delivery of a highly potent, antimicrotubule derivative of maytansine called DM1. The new drug selectively delivers DM1 to HER2-positive tumor cells. The drug is then internalized within the cell, and because DM1 is delivered intracellularly, the chemotherapeutic

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Hem/Onc Pharmacy

Pharmacy Practice News • December 2010

In Focus

T-DM1 continued from page H5

agent does not damage healthy tissue. “From the standpoint of overall response, both T-DM1 and docetaxel [plus] trastuzumab appear to be remarkably similar: 48% response rate for T-DM1 and 41% response rate for docetaxel/trastuzumab,” said Eric P. Winer, MD, director of the Breast Oncology Center, Dana-Farber Cancer Institute, Boston, who critiqued the trial at the ESMO Congress. “The key difference relates to safety and tolera-

‘There was no incidence of grade 3/4 neutropenia with T-DM1 and there was a rate [any grade] of only 1.5% alopecia. These are side effects that are critically important to our patients.’ —Edith Perez, MD bility. T-DM1 is highly effective and has very limited toxicity from the standpoint of the patient. In my view, T-DM1 is an agent that we need to bring to patients, particularly in the refractory

setting, as soon as possible.” The study included 137 patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy for their disease. Patients were

ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

randomized in a 1:1 fashion to receive T-DM1 3.6 mg/kg IV every three weeks until disease progression or trastuzumab 6 mg/kg IV (8 mg/kg in cycle 1) plus docetaxel 75 or 100 mg/m2 IV on day 1 every three weeks. Patients in the traditional therapy arm were allowed to cross over to the T-DM1 arm at disease progression. Treatment was ongoing in 65.6% of the T-DM1 arm and 58.6% of the trastuzumab with docetaxel arm. Characteristics such as performance status were well balanced between arms, and 19.4% of the patients in the T-DM1 arm had received previous trastuzumab therapy compared with

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 Chills1 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 3 43 2 21 1 Alanine Transaminase, high 3 38 1 24 1 Aspartate Transaminase, high 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction. Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

Hem/Onc Pharmacy H7

Pharmacy Practice News • December 2010

In Focus 25.7% in the trastuzumab with docetaxel arm. Tumor assessments were conducted every nine weeks. At the ESMO Congress, investigators highlighted data on two of the secondary end points, overall response rate (ORR) and clinical benefit rate (CBR). At a median follow-up of six months, the ORR in patients receiving T-DM1 was 47.8% (95% confidence interval [CI], 35.4-60.3) compared with 41.4% (95% CI, 30.2-53.8) in patients receiving trastuzumab and docetaxel. The CBR was 55.2% (95% CI, 43.1-67.2) in the T-DM1 arm and 57.1% (95% CI, 44.6-68.9) in the traditional

therapy arm. Complete responses (4.5% vs. 1.4%) and partial responses (43.3% vs. 40%) were higher in the T-DM1 arm. T-DM1 was far better tolerated by patients. The three most common AEs of any grade in the T-DM1 arm were nausea (47.8% vs. 39.7%), fatigue (46.3% vs. 46.2%) and pyrexia (35.8% vs. 20.6%). The three

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2:

Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 Body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 3 Infusion Reactions 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 Mouth Dryness 11 0 4 0 Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. Adverse events were graded using the NCI CTC, V 2.0. 3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care 1 2

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. • Aseptic meningitis DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

most common AEs of any grade in the traditional therapy arm were alopecia (66.2% vs. 1.5%), neutropenia (57.4% vs. 7.5%) and diarrhea (45.6% vs. 10.4%). “There was no incidence of grade 3/4 neutropenia with T-DM1 and there was a rate [any grade] of only 1.5% alopecia,” Dr. Perez said. “These are side effects that are critically important to our patients.”

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

ER-B0001A-09-10

Rev September 2010

Grade 3 thrombocytopenia was more common in the T-DM1 arm (7.5% vs. 1.5%), as was hepatic dysfunction (13.4% vs. 1.5%), but neither arm had thrombocytopenia or hepatic dysfunction higher than grade 3. “T-DM1 was not associated with an increased risk of cardiac toxicity compared with trastuzumab and docetaxel,” Dr. Perez said. Investigators say final PFS data are expected in the second quarter of 2011. In July, Roche submitted a request for accelerated approval for T-DM1 based on the results of a single-arm Phase II study, which showed that T-DM1 shrank tumors in one-third of women with advanced HER2-positive breast cancer, who had received an average of seven previous medicines, including two HER2-targeted agents. The FDA issued a “Refuse to File” letter, saying the drug did not meet the standards for accelerated approval because all available treatment choices approved for metastatic breast cancer had not been exhausted in the study population. According to a press statement, Roche plans to submit data from the ongoing randomized Phase III EMILIA study to support a global regulatory submission in mid-2012. The EMILIA trial compares T-DM1 with lapatinib (Tykerb, GlaxoSmithKline) in combination with capecitabine, in patients with advanced HER2-positive breast cancer whose disease progressed after treatment. A Phase III first-line trial evaluating T-DM1 also has been initiated.

Hem/Onc Pharmacist’s Take Cindy O’Bryant, PharmD, BCOP, associate professor, Department of Clinical Pharmacy, University of Colorado School of Pharmacy, Aurora, said the T-DM1 study “is a well-designed, Phase II trial.” But as with all Phase II trials, “its primary outcome is to show effectiveness in a specific cancer type, rather than demonstrate superiority over any one treatment option.” Thus, until more data on PFS are obtained in this and subsequent trials, “I think we need to temper our enthusiasm just a bit” before aggressively pushing for approval of the drug. Still, “the preliminary results are promising; the intracellular delivery mode clearly succeeded in targeting areas of malignancy,” as opposed to the scattershot approach of systemic therapy, “and was likely responsible for the minimal side effects seen.” That superior side-effect profile is a major plus in these patients, Dr. O’Bryant noted. “They can typically be older and more heavily pretreated and have risk factors that make them vulnerable to high-grade neutropenia, with increased morbidity and mortality. If we can reduce that with this new regimen, that’s a major plus.” —Kate O’Rourke

Hem/Onc Pharmacy

Pharmacy Practice News • December 2010

In Focus

Warning Labels Added to GnRH Agonists

n late October, the FDA directed manufacturers of gonadotropinreleasing hormone (GnRH) agonists to add warnings to their labels advising of an increased risk for diabetes and cardiovascular disease (heart attack, sudden cardiac death, stroke) in men being treated for prostate cancer. Many oncologists say the labels are needed and applaud the decision. “Cardiovascular disease remains a big threat in these men,” said Michael Carducci, MD, an oncologist at Johns Hopkins Kimmel Cancer Center, Baltimore. “So selecting the right patients to use hormonal therapy may come of this recommendation.” Although the risk for diabetes and cardiovascular disease appears to be low, the FDA has advised physicians to carefully weigh the risks and benefits of using GnRH agonists in patients with prostate cancer. In its Oct. 20, 2010 safety announcement, the FDA also recommended that such patients should undergo periodic monitoring of blood glucose and/or glycosylated hemoglobin levels and for signs and symptoms suggestive of cardiovascular disease.

Everolimus Gets New Indication

he FDA has approved everolimus (Afinitor, Novartis) for patients with subependymal giant cell astrocytoma (SEGA) who are not candidates for curative surgical resection. SEGA is a benign brain tumor associated with tuberous sclerosis (TS). The accelerated approval of everolimus is based on an open-label, single-arm study. In the study, 28 patients with evidence of SEGA growth initially received everolimus orally at a dose of 3 mg/m2. As of March 8, 2010, the median duration of treatment was 24.4 months (range 4.7-37.3 months). The study showed that 32% of patients experienced a reduction of 50% or greater in the size of their largest SEGA at six months relative to baseline. None of the patients developed a new SEGA while receiving everolimus. The median age of patients in the study was 11 years (range, 3-34 years). As of March 8, 2010, the median duration of treatment was 24.4 months (range, 4.7-37.3 months). The most common adverse reactions observed (incidence ≥30%) in the trial were mouth sores, upper respiratory tract infections, sinusitis, middle ear infections and fever. Common laboratory test abnormalities included liver enzyme elevations,

The wave of evidence that persuaded the FDA to add the labels has been a long time building. In February 2010, a joint advisory issued by the American Cancer Society, the American Heart Association and the American Urological Association warned that “there may be a relationship” between cardiovascular risk and androgen-deprivation therapy (ADT) for prostate cancer. In May, the FDA announced it was conducting a preliminary and ongoing analysis of GnRH agonists after several recent observational studies and one randomized clinical trial reported “small increased risk for diabetes and/ or cardiovascular disease” in prostate patients undergoing ADT. In its October announcement, the agency concluded “most of the studies reviewed by FDA reported small, but statistically significant increased risks for diabetes and/or cardiovascular events in patients receiving GnRH agonists.” GnRH agonists are approved for palliative treatment of advanced prostate cancer as well as for management of endometriosis. Brand-name GnRH agonists include Lupron (Abbott Laboratories), Zoladex (AstraZeneca), Trel-

star (Watson Pharma), Viadur (Alza Corp.), Eligard (Sanofi-aventis), Vantas (Endo Pharmaceuticals) and Synarel (Pfizer). The benefits of GnRH agonists use for nonmetastatic prostate cancer have not been established. Marc Earl, PharmD, oncology pharmacy residency director at the Cleveland Clinic, believes that the additional warning is appropriate. “Although the risks vary by study, I believe there is an association between these drugs and an increased risk of diabetes and cardiovascular disease. The true risk is patient-dependent,” Dr. Earl said. While most physicians inform patients about these sorts of risks, mandating that the warning be added to labeleing increases the likelihood of patients being exposed to the infomation, he added. “I believe we may see similar announcements from the FDA concerning other drug categories as they continue to focus on patient safety.” The new FDA-mandated warnings “will hopefully help minimize the indiscriminant use of ADT,” said Philip W. Kantoff, MD, director, Lank Center for Genitourinary Oncology, DanaFarber Cancer Institute, Boston. “The

high blood cholesterol and triglycerides (MMR) by 12 months in newly diagnosed (hyperlipidemia), high blood sugar, and CML-CP patients. The CCyR rate was decreases in white blood cells, red blood 77% for 259 patients randomized to dasatinib compared with 66% for cells and platelets. IN BRIEF 260 patients randomized to A Phase III study is under imatinib (Gleevec, Novartis) way that compares everolimus with placebo to explore the clini- (P=0.0067), after 12 months of followcal benefits of everolimus for the treat- up. The MMR rates on dasatinib and ment of patients with SEGA associated imatinib were 46% and 28%, respectively with TS. Prior to the approval of this (P<0.0001). The most frequently reported serious drug, brain surgery was the only treatment option for patients with growing adverse reactions included pleural effusion (2%), hemorrhage (2%), congestive SEGAs. heart failure (1%) and pyrexia (1%).

Dasatinib Gets First-line Indication For CML-CP

he FDA has approved dasatinib (Sprycel, Bristol-Myers Squibb) 100 mg once daily for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP). Approval of dasatinib was based on the DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CP-CML Patients) study, which showed dasatinib demonstrated superior efficacy in terms of complete cytogenetic response (CCyR) rate and major molecular response

Eribulin Approved For MBC

he FDA has approved eribulin mesylate (Halaven, Eisai) for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane for early or advanced breast cancer. The approval is based on results from the pivotal Phase III clinical study EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin). This trial revealed that median overall survival was 13.12 months

risks are relatively small but warrant consideration in the clinical setting.” The FDA warning “will make practitioners more conscious of comorbidities when treatments are considered,” he added. Dr. Kantoff and his colleagues have published studies analyzing the relationship between hormonal therapy for prostate cancer and cardiovascular events (J Clin Oncol 2007;25:2420-2425). Steven E. Vogl, MD, a community oncologist in Bronx, N.Y., believes that the warning won’t have much practical impact on oncologists, because many of the specialists “think that life with a detectable PSA [prostatespecific antigen] is still worth living, and so do not treat asymptomatic men with toxic agents that have major detriments on sexual function and bone density.” Urologists, on the other hand, “often think that life is not worth living unless the PSA is undetectable. The FDA warning may have considerable impact on their practices and administration of these agents. Indeed, I think it should, and I hope it does.” —Ted Agres

in patients who received eribulin and 10.65 months in the control arm (hazard ratio, 0.81; 95% confidence interval, 0.66-0.99; P=0.041). In the study, 508 women with heavily pretreated metastatic breast cancer received eribulin 1.4 mg/m2 two to five minutes IV bolus on days 1 and 8 of a 21-day cycle. Then 254 women received a treatment chosen by their physician, which was any single-agent cytotoxic, hormonal or biologic therapy, or supportive care only. No doctors chose biologic therapy or best supportive care alone; 96% of patients received chemotherapy and 4% received hormone therapy. Women already had received an average of four previous chemotherapy drugs, two of which had to be an anthracycline and a taxane; 73% had also received capecitabine. Median age was 55 years, 16% had HER2-positive tumors and 20% were triple-negative. The most common side effects (incidence ≥ 25%) reported by patients receiving eribulin were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea and constipation. Grade 3/4 adverse events associated with eribulin were neutropenia (57%), febrile neutropenia (5%) and peripheral neuropathy (8%). —Kate O’Rourke

Pharmacy Practice News • December 2010

Clinical 23

Generic Drugs

FDA Eyes Adjusting Generic Bioequivalence Standards Agency feeling pressure from outside groups and its own advisory panel

n light of the continuing controversy surrounding the bioequivalence of generic drugs to their brand name counterparts, the FDA is considering tightening its approval criteria, especially for narrow therapeutic index (NTI), or critical dose, drugs. As part of the evaluation, the agency also is weighing the impact that any such changes might have on drug availability for patients. “We are currently in the process of assessing the need for and the anticipated impacts of changing our bioequivalence standards for narrow therapeutic index drugs,” FDA spokeswoman Crystal Rice told Pharmacy Practice News. “Regulatory policies can have a significant impact on the availability of safe and efficacious drugs. As such, setting and changing our policies must be done with great care.”

Ms. Rice said the agency was considering the recommendation. Additionally, several patient organizations and professional societies, including the American Academy of Neurology, oppose generic substitution of anticonvulsant drugs for epilepsy without the attending physician’s approval, citing instances of breakthrough seizures and increased seizure frequency in patients who switched to generic AEDs (Neurology 2008;71:525-530).

Studying ‘Switchability’ Although neither Dr. Woodcock nor Ms. Rice indicated when any decision about changes in bioequivalence standards might be announced, it is unlikely to be anytime soon. In October, the FDA awarded a two-year, $1.1-million contract to the University of Maryland’s

name cardiovascular drugs (JAMA 2008;300:2514-2526) and AEDs (Drugs 2010;70:605-621) were not more effective than generic drugs with respect to clinical outcomes. But, he said in an interview, “if there is good evidence … that current bioequivalency standards may be leading to unsafe differences between generic and brand-name drugs in specific drug classes, like certain critical dose drugs, then certainly a re-examination of bioequivalency standards is appropriate.” The FDA’s decision to review NTI drug bioequivalence standards appears

lenged the findings at the time, the FDA consulted with Barbara M. Davit, PhD, JD, lead author and acting director of FDA’s Division of Bioequivalence II, Office of Generic Drugs, and had issued this statement to Pharmacy Practice News: “We would like to see data that show that the generics are not performing the way they should and then by data, we mean not anecdotes from random patients, but actual data that show that the generics are not performing the way they performed in the bioequivalent study that we have on file. If we see scientific evidence that there is a problem with a generic, we will take action.”

to signal a shift from its previous stance on this issue. Last year, CDER scientists published a retrospective analysis of generic and innovator bioequivalence measures from 2,070 single-dose clinical studies of orally administered generic drugs and concluded that the agency’s bioequivalence standards were satisfactory (Ann Pharmacother 2009;43:1583-1597; Pharmacy Practice News, December 2009, p. 25). In response to critics who chal-

There is a risk of not knowing whether generics are adequate—unrecognized failure of drugs in some patients, said Michel J. Berg, MD, associate professor of neurology and medical director of the Strong Epilepsy Center at the University of Rochester in New York. “If the appropriate studies are not done, it may never be known, and some people may suffer from the consequences of our ignorance.” —Ted Agres

A Shift in Viewpoint

Single-dose generic bioequivalence studies in healthy individuals are ‘not a particularly good measure of how the product will perform if the person is taking it daily and over a long period of time.’

—James Cloyd, PharmD

Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research (CDER), said that the agency also was considering tightening generic drug standards “so there is less variability.” In October, Dr. Woodcock told the Generic Pharmaceutical Association that the FDA had received numerous anecdotal reports of quality problems with generic drugs, primarily from employees and company officials involved in manufacturing. “I’ve heard it enough times from enough people to believe that there are a few products that aren’t meeting quality standards,” Dr. Woodcock said. The bioequivalence issue has become particularly important for NTI drugs, where small changes in blood concentrations can result in adverse reactions and serious treatment failures. Many such reactions have been reported with generic antiepileptic drugs (AEDs) as well as drugs for certain cardiovascular conditions and organ transplant patients. In April, in an 11-to-2 vote, members of the FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology suggested that the agency’s confidence intervals for bioequivalence should be narrowed to a range of 90% to 111% from the current range of 80% to 125%, saying the current intervals were not sufficient for generic NTI drugs.

School of Pharmacy to conduct a clinical trial on the “switchability” of generic and brand name versions of the AEDs carbamazepine and levetiracetam. “The outcome of this study can help address the public concerns regarding the quality of generic antiepileptic drugs and improve regulatory practices of generic AEDs when necessary,” noted principal investigator James Polli, PhD, professor of pharmaceutical sciences at the University of Maryland, Baltimore. Such “real-world” studies are essential to determine the effectiveness of generic NTI drugs, said James Cloyd, PharmD, director of the Center for Orphan Drug Research at the University of Minnesota, Minneapolis-St. Paul. This is because generic NTI drugs usually are studied in healthy volunteers who often are given single doses over a short period of time, such as a two-week interval, Dr. Cloyd told Pharmacy Practice News. “It’s not a particularly good measure of how the product will perform if the person is taking it daily and over a long period of time,” he said. Aaron S. Kesselheim, MD, JD, MPH, instructor in medicine at Harvard Medical School and associate physician in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital, Boston, has conducted two studies showing that brand-

FDA’s Guidance on Generics

✪

For detailed information on the FDA’s policies

✪

and studies on generic drugs, scan this tag with your smart phone. For instructions, see page 3.

For individual product bioequivalence

recommendations database, scan this tag with your smart phone. For instructions, see page 3.

24 Clinical

Pharmacy Practice News • December 2010

Women’s Health

Closing the Knowledge Gap for Teratogenic Drugs Austin, Texas—Physicians were nearly twice as likely to document their discussions of teratogenic risks posed by heart and diabetes drugs with patients if they attended an educational session that included a pharmacist, researchers reported at the annual meeting of the American College of Clinical Pharmacy. The retrospective analysis (abstract 217E), conducted at a primary care center in Indianapolis, reviewed the medical records of 200 women, aged 15 to 45

years, who were taking at least one of three classes of drugs: angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARB) or a statin. The study examined how frequently physicians discussed and documented the risk of these drugs for birth defects, if subjects were to become pregnant. “We are seeing younger women who are developing diabetes and hypertension and hyperlipidemia,” said co-investigator Alison Walton, PharmD, BCPS, clinical

pharmacy specialist in ambulatory care at St. Vincent Health, in Indianapolis. “These medications are considered the standard of care. It may be appropriate to prescribe these for these women, but they need to have a clear understanding of the potential risk.” Prior to the lunchtime educational session for the physicians, 20% of the women with childbearing potential were counseled appropriately. A subsequent analysis of a second group of 131

Physician Reminders Also Key

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Dr. Wheeler, who teaches her pharmacy students to routinely counsel this patient population, said this study illustrates the need to remind physicians to do so, as well. “Plans can change, whether or not you are planning on having a child,” she said. “It’s something that a woman should be aware of.” In the St. Vincent study, the 200 women were most likely to be taking an ACE inhibitor (64.5%). Nearly half (44%) were prescribed a statin and 14.5% were on an ARB. The research project, conducted at St. Vincent Joshua Max Simon Primary Care Center, was launched after a couple of women became pregnant while on the drugs, without any knowledge of the risks to the fetus, Dr. Walton said. The educational session focused on the teratogenic risks of the three classes of drugs, as well as the importance of documenting the discussions with the patients. A particular concern, Dr. Walton said, was the limited physician counseling about risks of statins, documented in only 4.5% of cases before the intervention, compared with 27.7% for an ARB or ACE inhibitor (P=0.002). It became clear that several of the residents did not realize that a statin could pose a teratogenic risk, she said. Subsequently, statin users were about as likely to hear about potential birth defects, with 38.1% receiving the counseling, as nearly 41% of those prescribed either an ACE or an ARB (P=0.484). In both data sets, the physicians perceived that they were documenting the discussions far more frequently than they actually were, according to a secondary finding of the study. After the educational session, nearly 74% perceived they had documented appropriately, and 37.4% actually had done so. The physicians knew in advance which of their patients were taking the drugs, Dr. Walton said. She added that her group plans to continue the same retrospective review every quarter, at least until the end of 2010, to see if they can build on the improvement in counseling rate.

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women found that 37.4% were similarly counseled (P=0.001). The counseling may occur more frequently but simply not be documented, said Kathryn Wheeler, PharmD, BCPS, assistant clinical professor in the School of Pharmacy at the University of Connecticut, in Storrs, and a medication safety pharmacist at William Backus Hospital, in Norwich. Still, the potential teratogenic risk was not disclosed even half of the time, after the educational intervention, she pointed out.

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—Charlotte Huff

Pharmacy Practice News • December 2010

Clinical 25

Critical Care

In Medical Emergencies, Drug Errors Common Austin, Texas—Medication errors are known to frequently occur amid the high-intensity swirl of a medical code, at least based on empirical observations from medical emergency team members. Now, the extent of the problem has been quantified via a direct-obervation study by critical-care pharmacists. In the study, 296 medication errors were identified by pharmacists in the course of delivering 186 doses, according to researchers at the University of Pittsburgh Medical Center (UPMC). The project, conducted at UPMC Presbyterian, tracked 36 unique medications given to 50 patients treated by the medical emergency team between March 2009 and February 2010. Two-thirds of the medication errors, 196 of the total, involved failures in aseptic technique, said Sandra Kane-Gill, PharmD, MS, FCCM, whose research team presented the results at the annual meeting of the American College of Clinical Pharmacy. Although not ideal, those types of errors are not considered to be significant in a crisis situation, she noted. “Patients need the drug quickly, so if that step had been left out, we consider those minor errors,” said Dr. Kane-Gill, a critical care medication safety officer in the Department of Pharmacy at UPMC. Of the remaining 100 errors, 46% were classified as a prescribing error, 28% as an administration error, 14% as mislabeling and 10% related to drug preparation. Of the 100 errors, 14% had the potential to cause harm, Dr. Kane-Gill said. A breakdown in communication was one common thread, such as a physician not fully specifying the medication order. “If a physician states a drug, but doesn’t state the dose, that leaves some ambiguity for the nurse to interpret.” These types of error surveillance projects are difficult to conduct, in part because of the inherent nature of a medical crisis, said Greene Shepherd, PharmD, professor in the College of Pharmacy at the University of Georgia, in Augusta. “When emergencies happen, people are moving very quickly and it’s hard to do research on any emergency event that’s a true emergency.” Dr. Shepherd authored a previous study, published in the American Journal of Health-System Pharmacy (2009;66:6569), which showed that only 71% of patients admitted to the emergency department were interviewed and evaluated for complete medication histories. The Pittsburgh study, because it was confined to one location, might not have similar results at another institution, he said. But he was not surprised that multiple medication errors were caught, as they are frequently associated. “This study shows that during

these highly critical points, there are a lot of errors being made,” Dr. Shepherd said. “Fortunately, the majority only caused minor discrepancies and no patient harm. But the potential is there for a [more serious error.]” For clinicians involved in a medical crisis, there is a fine line to walk, he added. “You’ve got somebody who is dying in front of you. If you don’t [administer] the drug, it could be fatal. If taking the time to check for errors is going to kill them,

I’d rather run the risk of the error.” The medications involved in the study were directly observed by a pharmacist, who was unable to be present at all codes and did not work the night shift, Dr. Kane-Gill said. In that sense, the study’s subjects were truly random. Three physicians then reviewed the medication errors and conducted a severity assessment, she said. In 14% of the 100 non-aseptic errors, at least two out of three physicians found that they could

potentially have caused harm. Along with steps to improve communication, the study also has spawned discussion about adding cases with a medication administration component to the code simulation training that nurses and doctors complete, Dr. Kane-Gill said. The study’s findings also illustrate the benefit of having a pharmacist participating in codes, which does not currently occur at UPMC Presbyterian, she noted. —Charlotte Huff

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26 Clinical

Pharmacy Practice News • December 2010

Pain Medicine

Hot Peppers Burn Out Postoperative Pain A

pplying capsaicin, the active component of hot chili peppers, into a wound postoperatively may provide longlasting pain relief, a new study suggests. The study showed that joint surgery patients who received instillations of capsaicin reported improved mobility and required less opioid analgesia for their pain than those given a placebo. “A good deal of the pain following surgery, particularly after the first day, can be prevented, potentially allowing the patients to participate more fully in their rehabilitation,” said Craig Hartrick, MD, director of anesthesiology research at Beaumont Hospital in Troy, Mich., who led the research (abstract A1703). After data from most of the study sites became unavailable when the drugmaker declared bankruptcy, Dr. Hartrick and his colleagues were left with results from their hospital’s 14 subjects who underwent total knee arthroplasty. Still, they found that seven patients randomized to receive capsaicin instillation into the knee joint just before wound closure required significantly less morphine during the first three days compared with seven patients receiving placebo (163 versus 270 mg; P=0.03). Patients on capsaicin also had significantly better average active range of motion in their knee joint 14 days after the surgery (99.3 vs. 83.7 degrees; P<0.01). A concern regarding capsaicin is the pain upon application. “Just like when you put hot peppers on your tongue, you initially get intense burning,” said Dr. Hartrick, whose group was scheduled to present the study findings at the 2010 annual meeting of the American Society of Anesthesiologists, in San Diego. “If you just took a raw surface and placed this into the wound, the pain would be very, very intense—excruciating. So you need to do something first.” All patients in the study had spinal anesthesia and femoral nerve block, which masked this pain from capsaicin’s initial activation phase. The compound subsequently causes the degeneration of C fibers, the nerves involved in the transmission of the slow, dull, long-lasting pain that follows surgery. Capsaicin spares the other nerves that are responsible for other sensation and motor function. Before the C fibers can start firing again, they have to regenerate, which can take several weeks. “The beauty is that you don’t actually need to feel this type of pain,” Dr. Hartrick said. “But if you just used a local anesthetic, all types of sensory fibers could be blocked, and you may not notice if something is going wrong, such as pushing yourself so hard in therapy that you could do damage.” In addition to obviating this possibil-

ity, capsaicin may also lower the risk for infection since a catheter is unnecessary. Side effects were limited to some warmth in the application area. “This continues to represent a compelling story,” said James Campbell, MD, professor of neurosurgery at Johns Hopkins University and chief executive officer of Vallinex, the Baltimore, Md.based company that took over developing the drug. Dr. Campbell said his company hopes to launch a pair of clini-

cal trials with capsaicin in the next few months for pain conditions.

Pain Pharmacist’s Perspective “There is much interest right now in exploring the pharmacologic activity at the receptors where capsaicin works,” said Lee Kral, PharmD, BCPS, The University of Iowa Hospitals and Clinics Center for Pain Medicine, in Iowa City. “With regard to applying capsaicin to exposed tissue, there are inherent risks,

such as increasing the acute inflammatory response. Local anesthetics are used when we apply capsaicin topically to intact skin, so using a regional block or epidural is essential.” As for applying the results clinically, “more studies are definitely required,” Dr. Kral said. “The data presented aren’t robust enough to make any conclusions, but it is definitely thought-provoking.” —Lynn Peeples

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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.

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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.

Pharmacy Practice News • December 2010

Clinical 27

Pain Medicine

FDA Approves Injectable Drug To Treat Opioid-Dependent Patients T

he FDA has approved Vivitrol to treat and prevent relapse after patients with opioid dependence have undergone detoxification treatment. Vivitrol, manufactured by Alkermes, Inc., is an extended-release formulation of naltrexone administered by intramuscular injection (IM) once per month. Naltrexone works by blocking opioid receptors in the brain, thus halting the effects of drugs like morphine, heroin and other opioids. In 2006, naltrexone was approved to treat alcohol dependence. The safety and efficacy of Vivitrol were

studied for six months, in a the placebo group. trial comparing Vivitrol treatPatients must not have any ment to placebo treatment in opioids in their bodies when patients who had completed they start taking Vivitrol; if they detoxification and who were do, they may experience withno longer physically dependrawal symptoms. In addition, dent on opioids. Patients patients may be more sensitive treated with Vivitrol were more to opioids while taking Vivitrol likely to stay in treatment and at the time of their next schedScan for FDA to refrain from using illicit approval documents. uled dose. If they miss a dose, drugs. Of the Vivitrol-treated or if treatment with Vivitrol has Instructions, p. 3 patients, 36% were able to stay ended, patients can accidenin treatment for the full six months withtally overdose if they restart opioid use. out using drugs, compared with 23% of Side effects of Vivitrol included nausea,

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.

tiredness, headache, dizziness, vomiting, decreased appetite, painful joints and muscle cramps. Other serious side effects were reactions at the injection site, which can be severe and may require surgical intervention; liver damage; allergic reactions; pneumonia; depressed mood; and suicidal thoughts and suicidal behavior. Vivitrol should be administered only by a physician as an IM injection, using special needles that are provided with the product. Vivitrol should not be injected using any other needle. The recommended dosing regimen is once per month.

28 Clinical

Pharmacy Practice News • October 2010

Infectious Disease

Antibiotics Stave Off Post-Colectomy Infections, Ileus Study shows no increase in Clostridium difficile colitis when oral medications administered

ll patients who undergo an elective colectomy should receive oral antibiotics as part of their bowel preparation, according to a team of Michigan surgeons. At the 2010 annual meeting of the American Surgical Association, the researchers presented findings showing that oral antibiotics significantly reduced both surgical site infections and

‘At this time, these data have significantly changed practice in our state.’

—Michael Englesbe, MD

prolonged ileus, and did not increase the risk for Clostridium difficile colitis in 34 hospitals across the state.

Yet about half of surgeons studied failed to include oral antibiotics as part of the bowel preparation routine for

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.

patients—a trend that investigators say is now changing. “At this time, these data have significantly changed practice in our state,” said lead author Michael Englesbe, MD, assistant professor of surgery in the Transplant Surgery Division of the University of Michigan Health System in Ann Arbor. The investigators conducted an observational study of all patients who underwent elective colectomy between August 2007 and April 2009 at 34 community hospitals in Michigan. All of the hospitals participated in the Michigan Surgical Quality Collaborative Colectomy Best Practices Study, an insurance-funded initiative that helps hospitals analyze and understand their surgical outcomes. It is the only statewide program of its kind in the country and considered a leading surgical quality initiative. Using propensity matching to analyze 740 cases, the investigators found that patients receiving oral antibiotics were significantly less likely to develop any kind of surgical site infection (4.5% vs. 11.8%; P=0.0001), an organ space infection (1.8% vs. 4.2%; P=0.044) or a superficial surgical site infection (2.6% vs. 7.6%; P=0.001), than patients who did not take oral antibiotics. In addition, patients receiving bowel preparation with oral antibiotics were less likely to have prolonged ileus (3.9% vs. 8.6%; P=0.011). The incidence of C. difficile colitis was similar between the groups (1.3% vs. 1.8%; P=0.58), alleviating fears that oral antibiotics may increase a patient’s risk for bacterial infection. However, other experts said that although the investigators’ conclusions may be correct, the study failed to account for important variables. The researchers did not control for systemic antibiotics, which may have an additive effect when combined with oral antibiotics. “You can’t make any statements about infection rates without taking into account systemic antibiotics. They left out a keystone piece of this question,” said Hiram Polk, MD, of the University of Louisville School of Medicine, in Kentucky, and a well-known authority in surgical wound infections, based in part on his landmark research into the use of perioperative antibiotics. Despite this, Dr. Englesbe said that the study findings were strong because the data reflect practices throughout numerous academic and communitybased hospitals. “Thus, the data are rooted in the real world,” he said. As a result of the findings, the

Pharmacy Practice News • October 2010

Clinical 29

Infectious Disease Michigan Surgical Quality Collaboration created a new “best practices” bundle for elective colectomy. It requires that all patients undergo a chlorhexidine skin preparation, weight-based preoperative IV antibiotic dosing, IV antibiotic redosing for all cases longer than three hours and mechanical bowel preparation with oral, nonabsorbable antibiotics. Just over one-third of patients studied—36.4%—received both mechanical bowel preparation and oral antibiotics. Almost half (49.3%) had mechanical bowel preparation alone; the preferred method was sodium biphosphate and sodium phosphate enema, accounting for 40%. The remaining 11.3% (n=233) had no bowel preparation. Several studies since the late 1990s have suggested that mechanical bowel preparation is not necessary for elective colorectal surgery (Arch Surg 2005;140:285288; Lancet 2007;370:2112-2117). Dr. Englesbe said he was surprised that more surgeons have stopped including oral antibiotics with bowel preparation than surgeons who had given up bowel preparation entirely. Nearly three-fourths of surgeons who gave patients oral antibiotics preferred to use a combination of neomycin and erythromycin, the study showed. “The Michigan Surgical Quality Collaboration is all about finding out what actually works at the bedside, and distributing that information to participating hospitals,” said senior author Darrell A. Campbell Jr., MD, professor of surgery and chief of clinical affairs at the University of Michigan. “Our finding about the importance of oral antibiotics as part of the standard bowel preparation is a great example of this process.”

likely lead to more resistance. That could be problematic, he noted, in

patients with community-acquired bacterial pneumonia. Dr. Rapp cited, as

an example, a poster presentation given at the ICAAC annual meeting in Boston in September. In the study, isolates of S. pneumoniae susceptible to the three macrolide antibiotics fell from 82.2% of isolates in 1998 to 60.8% of isolates in 2009 (poster C2-720). “We must always remember that antimicrobial use, even when it benefits one group of patients, in most cases will lead to increased resistance,” Dr. Rapp stressed. “This must be taken into consideration whenever we decide to use antimicrobials.” —Christina Frangou

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The Rapp on Study Results “Reducing the incidence of postoperative infections following elective colectomy is clearly a worthy goal to achieve,” said Robert P. Rapp, PharmD, FCCP, professor of pharmacy and surgery emeritus, University of Kentucky Medical Center, in Lexington. “We all have to remember, however, that even though the two oral antibiotics used are designated as ‘non-absorbable,’ the authors were most likely using entericcoated, erythromycin base combined with oral neomycin. While erythromycin base is poorly absorbed, some of it is in fact absorbed and would thus reach systemic exposure.” Such exposure, Dr. Rapp added, raises “collateral damage issues” associated with antimicrobial use. He also cautioned that although macrolide antibiotics (e.g., erythromycin, clarithromycin and azithromycin) may benefit post-colectomy patients, increased use of the medications will

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30 Clinical

Pharmacy Practice News • December 2010

Infectious Disease

VANCOMYCIN

a benefit with the guideline-based dosing,” he said. “As you can see, it actually doesn’t lean in that direction.” Dr. Giuliano cautioned that his study only provides a retrospective snapshot. Another limitation of the research, which also was presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy meeting earlier this year, was that the analysis did not include MIC data because it wasn’t available for all of the patients, he said. Despite these limitations, he stressed that “vancomycin is an important enough medication that larger studies do need to be conducted.”

continued from page 1

‘Since we’ve had this migration from hospital- to communityacquired MRSA, I think the average clinician is still getting up to speed and may still think vancomycin is the best therapy.’ —Robert Adamson, PharmD els (abstract 136E). Of the patients who received a recommended dose—at least 15 mg/kg every 12 hours per the recent consensus guidelines—16% died in the hospital, compared with 13% whose treatment did not meet that threshold (P=0.47). Although the results, based on six years of data from three Texas hospitals, did not reach statistical significance, they do provide food for thought, in light of the recent consensus recommendations, Dr. Giuliano said. Given that the trough reading won’t be available until later, it would be helpful to know the most effective upfront dose relative to short-term mortality, he said. “What we would expect to see is

switched to the more appropriate antibiotic after their infection was identified as community-acquired.

Pursuing Dose Targets When it is determined that vancomycin is the most appropriate therapy, clinicians still may have questions about the most appropriate dosing to use. During his residency at Texas Tech University Health Sciences Center, Dr. Giuliano conducted a multicenter retrospective study in 337 patients hospitalized with MRSA bacteremia, evaluating mortality among those who received the minimum initial vancomycin dosing compared with those who fell below the recommended lev-

Frequency of Antibiotic, %

PiperacillinTazobactam

Vancomycin Cefazolin

Levofloxacin Clindamycin

AmpicillinTazobactam

Ceftriaxone

A Revised Approach In another ACCP presentation, critical care pharmacist Tina Denetclaw, PharmD, BCPS, described a revised vancomycin protocol she developed that involves delivering a divided initial loading dose of vancomycin, rather than a single dose. Dr. Denetclaw conducted a retrospective medical records review of 256 patients treated from November 2008 to January 2010 at Marin General Hospital in Greenbrae, Calif., and compared the first trough level—drawn prior to the third vancomycin dose—in patients on the revised protocol with that in patients receiving the single loading dose (abstract 197). Patients dosed with the revised protocol were 15 times more likely to have their first trough serum concentration fall within the target range compared with those getting the prior protocol, who didn’t receive the divided initial loading dose (P<0.001). “The new protocol helps us reliably hit those target troughs within 24 hours of the initial dosing,” Dr. Denetclaw said. “Our impression that it’s working really well for us and working really well for our patients. It appears to us that our patients are getting better faster.”

Treating Pediatric Burns 40 30 20 10

) ,3

Figure. Most common antibiotics used for all cSSSI patients, 2003-2009.

9 0 20

,8 =1 (n 0 7 20

)

37 )

) ,9 =1

(n 5 0 20

4 0 20

4) =1

=1 (n

=1 (n 0 3

,7 1

,7 29

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to figure that out and I think it may be changing with increasing MICs [minimum inhibitory concentrations].” Several of the research projects, including a retrospective analysis by Dr. Giuliano, stemmed from last year’s consensus review developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America and the Society of Infectious Diseases Pharmacists (Am J Health Syst Pharm 2009;66:82-98). Along with applying some of the dosing guidelines, the researchers at ACCP also had studied specific populations, such as pediatric burn patients. The use of vancomycin has been increasing over the past decade. From 2003 to 2009, the drug’s use as part of initial therapy—either in isolation or in combination with other antibiotics— increased from 8.8% to 50.2%, according to a retrospective analysis at Saint Barnabas Health Care System looking at patients with complex skin-related infections (abstract 142). “We knew there would be a spike, but we didn’t expect it to be of this magnitude,” said Robert Adamson, PharmD, corporate vice president of clinical pharmacy services at Saint Barnabas Health Care System in West Orange, N.J. The expanded use of vancomycin illustrates the increasing proliferation of methicillin-resistant Staphylococcus aureus (MRSA), Dr. Adamson said. But it also might indicate that some clinicians haven’t shifted their treatment approach, now that an increasing portion of the MRSA treated in hospitals is community-acquired and can be treated with other drugs, such as clindamycin. At Saint Barnabas, for example, five years ago, nearly three-fourths of MRSA cases were hospital-acquired, he said. Now, roughly a similar percentage of diagnosed cases is communityacquired. Thus, he was a bit surprised to see vancomycin usage up so substantially since 2003. “Since we’ve had this migration from hospital- to community-acquired MRSA, I think the average clinician is still getting up to speed and may still think vancomycin is the best therapy,” he said. One encouraging sign, however, is that clindamycin prescribing also is on the upswing, said Shilpa Amara, PharmD, another Saint Barnabas clinician who worked on the study. From 2003 to 2009, clindamycin use as part or all of the antibiotic treatment regimen increased from 5.8% to 14.8%. And because the analysis focused on antibiotics administered within the first 24 hours, Dr. Amara said, it might have been that additional patients were

Another group of researchers at ACCP turned their attention to the use of vancomycin in the treatment of children with burns, a population that is particularly difficult to treat, given their ability to rapidly metabolize the drug. Children without burns may require 60 to 80 mg/kg per day, roughly double the common daily dose for adults with relatively normal kidney function, noted presenter Daniel Healy, PharmD, FCCP, associate professor of pharmacy at the University of Cincinnati’s James L. Winkle College of Pharmacy, in Ohio. “When you add a burn on top of that, it drives up the numbers even higher,” he said. Dr. Healy and his colleagues evaluated initial trough levels in 87 pediatric burn patients treated at the Shriners

Pharmacy Practice News • December 2010

Clinical 31

Infectious Disease

Dispensing errors

28.4%

HIV DRUG ERRORS continued from page 1

who were hospitalized for at least 24 hours (abstract 160). Of those errors, 56% were prescribing errors, most frequently involving the wrong drug. Other errors included dispensing errors (28.4%) and administration errors (15.5%; see Figure). “What we wanted to do was not only understand what type of medication errors occur, but where they occur in the process and what the contributing factors are,” said Megan Winegardner, PharmD, one of the researchers and a medication safety coordinator at Henry Ford Hospital. “We thought we could use that information to identify system-based improvements to prevent future errors.” The hospitalization of HIV patients, when their antiretroviral regimen is assumed by the pharmacy, is a potentially vulnerable period with regard to medication errors. In a recent study involving 68 patients, 72% experienced at least one error in their initial HIV regimen. Slightly more than half of the time, the documented error was significant enough to potentially cause at

Hospitals for Children—Cincinnati (abstract 123). The average patient age was 6 years old; the mean initial vancomycin dose was 72 mg/kg. Based on the initial trough readings, 84% of the patients fell at or below 10 mg/L within the first two to four days; 49% fell at or below 5 mg/L. The mean trough was 6.7 mg/L; the range was 0.7-34.5 mg/L. “Those rather high doses resulted in very very low—some people would say subtherapeutic—concentrations,” Dr. Healy said. There was a significant linear correlation between initial total daily dose and trough concentration (P<0.0002). Some young burn patients may need 100 mg/kg per day or more to get them into the target range, said Dr. Healy, who added that the theory would have to be validated through a prospective study. He would like to pursue such a study, in the hopes of better quantifying the ideal starting dose, while still limiting the risk for nephrotoxicity. Otherwise, he said, “by the time you dial up the dose to get the concentrations you need to eradicate the infection, you might have added several days to your length of therapy and possibly to the patient’s hospital stay or intensive care unit stay.”

Assessing Close Monitoring Another strategy that has been used to improve vancomycin treatment is closer monitoring of therapy. However, closer ongoing monitoring of vancomycin dosing, albeit potentially beneficial,

Prescribing errors

56%

Administration errors

15.5%

Figure. Medication errors in hospitalized HIV patients. least moderate discomfort or clinical deterioration, according to the 2008 study published in The Annals of Pharmacotherapy (2008;42:491-497). Both Dr. Winegardner and Sonak Pastakia, PharmD, MPH, BCPS, who authored the Annals study, attribute the propensity for medication errors, at least to some extent, to the relative success of HIV treatment. “They are complex drug regimens,” Dr. Winegardner said. “They are unfamiliar to a lot of physicians who may not see HIV patients every day.” Dr. Pastakia, now an assistant professor in the Department of Pharmacy Practice at Purdue University, West Lafayette,

Ind., described the Henry Ford Hospital findings as consistent with his own study, given that a retrospective chart review likely won’t pick up all errors. (In his study, all antiretroviral drugs were reviewed by a pharmacist with HIV expertise on a daily basis.) “It’s an alarming number for a retrospective study, and further emphasizes the importance of reducing medication errors and focusing on HIV medication error reduction,” he said. “HIV medication errors are almost ubiquitous in hospital settings, and coming up with system-based solutions to address these problems is key to reducing them and essentially eliminating them in the future.”

Single Versus Combination Drugs Can Cause Confusion At Henry Ford Hospital, one frequent tripping point involved confusion between single-ingredient antiretrovirals and combination versions of the drugs, which many patients prefer because they are easier to take, Dr. Winegardner said. “At the time we did the study, we didn’t have the combina-

‘We have the ability [through a pharmacist-led vancomycin consult service] to make adjustments without calling the physician, which ultimately is safer for the patient, particularly on the weekend.’

— Jessica Clark, PharmD

isn’t a panacea either, according to a study that delved into the role of a pharmacist consult service. The project compared outcomes between patients managed using a pharmacy consult service, in which pharmacists have some dosing latitude for vancomycin and another antibiotics, and those receiving more traditional physician-

Scan for ASHP vancomycin consensus report. For instructions, see p. 3

managed dosing, said Jessica Clark, PharmD, a second-year resident at Methodist Dallas Medical Center in Texas. “It’s very time-consuming as a pharmacist to have the consult service,” she said. “On the other hand, these patients are followed more closely and we have the ability to make adjustments without calling the physician, which ultimate-

tion products at the hospital.” Thus, errors could and did occur when substitutions were made, she said. Beginning in spring 2010, several changes were made, including stocking of the combination drugs, Dr. Winegardner said. Other changes were designed to assist nurses in delivering the medications correctly. If two drugs were to be taken together, they were automatically listed that way in the medication administration record. Also, medications were automatically scheduled for mealtimes, if they were required to be taken with food. Dr. Winegardner acknowledged several limitations in the study, including the small number of people involved. Also, researchers did not know if any harm resulted from the errors, in part because HIV treatment failure can have multiple causes, she said. But, she said, “We think that these changes that we’ve implemented will be successful in preventing future errors.” Henry Ford researchers hope to conduct a follow-up analysis to validate that hypothesis. —Charlotte Huff

ly is safer for the patient, particularly on the weekend.” The retrospective analysis, which looked at 80 patients treated with vancomycin from August to December 2009, found that neither approach was particularly effective at helping patients reach the recommended initial trough levels (abstract 143). Overall, 29% of the 80 patients had levels that fell within the recommended goal range. “We were kind of alarmed that it was low,” Dr. Clark said. Of that group, 12 were pharmacist-dosed patients and eight were physician-dosed. She acknowledged that comparisons between the groups might be a bit muddied, given that it’s unknown whether pharmacists provided any input into the physiciandosing regimens. One possible explanation for the low percentage of patients reaching goal might involve the initial loading dose, Dr. Clark said. The Dallas hospital’s protocol includes an initial loading dose of 20 mg/kg, rather than the 25 to 30 mg/kg recommended by the consensus review, because of concerns about nephrotoxicity, she said. Since the study, education on vancomycin dosing has been conducted with the physician residents, as well as the pharmacists, she said. The next step is likely to discuss the results with the hospital’s pharmacy and therapeutics committee, to see if any vancomycin dosing adjustments should be made. —Charlotte Huff

32 Operations & Management

Pharmacy Practice News • December 2010

Special Report: PPMI Summit

FOCUS continued from page 1

on work-life balance as a key component of optimal practice models. And they could not agree on the importance of telepharmacy for providing pharmacy coverage in remote areas. Also to be determined: the degree to which the PPMI effort will succeed in accelerating the pace of practice change. After all, this is not the first summit aimed at ushering in a new era of patient-focused pharmacy care. Earlier efforts, such as the Hilton Head Conference in 1985, had some success, but wholesale change has been elusive. Henri R. Manasse Jr., PhD, ScD, American Society of Health-System Pharmacists’ executive vice president and chief executive officer, acknowledged the hard work that lies ahead. The PPMI Summit “is an important first step in our walk to the future, a unique opportunity to set a new direction for hospital and healthsystem pharmacy practice,” he said during the opening general session. “But it is only the first step. We all have a collective responsibility to do rigorous inquiry after this meeting and to keep doing the heavy lifting that will be required to effect fundamental, transformational change.” (For more of Dr. Manasse’s views on the PPMI Summit, see page 36.)

“My fear is that if we only deem some of these groups to be worthy of our medication management efforts, we are sending a very bad message to the patients who we exclude from that list,” said Judi Jacobi, PharmD, BCPS, FCCM, critical care pharmacy specialist at Methodist Hospital/Clarian Health, Indianapolis. “In some care settings, the groups who we exclude may very well be deserving of the highest-priority care,” noted Dr. Jacobi, who also is the president of the Society of Critical Care Medicine. Phil Johnson, MS, RPh, FASHP, pharmacy advocacy director, Moffitt Cancer

‘Deciding whether a patient is worthy of our drug therapy management services should not be based on where a patient sleeps.’

—Phil Johnson, MS, RPh, FASHP

Center and Research Institute, Tampa, Fla., agreed that the recommendation was fundamentally flawed. “Deciding whether a patient is worthy of our drug therapy management services should not be based on where a patient sleeps,” said Mr. Johnson, a voting PPMI attendee. A better approach? Developing a drug-therapy

acuity index that could be applied to all comers, so that no one patient group would be excluded. Summit participants eventually passed a new practice recommendation that included the concept of medication acuity indexes in hospitals with limited resources. (During the meeting, 80% of participants had to vote positively for

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Responsewith toleration!

PPMI Format Nearly 200 consensus recommendations are at the heart of the PPMI project, all with the stated goal of creating practice models “that are based on the effective use of pharmacists as direct patient care providers.” Before the Summit, 102 pharmacy stakeholders were surveyed and asked to vote on the recommendations. The respondents passed more than 70 of the initiatives, which included speeding the adoption of some pharmacy technologies, expanding the use of technicians, and tracking pharmacist interventions. Only those practice goals that failed to elicit at least a 77% favorable response rate in the pre-meeting survey were discussed and voted on during the PPMI Summit. One of the most contentious issues addressed during the meeting centered on the following recommendation: “Assuming limited availability of resources, pharmacist-provided drug therapy management should be prioritized for the following patient populations.” Several patient groups were specified, including those seen in oncology, the emergency department (ED), critical care, medical/surgical, the operating room and neonatal intensive care units. When the attendees began voting on which patients in those settings should receive pharmacist care, the whole premise behind the recommendation began to be challenged.

IMPORTANT SAFETY INFORMATION: Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Serious hypersensitivity reactions have been reported in patients receiving Venofer®. In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration. Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving IV iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose delivered. In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were taste disturbance (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). In an additional study of Venofer® with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events, whether or not related to Venofer® reported by 5% of Venofer® exposed patients are as follows: diarrhea (16.5%), edema (16.5%), nausea (13.2%), vomiting (12.1%), arthralgia (7.7%), back pain (7.7%), headache (7.7%), hypertension (7.7%), taste disturbance (7.7%), dizziness (6.6%), extremity pain (5.5%), and injection site burning (5.5%).

Leading anemia management.™

Pharmacy Practice News • December 2010

Operations & Management 33

Special Report: PPMI Summit

an initiative to be passed.) Mr. Johnson stressed that although such an index should reflect the amount of pharmacist services needed by each patient admitted, “everyone should be triaged.”

Michael Cohen, RPh, MS, ScD, president of The Institute for Safe Medication Practices, and an invited (nonvoting) observer at the PPMI Summit, applauded the new recommendation.

“Every patient who is admitted to your hospital needs to have their medications and lab values reviewed by a pharmacist,” Dr. Cohen told Pharmacy Practice News. “That was certainly how I practiced many years ago—every time a drug order was written, we’d look it over and make sure it was appropriate for the patient. Why should we not push for that now?” Besides, he stressed, “You can have fatal events due to allergies or interactions in patients who really aren’t all that sick. So if you ration pharmacist care based on extent of disease or area of care, you could miss a potentially lethal drug event.”

Over 9 million patients treated with 180 million units* 1

240

First-line IV iron for adult pre-dialysis CKD patients... In treatment of iron deficiency anemia • Raises hemoglobin levels and improves iron stores 2 • Effective with or without erythropoietin

With a demonstrated safety profile • Contains no dextran or modified dextran • No test dose required; no black box warning • Greater tolerability than oral iron with fewer gastrointestinal symptoms

For treatment of iron deficiency anemia in adult non-dialysis dependent-chronic kidney disease patients whether or not receiving an erythropoietin. Contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Serious hypersensitivity reactions have been reported in patients receiving Venofer ®.

Millions prescribed. Millions treated.

™

*100 mg vials and ampules worldwide from 1992 to February 2010.

Please see brief prescribing information and references on following pages. Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2010 American Regent, Inc. • Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com

Pharmacy Technicians Attendees agreed that adopting a more patient-focused mode of pharmacy requires a cadre of technicians who can take up the dispensing slack. But the best way to ensure that those technicians are credentialed and licensed was a hotly debated issue. After much discussion, Summit participants opted for advanced technician training, with licensure by state boards of pharmacy. Dr. Cohen said that he was very encouraged by this vote. “We’ve been advocating more stringent licensing procedures for

•

see FOCUS, page 34

34 Operations & Management

Pharmacy Practice News • December 2010

Special Report: PPMI Summit

FOCUS continued from page 33

years,” he said. “There has to be a level of accountability that can only be brought via licensure with certification exams, as well as beefed-up educational efforts, and not just on-the-job training.” Dr. Cohen added that he was not in favor of other groups, such as the Pharmacy Technician Certification Board (PTCB), handling the licensing process. “The PTCB or the various pharmacy organizations would no doubt create sound programs. But this has to

‘Sure, we sometimes all do a good job of measuring outcomes, but do the benefits and savings that accrue from our efforts get credited to pharmacy programs?’

be administered by the state boards; it needs to have the force of law.” Mr. Johnson agreed that a certification process with more muscle is needed. “You really can’t expect pharmacists, on a large scale, to leave the pharmacy department and start rounding with physicians and caring for patients if we don’t have a skilled and accountable technician workforce.” That focus on rounding resonated with Dr. Cohen. “We’re just not getting enough out of our pharmacists today,” he said. “They graduate with advanced doctor of pharmacy degrees; they’re

—Judi Jacobi, PharmD doing clinical rotations with physicians alongside medical students; and they’re learning to be accountable to the medical team and work collaboratively to improve patient safety. And then we put them in the basement pharmacy.” He acknowledged that many innovative health systems do a good job leveraging the clinical skills of their pharmacists.

Reference: 1. Data on file. American Regent, Inc., Shirley, NY. 2. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S, for the United States Iron Sucrose (Venofer®) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005;68:2846-2856.

(Table 2 continued)

Brief Summary (See Package Insert For Full Prescribing Information) Therapeutic Class: Hematinic CLINICAL INDICATIONS AND USAGE Venofer® (iron sucrose injection,USP) is indicated in the treatment of iron deficiency anemia in the following patients: • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin CONTRAINDICATIONS The use of Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. WARNINGS Hypersensitivity reactions have been reported with injectable iron products.See PRECAUTIONS and ADVERSE REACTIONS. PRECAUTIONS General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload.Patients receiving Venofer® require periodic monitoring of hematologic and hematinic parameters (hemoglobin,hematocrit,serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum iron values may be reliably obtained 48 hours after IV dosing.See DOSAGE AND ADMINISTRATION and OVERDOSAGE. Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving Venofer®. No life-threatening hypersensitivity reactions were observed in the clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening hypersensitivity reactions in patients receiving Venofer.See ADVERSE REACTIONS. Hypotension: Hypotension has been reported frequently in hemodialysis dependent chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose administered. Caution should be taken to administer Venofer® according to recommended guidelines. See DOSAGE AND ADMINISTRATION. Carcinogenesis,Mutagenesis,and Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer®. Venofer® was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Venofer® at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Venofer®. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response,this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Venofer® is excreted in milk of rats.It is not known whether this drug is excreted in human milk.Because many drugs are excreted in human milk,caution should be exercised when Venofer® is administered to a nursing woman. Pediatric Use: Safety and effectiveness of Venofer® in pediatric patients have not been established. In a country where Venofer® is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer®, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugs could be established. Geriatric Use:The five pivotal clinical trials did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients,but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Adverse Events observed in all treated populations The frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis dependent and 75 peritoneal dialysis dependent-CKD patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent-CKD patients for a total of 1,496 patients. In addition,over 2,000 patients treated with Venofer® have been reported in the medical literature. Treatment-emergent adverse events reported by 2% of treated patients with NDDCKD in the randomized clinical trials, whether or not related to Venofer® administration, are listed by indication in Table 2. Table 2. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Clinical Indication (Multidose Safety Population) NDD-CKD Oral Iron Adverse Events Venofer® (Preferred Term) (N=139) (N=139) % % Subjects with any adverse event 76.3 73.4 Ear and Labyrinth Disorders Ear Pain 2.2 0.7 Eye Disorders Conjunctivitis 0 0 Gastrointestinal Disorders Abdominal pain NOS* 1.4 2.9 Constipation 4.3 12.9 Diarrhea NOS 7.2 10.1 Dysgeusia 7.9 0 Nausea 8.6 12.2 Vomiting NOS 5.0 8.6 General Disorders and Administration Site Conditions Asthenia 0.7 2.2 Chest pain 1.4 0 Edema NOS 6.5 6.5 Fatigue 3.6 5.8 Feeling abnormal 0 0 Infusion site burning 3.6 0 Injection site extravasation 2.2 0 Injection site pain 2.2 0 Peripheral edema 7.2 5.0 Pyrexia 0.7 0.7 Infections and Infestations Catheter site infection 0 0 Nasopharyngitis 0.7 2.2 Peritoneal infection 0 0 Sinusitis NOS 0.7 0.7 Upper respiratory tract infection NOS 0.7 1.4 Urinary tract infection NOS 0.7 5.0 Injury, Poisoning and Procedural Complications Graft complication 1.4 0 Investigations Cardiac murmur NOS 2.2 2.2 Fecal occult blood positive 1.4 3.6 Metabolism and Nutrition Disorders Fluid overload 1.4 0.7 Gout 2.9 1.4 Hyperglycemia NOS 2.9 0 Hypoglycemia NOS 0.7 0.7 Musculoskeletal and Connective Tissue Disorders Arthralgia 1.4 2.2 Arthritis NOS 0 0

Treatment-emergent adverse events reported in 2% of patients by dose group are shown in Table 3. Table 3. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)

Adverse Events (Preferred Term) Subjects with any adverse event Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain NOS* Constipation Diarrhea NOS Dysgeusia Nausea Vomiting NOS General Disorders and Administration Site Conditions Asthenia Chest pain Edema NOS Fatigue Feeling abnormal Infusion site burning Injection site pain Peripheral edema Pyrexia Infections and Infestations Catheter site infection Nasopharyngitis Peritoneal infection Sinusitis NOS Upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications Graft complication Investigations Cardiac murmur NOS Fecal occult blood positive Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia NOS Hypoglycemia NOS Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp 0 Myalgia

NDD-CKD 200 mg 500 mg (N=109) (N=30) % % 75.2 80.0 0.9

6.7

1.8 3.7 6.4 9.2 9.2 5.5

0 6.7 10.0 3.3 6.7 3.3

0.9 0.9 7.3 4.6 0 3.7 2.8 5.5 0.9

0 3.3 3.3 0 0 3.3 0 13.3 0

0 0.9 0 0 0.9

0 0 0 3.3 0

1.8

2.8 1.8

0 0

1.8 1.8 3.7 0.9

0 6.7 0 0

0.9 1.8 2.8

3.3

3.3 3.3 6.7

(Table 3 continued)

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

Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Back pain Muscle cramp0.7 Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Hypoesthesia Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Dyspnea exacerbated Nasal congestion Pharyngitis Rhinitis allergic NOS Skin and Subcutaneous Tissue Disorders Pruritus Rash NOS Vascular Disorders Hypertension NOS Hypotension NOS *NOS=Not otherwise specified

2.2 3.6 4.3

0.7

3.6 0 0

6.5 2.9 0.7

1.4 0.7 0.7

2.2 3.6 2.2 1.4 0 0.7

0.7 0.7 0.7 2.2 0 2.2

2.2 1.4

4.3 2.2

6.5 2.2

4.3 0.7

Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Pharyngitis Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension NOS Hypotension NOS

NDD-CKD 200 mg 500 mg (N=109) (N=30) % % 4.6

3.3

5.5 3.7

10.0 0

0.9 1.8 0

6.7 10.0 0

0.9

6.7

6.4 0.9

6.7 6.7

*NOS=Not otherwise specified

Drug related adverse events reported by 2% of Venofer® (iron sucrose injection, USP) treated patients are shown by dose group in Table 4. Table 4. Most Common Adverse Events Related to Study Drug Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)

Adverse Events (Preferred Term) Subjects with any adverse event Gastrointestinal Disorders Diarrhea NOS* Dysgeusia Nausea General Disorders and Administration Site Conditions Infusion site burning Injection site pain Peripheral edema Nervous System Disorders Dizziness Headache Vascular Disorders Hypotension NOS

200 mg (N=109) % 23.9

NDD-CKD

500 mg (N=30) % 20.0

0 7.3 2.8

0 3.3 0

3.7 2.8 1.8

0 0 6.7

2.8 2.8

6.7 0

6.7

*NOS=Not otherwise specified Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients In a multi-dose efficacy study in non-dialysis dependent-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were taste disturbance (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). In an additional study of Venofer® with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events, whether or not related to Venofer® reported by 5% of Venofer® exposed patients are as follows: diarrhea (16.5%), edema (16.5%), nausea (13.2%), vomiting (12.1%), arthralgia (7.7%), back pain (7.7%), headache (7.7%), hypertension (7.7%), taste disturbance (7.7%), dizziness (6.6%),extremity pain (5.5%),and injection site burning (5.5%). Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. In clinical studies,several patients experienced hypersensitivity reactions presenting with wheezing,dyspnea,hypotension,rashes,or pruritus. Serious episodes of hypotension occurred in 2 patients treated with Venofer® at a dose of 500 mg. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse,bronchospasm with dyspnea,or convulsion) associated with Venofer® administration. OVERDOSAGE Dosages of Venofer® (iron sucrose injection,USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis.Periodic monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation.Venofer® should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines [1]. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia. Symptoms associated with overdosage or infusing Venofer® too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution as recommended or at a slower rate may also alleviate symptoms. Preclinical Data: Single IV doses of Venofer® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation,hypoactivity,pale eyes,and bleeding in the gastrointestinal tract and lungs. DOSAGE AND ADMINISTRATION The dosage of Venofer® is expressed in terms of mg of elemental iron.Each mL contains 20 mg of elemental iron. Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron,administered over sequential sessions,to achieve a favorable hemoglobin response and to replenish iron stores (ferritin,TSAT). Administration:Venofer® must only be administered intravenously either by slow injection or by infusion. Recommended Adult Dosage: Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period.There is limited experience with administration of an infusion of 500 mg of Venofer®,diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated. (See CLINICAL TRIALS,Study D: Non-Dialysis DependentChronic Kidney Disease (NDD-CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients sections.) HOW SUPPLIED Venofer® is supplied in 5 mL and 10 mL single dose vials. Each 5 mL vial contains 100 mg elemental iron (20 mg/mL) and each 10 mL vial contains 200 mg elemental iron (20 mg/mL).Contains no preservatives.Store in original carton at 25°C (77°F).Excursions permitted to 15°-30°C (59°-86°F).[See the USP controlled room temperature]. Do not freeze. Sterile NDC-0517-2340-01 100 mg/5 mL Single Dose Vial Individually Boxed NDC-0517-2310-01 200 mg/10 mL Single Dose Vial Individually Boxed NDC-0517-2340-10 100 mg/5 mL Single Dose Vial Packages of 10 NDC-0517-2310-05 200 mg/10 mL Single Dose Vial Packages of 5 NDC-0517-2340-25 100 mg/5 mL Single Dose Vial Packages of 25 NDC-0517-2310-10 200 mg/10 mL Single Dose Vial Packages of 10 Rx Only REFERENCE: [1] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis. 37:S182-S238,(suppl 1) 2001.

BS2340 Rev.5/10 Venofer® is manufactured under license from Vifor (International) Inc.,Switzerland.

“But have we reached a critical mass with such practice models? Not even close. Having accountable, skilled technicians is a great first step to getting there.”

Plenary Talks Trigger Debate Voting on the PPMI goals was not the only focus of the Summit: Several presentations by plenary session speakers were designed to give background to those goals. And like the voting process, the talks sparked lively debate during the meeting. Laurence Wellikson, MD, chief executive officer of the Society of Hospital Medicine, was a case in point: During his presentation, he cited better medication reconciliation as one laudable goal for pharmacy practice model change. That stance led Rita Shane, PharmD, FASHP, director of pharmacy services at Cedars-Sinai Medical Center, in Los Angeles, and a voting PPMI attendee, to ask the following question: “Should we really be focusing on medication reconciliation, or should we be spending more time at the patient’s bedside, helping to ensure that the medications they’re taking are in fact appropriate for their care?” Dr. Wellikson agreed that such pharmacist oversight would be beneficial. “People in this country are way overmedicated,” he said. “And it’s not just a pharmacy problem; it’s a physician problem as well. So, is there a role for pharmacists as a patient ombudsman? Absolutely.” In such a case, he noted, pharmacists would not just be passively gathering medication lists; rather, they’d be taking a much broader role in patient care. Although this strategy is in place at many innovator hospitals, he said, many pharmacists who try to start these types of programs from scratch “[will] be swimming upstream.” What is Dr. Shane’s solution for reducing such resistance? “We may need to change the rules of engagement,” she said, adding that a “re-engineering” of regulatory requirements and reimbursement for chronic medications prescribed during inpatient admission “should at least be considered.” Dr. Shane also offered her overall take on the PPMI Summit. “I believe it is the beginning of a journey that needs continued focus and discussion,” she told Pharmacy Practice News. “It would be of value to identify the top three to five priorities for the practice model, from the perspective of both attendees and non-attendees. This would enable the profession to focus efforts on attaining

Pharmacy Practice News • December 2010

Operations & Management 35

Special Report: PPMI Summit emergent patients out of there” in order to maximize patient safety, he stressed, adding that “there is a clear role for pharmacists” to provide such triage care.

Who Is Doing the Measuring? None of these efforts to expand clinical pharmacy practice will succeed if pharmacy performance is not measured with the right metrics, noted Dr. Jacobi. “We’re still ending up in budgetary silos, which works against team initiatives,” she said. “Sure, we sometimes all do a good job of measuring outcomes, but do the benefits and

specific goals over the next three to five years.” Based on the discussions at the Summit, Dr. Shane added, “the first draft of these [top priorities] would likely include prescriptive authority, an acuity index for medication management, and advanced technician training. The background papers [that were part of the materials

‘Step up, have some [courage] and drive the show. Change happens to you, or by you. Don’t let others determine how you are measured.’ —Laurence Wellikson, MD provided to Summit attendees] would support these priorities and the papers should also be used as a framework for further dialogue. I would think ‘journal clubs’ to discuss each of the papers would be extremely valuable.”

ED Pharmacy Still Lagging One of those background papers cited the ED as an area where pharmacists have significantly improved patient care. This point was echoed by an attendee during the opening session. Many studies have shown, the attendee noted, that having a pharmacist present in the ED can save money and improve patient outcomes. Yet the majority of hospitals don’t have ED pharmacists on staff. Dr. Wellikson agreed that such an expanded clinical role should be part of any model for pharmacy practice change. “We’ve bastardized our EDs into walkin medical clinics; we have to get non-

savings that accrue from our efforts get credited to pharmacy programs?” Not nearly enough, she suggested. “We have to rewrite how pharmacy defines and defends its staffing and operational budgets so that we can get rewarded for our positive contributions to team care.” That point was echoed by Michael Taylor, MS, senior vice president of operations at Baylor Health Care System, in Dallas, whose plenary session talk addressed the role of the health care executive in pharmacy practice model reform. “Nothing says that pharmacists

have to stay in their own group,” Mr. Taylor stressed. “Get a seat at the table, so that you can make sure your department is being measured the right way.” Dr. Wellikson put it more bluntly: “Step up, have some [courage] and drive the show,” he challenged the audience. “Change happens to you, or by you. Don’t let others determine how you are measured.” —David Bronstein Next page: Henri R. Manasse Jr., on accelerating the change curve via the PPMI effort.

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36 Operations & Management

Pharmacy Practice News • December 2010

Exclusive Interview Q&A: Henri R. Manasse Jr., PhD, ScD

Can PPMI Accelerate the Change Curve? A

ccelerating the pace of change is at the core of the Pharmacy Practice Model Initiative (PPMI), a joint project of the American Society of HealthSystem Pharmacists and the ASHP Foundation. During last month’s Summit on the initiative, held in Irving, Texas, Pharmacy Practice News editor David Bronstein sat down with Henri R. Manasse Jr., PhD, ScD, ASHP’s executive vice president and chief executive officer, to discuss the factors that will likely determine whether the practice goals passed during the meeting (story, page 1) become implemented on a widespread basis.

PPN: There have been several initiatives over the years aimed at pushing the pharmacy practice model forward, with varying levels of success. What is the plan to ensure that the PPMI initiative gains traction and actually brings about fundamental change? HM: The first step is to prepare a comprehensive proceedings, which will be published in AJHP in the spring [2011] and posted on the ASHP Web site to gain national dissemination. But we won’t limit our efforts to spreading the word on the proceedings themselves; we’ll also be laser-focused on keeping the spirit alive that created all of these recommendations in the first place. There are a variety of strategies we’re going to be looking at, to accomplish that. We have state affiliates, for example, that can be a huge help. We would like to see all the state affiliates begin to program the PPMI findings into their regular meetings and board discussions. We’d also like to incorporate the findings into the residency conferences that are held all over the country, so that the next generation of pharmacy leaders is aware of this and gains knowledge of the most pressing practice issues. We’d also like to build the PPMI findings into our policy planning process because they raise some issues that ultimately might need to come to our House of Delegates so that they can become official policy statements. Then we need to develop an advocacy plan on a couple of these areas, because we’re either going to need changes in state regulations and laws—for example, to support more aggressive training and credentialing of pharmacy technicians—or maybe even need federal support for some of these activities. The bottom line is that there is going to be a very strong commitment from our board of directors to keep this effort alive. Our goal is not to simply have this be a report on a shelf, but rather, a guidebook that moves us to the desired future for our profession. PPN: The concept of change—and how to promote its acceptance—was

a major theme of the conference. In the background paper by Max Ray and Burnis Breland, the authors pointed out that change can come from either external forces—for example, Joint Commission requirements, state boards of pharmacy rules and so on— or via intrinsic efforts. How important to its success is the fact that the PPMI initiative was developed internally by pharmacists, for pharmacists? Will that accelerate the change curve? HM: If your aim is sustained and transformational change—and with PPMI, that is certainly our goal—then yes, it’s going to have to be largely intrinsic. A major focus of this conference has been to change the habits of the heart, if you will; to make a personal and organizational commitment to change in the best interests of the patient. We’re always going to have those external forces to contend with. Some of that is political, some of it is financial, and it can be beneficial. But until the profession embraces the necessity to get closer to the patient, and become relevant to the integral care of the patient overall, we’re not going to see fundamental change. PPN: During one of the plenary sessions, Steve Pickette, PharmD, of Providence Health & Services, pointed to a striking disconnect between how pharmacy measures its own performance versus the metrics used by the c-suite. He presented data showing that pharmacists’ clinical interventions were saving one of the hospitals in his Renton, Wash.-based health system more than $1 million annually. Yet at the time he first presented those data to the region’s chief financial officer, outside consultants were poring over the pharmacy budget and suggesting staff cuts as a cost-savings measure at that hospital. How much of a problem is this? HM: Well, it’s certainly not unique to Providence Health. We have to do a better job of convincing the c-suite that investing in safety and quality is expensive. In other high-performance industries—

nuclear power and aviation, for example—we spend a lot of money to ensure consistent, safe service. We’re prepared to do that because we don’t want to suffer the consequences of not doing it. In health care, we haven’t yet embraced that concept. Part of the problem may indeed be that pharmacy has not done a good job of getting a seat at the administrative table. That’s where we can show that making an investment in pharmacy can actually save health care dollars via improved outcomes—but only if you’re using rational metrics to judge us. Now, you also have situations where the bottom line of the hospital is very bad, and we see that all over the country—more than 50% of hospitals are operating in the red. In such an environment, you’ve got lots of pressures on limited resources, so at some institutions, culturally it becomes a major battle to ask for a larger investment in pharmacy. I’m not so naïve as to think that because we have come to these conclusions at this summit, that all of a sudden we’re going to enter a future that’s going to be rosy. It’s going to be a tough road, particularly in an economy that’s under immense pressure. PPN: Should the pharmacy profession push for more widespread adoption of chief pharmacy officer or similar positions, in order to get better representation? HM: CEOs are sensitive to how many people they want reporting to them. So I’m not sure a chief pharmacy officer is the right solution for every hospital. But somehow, the expertise of the pharmacist has to be at the executive decisionmaking level, because in terms of medication safety, there is a lot at stake for the institution, to say nothing about the patients who are using these medicines. That shouldn’t be surprising, given the fact that medications, biologics, vaccines and contrast media literally pervade the hospital. In many respects, you might say it’s a bit out of control. If we’re going to have an integrated approach to the safe use of all of these agents, and if we’re going to monitor our patients appropriately and achieve the kind of outcomes that we want in the most cost-effective manner, then we’re going to have to get better control of these agents’ use and oversight. That can’t happen if the pharmacy department at your hospital doesn’t have a strong leadership voice. What it really comes down to is accountability—a word we heard a lot during the PPMI Summit. Pharmacy is

now ready and willing to come to the table and proclaim, “we are accountable for our patients’ safety.” That is a major change that is beginning to permeate in the profession itself, as well as in the hospital and health-system environment.

‘Our goal is not to simply have this be a report on a shelf, but rather, a guidebook that moves us to the desired future for our profession.’ —Henri R. Manasse Jr., PhD, ScD

PPN: At the outset of the PPMI Summit, ASHP president Diane Ginsburg said, “We’re making history.” Now that most of the deliberations are over, do you agree? Is this event going to be a watershed in the history of pharmacy? HM: As an organization, we’re committed to making this history. I participated in The Hilton Head Conference, as well as other meetings focused on fundamentally changing the pharmacy practice model. Although not all the issues of the profession have been resolved, those meetings laid the groundwork for the innovators in our profession—the early adopters—to lead us in a new direction.

Pharmacy Practice News • December 2010

Operations & Management 37

Exclusive Interview I am confident that the PPMI Summit will keep us on that path. PPN: Many PPMI attendees and speakers made the point that the Hilton Head Conference took place 25 years ago, and that we can’t afford to wait another 25 years for significant practice change to occur. Are you confident that the pharmacy profession can speed up the process? HM: I’m very confident, for several reasons. One is the positive collaboration that we often have with physicians and nursing leaders. They understand there is no way they can manage the complexities of medication therapy on their own. They realize they do have someone in the hospital—the pharmacist—who can help. But some things clearly have to change. I will [soon] be participating in a meeting of an organization that represents public members of regulatory boards in the health profession, where I will suggest that the entire legal prescribing paradigm needs to be re-examined. We’re working under a prescribing model that dates back to the 1800s, where if a person graduates from medical school and passes the board exams, he or she is authorized to write prescriptions. Does that system ensure that the most competent practitioners are prescribing medications? It’s a valid question, because there are trouble spots: Off-label prescribing of drugs, for example, is not always done in a safe manner. And then there’s the issue of inappropriate prescribing in other instances. There have been multiple studies showing that the biggest safety issues with medications occur on the prescribing and administration side. So I do think this is an issue of public health policy that needs to be examined. PPN: Would granting pharmacists prescribing authority help reduce some of those problem areas and improve medication safety? HM: I feel very strongly that we need the most competent people performing specific tasks in patient care. That doesn’t necessarily translate to advocating for pharmacist prescribing. As a matter of policy, ASHP has not pushed for that privilege. Rather, we’ve chosen to focus on getting the legal enablements in place to allow for collaborative practice agreements between physicians and pharmacists. From a public policy as well as a patient perspective, I think that’s a reasonable approach. Having said that, it may turn out at some point in time that independent prescribing by pharmacists, in certain instances, would be appropriate. But I don’t think we’re there yet. For a highly effective middle-of-theroad approach, I would suggest looking at the privileging model at the

‘The expertise of the pharmacist has to be at the executive decision-making level, because in terms of medication safety, there is a lot at stake for the institution, to say nothing about the patients who are using these medicines.’

Veterans Administration. In many VA centers, based on a thorough review of credentials and competency, a hospital committee will decide that, yes, pharmacists should take on a higher

degree of accountability and work with hypertensive patients, or those with COPD or diabetes, for example. If a pharmacist wants to change a patient’s therapy based on lab values or some

other critical factor, that’s allowed, and in fact encouraged, as long as the pharmacist works collaboratively with the patient care team and there is sufficient notification. That’s probably the optimal model. I’d add that the VA is not so unique that its successes won’t translate to the private sector. There are many centers of excellence in pharmacy that have shown that our profession can embrace change and improve patient care. It’s now all of our jobs to accelerate the pace of that change and keep moving forward.

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38 Technology

Pharmacy Practice News • December 2010

Medication Tracking

Strengthening Strategies To Deter Drug Diversions I

n October, Philadelphia’s Temple University Health System paid a $130,000 fine to the U.S. government and saw the drug conviction of two of its anesthesiologists. The hospitals, according to the feds, hadn’t done enough to try to prevent physicians from pocketing controlled substances intended for patients. The guilty medical centers are not alone. The rate of drug and alcohol addiction among practicing physicians is estimated to be between 10% and 12%, a figure similar to the general population. Around 7% of nurses are thought to misuse prescription drugs, and approximately 6% of pharmacists in one study identified themselves as drug abusers at some point in their careers (J Am Pharm Assoc 2001;41:392-400). Although it is difficult to know just how frequently drug diversions occur, experts have put the figure between 1% and 2%. Increasingly sophisticated tools, such as automated drug dispensing cabinets and software that mines the cabinet’s data in search of abnormalities, have helped a growing number of U.S. hospitals with the difficult task of tracking drug diversions. But even the facilities that now use some form of the technology—including the approximately 85% that have the kiosks to store, dispense, control and track medications near the point of care—still cannot rest assured that narcotics or sedatives will always make the full journey from pharmacy to patient. “We have the same cross-section of people who work in a hospital that we do in life. Not everybody is perfect,” said Ray Vrabel, PharmD, senior director for medication systems strategy at Omnicell, Inc. “And no matter how hard we work at having tight systems, it’s a continuous effort to try to outsmart people who are trying to beat the system.” Omnicell recently announced its acquisition of Pandora Data Systems, a leading developer of analytic software for medication diversion detection. Dr. Vrabel said he is hopeful that the union will result in more powerful tools to outsmart drug diverters than could be produced by the two individually. Two decades ago, before the advent of computerized tracking, drug diversions were extremely difficult to detect, let alone control. A locked box full of medicine generally sat in a nursing unit, with one shared key. Nurses were supposed to record in a ledger every dose removed from the box and given to a patient. “Filling out the ledger wasn’t exactly their highest priority,” recalled Dr. Vrabel, who also is a 40-year veteran pharmacist. “Discrepancies resulted from

even the best of them.” But just how often drugs were diverted is hard to know. Only when a nurse or other health care worker was caught would the ledgers be studied for evidence.

Drug Task Force John Burke, now commander of the Warren County Ohio Drug Task Force, probably knows the evolution of drug diversion tracking better than anyone. After more than 20 years with the Cincinnati police, he formed and, from 1990 to 1999, headed the division’s Pharmaceutical Diversion Squad. His team’s work

taking stuff out and keeping some for himself, and thereby endangering his patients, himself and those that might cross his path on his drive home?” Carl Washburn, PharmD, pharmacy director at Dominican Santa Cruz Hospital, in California, has several years of experience with both Omnicell and Pandora technologies. The hospital currently uses the duo prospectively every month to look for evidence of anything going wrong. Dr. Washburn noted that the system highlights a person of interest four to six times a year, with about half of them going on to some form of rehabilitation. When they find something, they look

‘Dispensing cabinets and analytic software [are] tremendous tools … if you’ve got a [drug] diversion and are trying to shore down the investigation to who might be responsible.’ —John Burke

lations vary by state, but the U.S. Drug Enforcement Administration requires hospitals and nursing homes to report any loss of controlled substances, which account for most of the diversions. Cmdr. Burke pointed out that diversions are not necessarily something that hospitals want to publicize to their potential customers. “It’s often the case that the perpetrating nurse just gets fired, which doesn’t help the nurse, and allows him or her to just go on to next facility and endanger other patients,” he said. “If a hospital doesn’t put emphasis on this, the facility will eventually get filled with people who are diverting drugs.” “I think diversion happens every day in this country, in multiple places, and is often not reported. We really need to drive home the message that we’re serious about reporting these diversions,” he added. “Then maybe we’ll get a better handle on the numbers, better protect patients, and catch addicts earlier so they can go into successful rehab.”

Enhanced Drug Tracking

originally entailed thumbing through piles of papers, looking for clues. “The age of computerization really changed the job. The dispensing cabinets and analytic software became tremendous tools to be proactive, or reactive if you’ve got a diversion and are trying to shore down the investigation to who might be responsible,” said Cmdr. Burke, whose unit was arresting a nurse every seven days in Cincinnati at the time he left. Continuous surveillance via the cabinets and coupled software can offer hints of abnormal drug movement, such as high usage and wastage, as well as drugs withdrawn from the cabinet after cases are finished or for patients to whom the dispensing provider was not assigned. “These reporting solutions can look at behaviors of people handling controlled substances to determine whether or not their behaviors are different from the norm,” noted Dr. Vrabel. “Why is it when Nurse Joe is the nurse his patients seem to be in pain more than when Nurse Jane is the nurse? Is Nurse Joe

deeper and then try to intervene early. Of course, just because someone gets flagged as having unusually high numbers of dispensed drugs, doesn’t mean there has been any wrongdoing, Dr. Washburn noted. One individual’s work schedule, for example, may simply be different from that of their colleagues. The challenging investigative work has become further complicated in recent years with the shortage of nurses. Rather than sticking with one unit, nurses now frequently work several, which means the use of several different dispensing cabinets. Perhaps even more difficult to track now is the behavior of traveling nurses. Most of their contracts last only 13 weeks, noted Dr. Washburn, while the reports generally don’t have the power to detect anomalies without at least 90 days of data. Not all hospitals are as cooperative as Dominican Santa Cruz in reporting diversions, despite the fact that the failure to do so is a federal crime. Rules and regu-

With the Omnicell-Pandora merger, Dr. Vrabel anticipates fewer gaps for abusers to slip through. One of the new features is the tracking of the final leg of a drug’s journey: administration to a patient. “At end of the day, the health care provider that has the drugs in their hand to administer has an opportunity that no other people have, because that patient will not necessarily know if they got exactly what they were supposed to get,” said Dr. Vrabel. “That’s been one of the missing pieces of the puzzle.” Obtaining these new data would entail linking the cabinet’s dispensing data with electronic documentation of drug administration, which is currently available in about 45% of hospitals and expected to reach 100% in the next two years due to new federal requirements. When what was dispensed, wasted and returned doesn’t match up with what was administered, a report will be triggered just as it is for the currently retrievable clues of abnormal behavior. “These reporting and analytical solutions create an environment in which a good person, who might stray to sneak through a red light if there wasn’t a camera, will likely be a lot more cautious,” Dr. Vrabel said. “That’s what we want,” he added, “to keep good people good and delivering care to patients. And then if someone bad comes along, we can catch them.” —Lynne Peeples

2010/2011

CATEGORIES Pharmacy Automation Information Systems

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Medication Management Systems IV Devices

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B I O L O G I C A L

S A F E T Y

C A B I N E T S

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L A M I N A R

F L OW

WO R K STAT I O N S

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I S O L AT O R S

Pharmacy Automation

BarCode Packaging Systems

4 1

Medical Packaging Inc.

BarCode Packaging Systems

Pharmacy Accessory Label Printer (PALP)

Medical Packaging Inc.

Address: 470 Route 31, P.O. Box 500, Ringoes, NJ 08551 Phone: (800) 257-5282 Fax: (609) 466-3775 E-mail: medpak@medpak.com Web Site: www.medpak.com

Auto-Print™ Bagging System for Overwrapping Address: 470 Route 31, P.O. Box 500, Ringoes, NJ 08551 Phone: (800) 257-5282 Fax: (609) 466-3775 E-mail: medpak@medpak.com Web Site: www.medpak.com

Product Description: The Pharmacy Accessory Label Printer (PALP) completes the solution for a pharmacist’s ancillary barcoding and labeling needs. Ampoules, vials, syringes and other parenteral medications can be quickly labeled and barcoded with Medical Packaging Inc.’s freezergrade, pressure-sensitive labels.

Product Description: The Auto-Print™ Bagging System provides the capability to barcode, package and label ampoules, vials, syringes and other ancillary medications in a variety of bag sizes, creating an efficient packaging solution for parenteral medications.

BarCode Packaging Systems Medical Packaging Inc.

Talyst

Auto-Print™ Oral Solid Packaging System

AutoPack™

Address: 470 Route 31, P.O. Box 500, Ringoes, NJ 08551 Phone: (800) 257-5282 Fax: (609) 466-3775 E-mail: medpak@medpak.com Web Site: www.medpak.com Product Description: The Auto-Print™ packaging system is a cost-effective, affordable barcode packaging solution for oral solid medications that eliminates the need for manual packaging and sorting, while adding safety and compliance in the medication distribution process through Medical Packaging Inc.’s exclusive WinPak™ software. The system is available as standard Auto-Print™ (60/ppm) or Auto-Print™ Express 90 (90/ppm) models.

BarCode Packaging Systems

Address: 11100 NE 8th Street, Suite 600, Bellevue, WA 98004 Phone: (425) 289-5400 Fax: (425) 289-5401 E-mail: info@talyst.com Web Site: www.talyst.com Product Description: AutoPack™ offers accessible, fully automated packaging for oral solid medications. It is scalable, reliable, and includes workflow management features that can help improve the efficiency of pharmacy operations. AutoPack™ integrates easily with all pharmacy systems to provide a fully automated packaging solution.

BarCoding Systems

Medical Packaging Inc.

Talyst

Fluidose™ Series 5 Oral Liquid Packaging System

AutoLabel®

Address: 470 Route 31, P.O. Box 500, Ringoes, NJ 08551 Phone: (800) 257-5282 Fax: (609) 466-3775 E-mail: medpak@medpak.com Web Site: www.medpak.com Product Description: The Fluidose Series 5, an automated barcode packaging solution for liquids, increases the safety of administration of oral liquid medication and saves costs by packaging bulk liquids into unit doses (~15/ppm). Available cup sizes include 15 mL, 25 mL and 35 mL, in multiple colors for safety and compliance. ™

Address: 11100 NE 8th Street, Suite 600, Bellevue, WA 98004 Phone: (425) 289-5400 Fax: (425) 289-5401 E-mail: info@talyst.com Web Site: www.talyst.com Product Description: AutoLabel® allows barcode labeling of virtually 100% of your formulary. It uses a special, patent-pending transfer label to ensure your medications have a scan-ready barcode and a human-readable label. AutoLabel® creates transferable circle labels for barcoding multi-dose medications and a Flag Label™ for vials and ampoules.

P h a r m a c y P r a c t i c e N e w s D e c e m b e r 2010 | SPE C IA L S U P P L EMEN T

CENTRALIZED WARD-BASED CABINETS

iv automated devices

Omnicell, Inc.

Baxa Corporation IntelliFill™ i.v.

WorkflowRx Address: 1201 Charleston Road, Mountain View, CA 94043 Phone: (800) 850-6664 Fax: (650) 251-6266 E-mail: info@omnicell.com Web Site: www.omnicell.com

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) E-mail: info@baxa.com Web Site: www.baxa.com

Product Description: Complete inventory management of the entire pharmacy formulary, including bulk storage, refrigerated cases and static shelving. Robust integrated control of the carousel and packager. Software-only solution replaces existing central pharmacy software, without installing new pharmacy equipment. Intelligent Order Routing dynamically routes orders between the packager and unit-dose locations.

DeCENTRALIZED WARD-BASED CABINETS

Product Description: With IntelliFill™ I.V., each dose is individually labeled, barcoded, scanned and matched to order. It captures source images for review and verification. IntelliFill™ I.V. also provides highspeed automation and on-demand reconstitution and filling. It saves significant costs in medication acquisition.

iv automated devices

Omnicell, Inc.

Baxa Corporation

OmniRx

RapidFill™ Automated Syringe Filler Address: 1201 Charleston Road, Mountain View, CA 94043 Phone: (800) 850-6664 Fax: (650) 251-6266 E-mail: info@omnicell.com Web Site: www.omnicell.com

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) E-mail: info@baxa.com Web Site: www.baxa.com/rapidfill

Product Description: Offering flexibility and unique features such as guiding lights, single-dose dispensing (OmniDispenser) and barcode confirmation (SafetyStock). SinglePointe combines the rigorous safety features of our cabinet with innovative software to create a secure and easy way to stock all of a patient’s medications in one convenient place—the cabinet—without dangerous workarounds.

iv automated devices

Other

Baxa Corporation

Omnicell, Inc.

ExactaMix™ 2400 Compounder (EM2400)

PandoraVIA

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) E-mail: info@baxa.com Web Site: www.baxa.com Product Description: The EM2400 streamlines multisource mixing applications—improving productivity and reducing labor costs. It features barcode verification, a closed system with no sterility breaks, accurate delivery with a secondary check, easy setup, high-speed delivery, air occlusion detection as well as an electronic Y-site for high-use ingredients and lockout for incompatible ingredients. Disposables are available on group purchasing organization contracts.

Product Description: The RapidFill™ Automated Syringe Filler reduces costs from premade syringes. RapidFill automates filling, capping, labeling and barcoding of sterile batch syringes—800/hour. It is designed to fit in the hood, and colored labels are available. Disposables are available on group purchasing organization contracts. Visit www.baxa.com/rapidfill for more information.

Address: 1201 Charleston Road, Mountain View, CA 94043 Phone: (800) 850-6664 Fax: (650) 251-6266 E-mail: info@omnicell.com Web Site: www.omnicell.com Product Description: PandoraVIA facilitates the analysis, understanding and management of hospitals’ medication distribution and usage. PandoraVIA provides reporting and analytics functionality around the data collected by BPOC and automated dispensing systems. Medication Surveillance Service is a Web-based service that monitors drug use 24/7 and alerts pharmacy personnel and nurse managers to unusual transactions.

S P EC I AL S U P P L EMEN T | P h a r m a c y P r a c t i c e N e w s D e c e m b e r 2 0 1 0

Other

BarCoding Systems

Talyst

Talyst AutoSplit® 340B

AutoCarousel™ Address: 11100 NE 8th Street, Suite 600, Bellevue, WA 98004 Phone: (425) 289-5400 Fax: (425) 289-5401 E-mail: info@talyst.com Web Site: www.talyst.com

Address: 11100 NE 8th Street, Suite 600, Bellevue, WA 98004 Phone: (425) 289-5400 Fax: (425) 289-5401 E-mail: info@talyst.com Web Site: www.talyst.com

Product Description: AutoCarousel™ provides maximum medication storage in an organized, accessible and compact footprint. Its easy-to-use vertical design provides secure, automated storage and accurate retrieval. AutoCarousel™ decreases required storage space by 30% to 50% and enables you to easily store, track and access medications.

Product Description: AutoSplit® 340B software is the industry leader in 340B purchase order splitting. The automated system provides full audit trails for all eligible 340B dispenses and splits. AutoSplit® is easy to implement, and maximizes 340B savings while reducing program administration hours. It works with multiple wholesalers, and has exportable reports to help maintain regulatory compliance.

Information Systems

Other

Talyst

Lab Monitoring Software

AutoCool®

Cooper-Atkins Corporation

Address: 11100 NE 8th Street, Suite 600, Bellevue, WA 98004 Phone: (425) 289-5400 Fax: (425) 289-5401 E-mail: info@talyst.com Web Site: www.talyst.com

Temp Trak Temperature Monitoring System Address: 33 Reeds Gap Road, Middlefield, CT 06455 Phone: (860) 347-2256 ext. 162 Fax: (860) 347-5135 E-mail: healthcare@cooper-atkins.com Web Site: www.cooper-atkins.com

Product Description: AutoCool® delivers access-controlled refrigerated storage and automated dispensing for your valuable refrigerated medications. It’s flexible, scalable, and can be installed in remote locations. It provides pharmacy-grade refrigeration with passwordprotected access, and enables perpetual inventory management with par-levels and order preparation.

Other

Talyst

Product Description: Temp Trak is a real-time, 24/7 monitoring system that combines an automated collection of temperature data with real-time notification alerts that can be customized to specific pharmacy requirements. It is a wireless system that monitors temperatures from –200°C to 450°C.

Other

Baxa Corporation

AutoPharm®3

DoseEdge™ Pharmacy Workflow Manager

Address: 11100 NE 8th Street, Suite 600, Bellevue, WA 98004 Phone: (425) 289-5400 Fax: (425) 289-5401 E-mail: info@talyst.com Web Site: www.talyst.com Product Description: AutoPharm®3 is a powerful software platform designed to deliver improved patient safety through better medication inventory control and workflow management in your central pharmacy. It works throughout your organization to automate your medication ordering, receiving, stocking, picking, barcoding and return processes.

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) E-mail: info@baxa.com Web Site: www.baxa.com/doseedge Product Description: DoseEdge™ Pharmacy Workflow Manager is the first and only completely integrated system for managing IV and oral dose preparation. DoseEdge provides real-time status of incoming and in-process doses, barcode drug verification, dose tracking and automatic dose calculation. It offers a best-practices approach for pharmacy workflow and remote inspection of pharmacy preparation steps. Also available: DoseEdge™ TPN for managing the parenteral nutrition compounding process, including manual additions. Visit www.baxa.com/doseedge for more information.

P h a r m a c y P r a c t i c e N e w s D e c e m b e r 2010 | SPE C IA L S U P P L EMEN T

Medication Management Systems

Baxa Corporation

Drug Delivery Systems

Tamper-Evident Luer Lock Tip Caps

Baxter Healthcare

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) E-mail: info@baxa.com Web Site: www.baxa.com

Sigma Spectrum Infusion System Address: 25212 West IL Route 120 WG1-1N, Round Lake, IL 60073 Phone: (847) 270-5772 Fax: None E-mail: jo_ann_fujii@baxter.com Web Site: www.baxter.com

Product Description: Tamper-Evident Luer Lock Tip Caps are latex-free—no natural-rubber latex components—and made of nonDEHP materials. A three-part cap requires the user to break off the outer sleeve to dispense medication. A red ring remains, indicating the outer sleeve has been tampered with. The caps are sold in sterile packs of 10 for convenient use. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

Product Description: The Sigma Spectrum Infusion System is a Generation 2 Infusion System that redefines smart pump technology by making patient safety a top priority. Features go beyond dose error reduction software (DERS) to support the goal of reducing potential medication errors. Spectrum pumps are manufactured by Sigma and distributed exclusively by Baxter Healthcare Corporation.

ORAL & ENTERAL DEVICES

Baxa Corporation

ExactaMed® Oral Dispensers

DiscPac™ Self-Righting Luer Tip Caps

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Product Description: ExactaMed® includes market-leading dispensers and accessories for accurate and safe filling and delivery of oral medication. Unique tip design, gray piston and blue printing provide clear differentiation from IV syringes. They are the only complete range of dispensers—from 0.5 to 60 mL—that ensures precise delivery as low as 0.01 mL. Also available: specialty dispensers for enteral, vaginal and topical medications. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

Product Description: DiscPac™ Self-Righting Luer Tip Caps secure easily to any size Luer syringe. Available in 12 colors, the caps are packaged individually or in convenient DiscPacs of 25 and 100. They are latex-free—no natural-rubber latex components—and made of non-DEHP material that withstands freezing. DiscPacs may be closed and stored in the hood for later use. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

IV Devices

OTHER

FLUID DISPENSING SYSTEMS

Baxa Corporation ExactaMix™ EVA Containers

Baxa Corporation

Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) E-mail: info@baxa.com Web Site: www.baxa.com

Repeater™ Pump Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) E-mail: info@baxa.com Web Site: www.baxa.com Product Description: Tired of reconstituting, pooling and then filling syringes, dispensers and elastomeric devices? The Repeater Pump automates fluid transfer needs with high flow rates, variable speeds and delivery accuracy as low as 0.2 mL. Disposables available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

OTHER

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Product Description: ExactaMix™ EVA Containers offer better bag clarity for ease of visual inspection, attached bag clamp for convenient closure and covered addition port to keep the area protected until used. New lay-flat tube material minimizes the risk of particulates in the bag. EVA construction provides cleaner disposal for incineration. Manufacturing in North America reduces shipping time. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

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Baxa Corporation RapidFill™ Connectors Address: 9540 South Maroon Circle, Suite 400, Englewood, CO 80112 Phone: (800) 567-BAXA (2292) Fax: (800) 494-BAXA (2292) E-mail: info@baxa.com Web Site: www.baxa.com

For additional information about the products listed in this Buyer’s Guide, please fill out and return the reader service card on page 3 or visit our advertisers’ Web sites by scanning the following 2D bar codes with your smart phone:

Baxa http://www.baxa.com/ PharmacyProducts/

Product Description: RapidFill Connectors enable connections of male Luer syringes, tube sets, repeating syringes, bag ports and other containers. They are available with caps, allowing intermittent fills and capped storage. The connectors are latex-free—no natural-rubber latex components—and made of non-DEHP materials. Available 50 per case. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

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Product Description: TwoFer™ dual-purpose Luer-lock needles allow for vented and non-vented vial additions and withdrawals. Huber points minimize the risk for coring. Reconstitution and fluid transfer applications can be performed without changing needles. Available on group purchasing organization contracts. Visit www.baxa.com for order numbers.

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Pharmacy Practice News • December 2010

Technology 39

Rural Health

EHR ADOPTION continued from page 1

brought not only recognition but also the promise of financial rewards for the 25-bed hospital located some 70 miles north of Minneapolis. In recent strategic planning, Dr. Thompson said, hospital leaders concluded that “we can actually meet the deadlines” for the EHR meaningful use standards required to receive Medicare and Medicaid payment incentives that are set to begin in 2011. Kanabec’s accomplishment is hardly typical. Most small and rural hospitals continue to face financial, technical and manpower challenges that have positioned them well behind their larger counterparts in EHR adoption. “It’s as if the gun were about to fire for the 100-yard dash, but these hospitals are 50 yards behind the starting line,” said Brock Slabach, MPH, senior vice president at the National Rural Health Association (NRHA). This past winter, the NRHA conducted a survey that quantified the challenges that its member hospitals face. Using HIMSS Analytics’ seven-stage assessment model, the survey found that 59% of rural hospitals were at or below stage 2. According to Mr. Slabach, the NRHA estimates that hospitals need to reach an EHR development level of approximately 3.7 if they want to qualify for a slice of the nearly $20 billion that the Centers for Medicare & Medicaid Services (CMS) is expected to pay out in incentives over the next six years. “If six out of 10 rural facilities are at stage 2 or below,” he said, “there is a fairly significant gap between where a lot of our hospitals are and the threshold required to qualify them for funding.” A recent Health Affairs paper [doi: 101377/ hlthaff.2010.0502 Health Affairs 2010;29] reported similar findings. Examining changes in EHR adoption rates following the enactment of the 2009 stimulus legislation, which authorized CMS incentives, the authors found implementation rates had “increased modestly,” but “smaller, rural and public hospitals fell further behind their counterparts.” In September, the U.S. Department of Health and Human Services (HHS) awarded nearly $20 million to state regional extension centers to provide technical support for small and rural hospitals trying to convert to certified EHR systems. The grants were meant to address the financial and manpower constraints imposed by limited hospital budgets. “The challenge is a shortage of upfront capital needed to invest in the technology. The nearly $20 million in grants are meant to help address that shortage,” said Paul D. Moore, DPh,

‘From what I can see from just looking over the landscape, most health systems, not just the rural ones, are really going to struggle with meeting the [meaningful use funding] deadlines.’ —Brent Thompson, PharmD senior health policy adviser for the Health Resources and Services Administration’s Office of Rural Health Policy. “Most small and rural hospitals operate on such a small profit margin that cash reserves sufficient for this large capital expenditure are rare. They’re not thinking about plunking down large sums of money, they’re thinking about the payroll.” Even when financing is available, Dr. Moore added, there are still technical workforce issues that can impede progress. “This is where the resources of the regional extension centers will be strategically meaningful,” he said. “My understanding is that the regional extension centers will be on the front end of it, too. They’re going to be out there encouraging hospitals” in their health IT efforts.

Feeling the Slump In the Rockies Typical of the small rural facilities facing financial pressures is Grand River Hospital and Medical Center in Rifle, Colo. Located on the western slopes of the Rockies in a community whose economy rises and falls on the vagaries of oil and gas production, Grand River Hospital lately has been feeling the impact of a declining population brought about by the national slump in energy demand. Sharon Hanson, PharmD, director of pharmacy and the only pharmacist employed at the hospital, said that both management and staff had recently taken furlough days to avoid layoffs stemming from the reduced patient population. Before financial pressures mounted, Dr. Hanson said the critical access hospital, licensed for 25 beds, had begun to move ahead on its health IT plan, introducing an EHR system in two of

its clinics, one in the main hospital in Rifle and the other at a satellite site in Battlement Mesa, Colo. However, the remainder of the plan, including computerized prescriber order entry (CPOE), is now on hold. “Even with these challenges,” Dr. Hanson said in a follow-up e-mail, “Grand River expects to meet the meaningful use deadlines. We are pretty good at making things happen here.” EHR implementation is further along at Angel Medical Center, a 25-bed critical access hospital in Franklin, N.C., a rural community on the western edge of the state in the heart of Great Smokies. “We have implemented enough that I think we’re going to meet the meaningful use criteria,” said Debby Cowan, PharmD, director of pharmacy. Dr. Cowan added that CPOE had been employed in the emergency department for about three years, “and we’re working to expand that to our inpatients, which is why we say that we’re going to meet meaningful use criteria.” She said the hospital was now “in the process of building order sets so that we’ll have [CPOE] on our inpatient floors.” Dr. Cowan speculated that one reason many small and rural hospitals have lagged behind larger facilities may be that they have “been quicker to put in smart pumps and bar coding” than CPOE.

Going Live With McKesson Next May Paynesville Area Health Care System in Paynesville, Minn., is another critical access hospital that anticipates meeting the meaningful use deadline. “We’re implementing McKesson Paragon system, an electronic medical record (EMR) system for smaller hospitals,” said Todd Lemke, PharmD, CDE, direc-

tor of pharmacy. “We will probably be live next May, but it has been about a year and a half process so far.” Dr. Lemke, who also is this year’s chair of the Advisory Group on Small and Rural Hospitals at the American Society of Health-System Pharmacists, said one reason the EHR system was able to move “through our administration” was the “dollars that are going to be coming in to help pay for it.” Of course, he added, improvement in patient care was the other main factor. One stumbling block for many small rural hospitals, according to Dr. Lemke, has been the dearth of EHR systems suited to their needs. “We found that there are a lot of systems out there that say they’re truly integrated, but when we really get down to it, they’re not,” he said. “They have a nursing home system, a hospital system and a clinic system that kind of talk to each other, but a lot of times they don’t.” He added: “We wanted a system that truly integrated a patient visit. A person comes into the clinic. The information in the clinic’s system can be transferred to the hospital for patient admission. The information developed in the hospital can easily flow over into our nursing home.” The system chosen by Paynesville can integrate the clinic and hospital, he said, but so far not the nursing home. “So we’ll have a second EMR for our nursing home,” he added. Although some small and rural hospitals will be able to meet the meaningful use deadline, Dr. Thompson said, “from what I can see from just looking over the landscape, most health systems, not just the rural ones, are really going to struggle with meeting the deadlines to be incentivized.” Dr. Thompson, who also is president of the Minnesota Pharmacists Association, said most of the hospital pharmacists he had spoken to “are really shooting toward a goal of not being penalized.” Escalating penalties for not adopting EHRs are set to kick in starting in 2015. —Bruce and Joan Buckley

Take a look…. Part 2 of our Oncology Automation series, which discusses the electronic chemotherapy process in place at St. Jude Children’s Research Hospital, can be found

@ Pharmacypracticenews.com.

40 Technology

Pharmacy Practice News • December 2010

Bar Coding

BCMA Lessons Learned Early adopters of medication safety technology offer implementation tips

hen implemented successfully, a bar code medication administration system (BCMA) can improve patient safety and reduce overall costs. However, although BCMA is very valuable and has afforded early adopters significant safety benefits, the road to safety is not always a simple one, according to presentations during a recent webinar sponsored by the health information technology (IT) consulting firm Technical Education Solutions (TES). “A lot of folks will say that since we have been doing bar coding in grocery stores forever, why is it so difficult in health care,” noted Mike Wisz, president of the Mike Wisz Associates, a company with more than 17 years of experience with health care information systems. “But a hospital is not a grocery store. Scanning medications is not like scanning a bag of M&Ms. In a hospital, we are scanning each individual M&M, some of which have been repackaged and labeled and we’re tracking and measuring many different things. So a hospital is a much different environment.”

Causes of Trip-Ups In his webinar presentation, Mr. Wisz shared lessons learned, “some the hard way,” by the 25% of U.S. hospitals that have some experience with BCMA. The factors that can cause a BCMA implementation to stumble, according to Mr. Wisz, include “lack of leadership, failure to consider the broader nursing process, and issues associated with being able to read the bar code, which depends on both the quality of the bar codes and the proficiency of the user.” With that in mind, Mr. Wisz encouraged hospitals to begin the planning process by doing the following: • Assess interdepartmental collaboration needs and identify ways for nursing, pharmacy and IT to work together fluidly. • Outline, identify and assess the challenges and changes to nursing workflow catalyzed by BCMA. • Identify key technology considerations. • Identify workarounds and then mitigate the need for them. • Identify key workflow considerations and changes in pharmacy processes. • Learn from the expensive lessons of early adopters. “It is worth [taking] the time to identify all the issues that could slow down or complicate an implementation before they take the process off the track,” he said. In an interview after the webinar, Edward Lanoue, RPh, informatics

Determine medications to give

Scan badge Scan patient

Hunt and gather

To bedside

Auto-discriminates symbology

Scan medication Delivers a string of data

Many opportunities for workarounds!

Warning BCMA Application Deal with Warning

Figure. BCMA workflow. BCMA, bar code medication administration; EMAR, electronic medication administration record

pharmacist for Southwestern Vermont Health Care, Bennington, described how his health system approached the process of implementing bar coding at the bedside. “We wanted to ensure that we were not creating holes in the BCMA system that would enable workarounds,” he said. Mr. Lanoue and his team said they also wanted to ensure that they “were creating a consistent [scanning] process and that when nurses were going to scan an item, they had all the tools for doing it successfully the first time.” Mr. Wisz stressed that for things to move forward, hospital pharmacies need “to get to where just about 100% of medications are scannable,” and he noted that “leading implementers of BCMA are doing this.” Mr. Lanoue, who recently designed the workflow for the repackaging operation that supports BCMA at Southwestern, said that another important shift for hospitals is investing in imaging scanners that can read two-dimensional symbologies, and area or camera-based imagers that can read both one- and two-dimensional symbologies. He stressed that two-dimensional imaging is crucial. To ensure that nurses would like

•

see BCMA, page 42

At Southwestern Vermont Health Care, the aim was to create ‘a consistent [scanning] process [so] that when nurses were going to scan an item, they had all the tools for doing it successfully the first time.’ —Edward Lanoue, RPh

Going Live: To ‘Big Bang’ or Not?

oth methods of going live with a BCMA implementation—activating all units at once in a “big-bang” activation or going live one unit at a time—have pros and cons, according to health IT consultants Mike Wisz and Charles Still, MBA. Mr. Still said the decision partly depends on the hospital’s size and partly on its ability to tolerate the challenges of a “big-bang” activation that, he said “can be very stressful.” On the other hand, he added, “it also can be very painful to stretch the implementation out.” In large hospitals there are a lot of patient transfers between units, he explained. “Jumping back and forth from a BCMA floor to a non-BCMA floor is very problematic and is one of the most challenging parts for hospitals going live.” Mr. Still’s health care system “went live unit by unit and did a lot of handholding. For two weeks 24/7, we had dedicated nurses on the floor who were not there for nursing duties but to support medication deliveries.” For large hospitals with multiple locations and hundreds of beds, he recommended a strategy of calling on the expertise of “super users” to support the rollout and creating a centralized help desk or command center. “With all the transfers you do, you want to bring each unit live as closely together as possible.” Mr. Wisz said he has been seeing “a lot more big bangs out there, as part of large [electronic medical record] initiatives, and a critical success factor is to ensure adequate go-live support.” He also recommended “going live first with a pilot unit to work out the process and deal with issues as they arise.” —L.P.

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42 Technology

Pharmacy Practice News • December 2010

Bar Coding

BCMA continued from page 40

the scanners they selected and did not have reasons to work around them, the team at Southwestern narrowed the field down to several top wireless twodimensional imaging readers but then asked their nurses to make the final selection. Another factor to consider when implementing BCMA is that although about 70% to 80% of doses have a bar code at the unit-dose level, there are exceptions such as respiratory medications that have reflective packaging. Mr. Wisz noted that hospitals have developed different ways of dealing with these exceptions. Some hospitals repack exceptions down to the unitdose level and relabel the products themselves. Others are outsourcing to third parties, he said, noting that evidence suggests that “third parties may be the most economical solution based on the cost-per-dose evaluations.” For example, at Southwestern Vermont, about 80% of exceptions are repacked down to the unit-dose level in-house and the rest through a third party, said Mr. Lanoue. He noted that the hospital is evaluating “whether it makes financial sense to do more outsourcing.”

Scan—and Then Scan Again Mr. Wisz also noted that there is a growing trend for hospital pharmacies to scan medications upon receipt and scan again as they dispense. “Not only are you improving your pharmacy workflow, becoming more efficient and having better control over your inventories, you also are doing a check of the bar code before it gets up to the floor, where it could potentially cause prob-

‘No one wants to go back to the paper way, not having the [bar coding] safety net at the patient’s bedside. But what does happen is that projects can stumble and delays can occur that result in costs being higher than they should be.’

—Mike Wisz

lems for the nurses.” Two key benefits of scanning on receipt are “to make sure that each [National Drug Code (NDC)] is in your database and to make sure you have the right information on receipt,” said webinar presenter Charles J. Still, MBA, project manager of information systems for Southwestern and the founder of TES. “We’ve had drugs come in with the right information on the drug but the wrong NDC on the bar code. One large manufacturing company put a 1-mg NDC on a 2-mg dose.” For materials management items, Southwestern also scans all the IV fluid bags stored in nursing, said Mr. Lanoue. “We took a computer on wheels [COW] into nursing and scanned every one of those items. I created a separate line item so we could scan them directly into our drug dictionary. The goal is to get as close to 100% as you can.” Southwestern cut medication administration errors in half by scanning at the bedside, Mr. Still noted. Addition-

‘We’ve had drugs come in with the right information on the drug but the wrong NDC on the bar code. One large manufacturing company put a 1-mg NDC on a 2-mg dose.’

One-Stop Shopping a Best Bet

ally, when they went live with an electronic medical records system, they also discovered that their automated dispensing cabinet fillerror rate “doubled,” he said. “Th ose wrong drugs probably were getting to the patients in the past because of an automated cabinet fill error; that’s something we’re working on by taking scanning into the automated fill station.” Another important step in the process of instituting BCMA systems is ensuring that technologies that support BCMA, such as wireless networks, workstations on wheels and software applications, are tested to ensure they are working properly. “Getting the mobile computing right is probably one

any hospital pharmacies, wanting to keep the BCMA process as simple as possible, are trying to centralize their clinical databases as well as buy as much hardware and software from as few vendors as possible. Charles J. Still, MBA, speaking from his experience at Southwestern Vermont Health Care, Bennington, noted that hospitals implementing BCMA have to adapt to the room sizes and the supporting infrastructure of their individual environments. Southwestern has rooms built as far back as 1913 as well as rooms built as recently as the 1970s, so they need different devices. “I haven’t found a good one-fits-all solution,” he noted, “so compromising is really key.” To keep medication information data synchronized, there is a trend to have “one clinical information system with integrated CPOE [computerized prescriber order entry], pharmacy and BCMA applications and to pair that with one pharmacy automation system to keep data information down to a manageable level,” noted health IT consultant Mike Wisz. At Southwestern Vermont, Edward Lanoue, RPh, had to determine how to limit the variety of systems, applications and equipment in the program so there would not be “a lot of extra maintenance and work for IT to support multiple systems.” He said he was able to get down to just two NDC databases: one to generate labels for repackaged tablets and oral solids and one for auxiliary labels using their host MEDITECH system. He noted that he also downloads dictionary data from MEDITECH and imports it into the hospital’s repackaging software “to keep the data consistent and eliminate one more failure point.” —L.P.

Wisz, is to continue to monitor and make changes “to optimize the system.” Mr. Still described the process that Southwestern Vermont uses to monitor compliance. “We do monthly reporting right now and statistical standard deviation analysis on the nurses’ scan rates. For every single unit, we are calculating the average over the course of a month of what the nurses scan rate is and then we compare each nurse’s scan rate to that average using a standard deviation analysis” to identify deviations that might signal the need for training. M r. S t i l l a l s o pointed out that the statistics also are “super valuable in identifying when there is an IT problem developing. If the average begins going down for every nurse in the unit,” he said, “it probably means a technological malfunction somewhere that nurses are too busy to keep calling about.” Installing technology, said Mr. Wisz, “is not arriving at a destination. It’s beginning a journey and it’s working to continually identify holes in the Swiss cheese and identify opportunities for error. The near-miss and preventederror reports that you can generate from the system are great opportunities to do root-cause analysis, track trends and find coachable moments.” —Liz Parks

—Charles J. Still, MBA

Help With Bar Coding of the most difficult parts of these projects,” said Mr. Wisz. “Applications typically can be deployed on handheld computers or full-screen versions on laptops, and a best practice is to think about a mixed fleet of computers.” Mr. Wisz said he has not heard of any hospital de-installing a BCMA system once the technology has been implemented. “No one wants to go back to the paper way, not having the safety net at the patient’s bedside. But what does happen is that projects can stumble and delays can occur that result in costs being higher than they should be.”

Monthly Reports, Standard Deviations Can Help Hone Systems One key practice that successful implementers have adopted, said Mr.

Pointofcareforum.com includes links to reference materials and toolkits for implementing bar code medication safety programs. Highlights include: •A checklist for preparing the organization •E stimated cost savings worksheet •N eeds assessment and product evaluation •A n assessment of the medication use process To access, scan the 2-D bar code below.

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